Ageless Brain

SCIENTIFIC RESEARCH ON THE FOLLOWING INGREDIENTS:

Niacin (as Niacinamide)

Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications ^*

Niacin (also known as “vitamin B₃” or “vitamin PP”) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B₃ has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer’s, Parkinson’s, and Huntington’s diseases), as well as in other.

Source: Valeria Gasperi, Matteo Sibilano, Isabella Savini, and Maria Valeria Catani. “Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications” International Journal of Molecular Sciences (2019): 20(4): 974.

The Influence of Nicotinamide on Health and Disease in the Central Nervous System ^*

Nicotinamide, the amide form of vitamin B3 (niacin), has long been associated with neuronal development, survival, and function in the central nervous system (CNS), being implicated in both neuronal death and neuroprotection. Here, we summarise a body of research investigating the role of nicotinamide in neuronal health within the CNS, with a focus on studies that have shown a neuroprotective effect. Nicotinamide appears to play a role in protecting neurons from traumatic injury, ischaemia, and stroke, as well as being implicated in 3 key neurodegenerative conditions: Alzheimer’s, Parkinson’s, and Huntington’s diseases. A key factor is the bioavailability of nicotinamide, with low concentrations leading to neurological deficits and dementia and high levels potentially causing neurotoxicity. Finally, nicotinamide’s potential mechanisms of action are discussed, including the general maintenance of cellular energy levels and the more specific inhibition of molecules such as the nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin 1 (SIRT1).

Source: Rosemary A Fricker, Emma L Green, Stuart I Jenkins, and Síle M Griffin. “The Influence of Nicotinamide on Health and Disease in the Central Nervous System” International Journal of Tryptophan Research (2018): 11: 1178646918776658.

Nutraceuticals and Other Natural Products in Parkinson’s Disease Therapy ^*

Vitamin B3

Vitamin B3 (niacin/nicotinic acid) and nicotinamide elicit antioxidant properties and increase high density cholesterol with implications for cardiovascular diseases. Nicotinic acid raised the DA content in the brain (Grenhoff and Svensson, 1988), while nicotinamide treatment caused significant neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine1 (MPTP) model of PD (Anderson et al., 2008). Niacin protected against oxidative damage and mitochondrial dysfunction and reversed locomotor dysfunction in flies (Jia et al., 2008). However, limited niacin content could assist in the prevention of PD (Fukushima, 2005). An epidemiological survey suggested that niacin deficiency protects against PD (Hellenbrand et al., 1996; Tanner et al., 1989).

Source: Rajeswara Babu Mythri, ... Muchukunte Mukunda Srinivas Bharath. “Nutraceuticals and Other Natural Products in Parkinson’s Disease Therapy” Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease (2015).

Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau ^*

Abstract

Memory loss is the signature feature of Alzheimer's disease, and therapies that prevent or delay its onset are urgently needed. Effective preventive strategies likely offer the greatest and most widespread benefits. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance memory and synaptic plasticity. We evaluated the efficacy of nicotinamide, a competitive inhibitor of the sirtuins or class III NAD⁺-dependent HDACs in 3xTg-AD mice, and found that it restored cognitive deficits associated with pathology. Nicotinamide selectively reduces a specific phospho-species of tau (Thr231) that is associated with microtubule depolymerization, in a manner similar to inhibition of SirT1. Nicotinamide also dramatically increased acetylated α-tubulin, a primary substrate of SirT2, and MAP2c, both of which are linked to increased microtubule stability. Reduced phosphoThr231-tau was related to a reduction of monoubiquitin-conjugated tau, suggesting that this posttranslationally modified form of tau may be rapidly degraded. Overexpression of a Thr231-phospho-mimic tau in vitro increased clearance and decreased accumulation of tau compared with wild-type tau. These preclinical findings suggest that oral nicotinamide may represent a safe treatment for AD and other tauopathies, and that phosphorylation of tau at Thr231 may regulate tau stability.

Source: Kim N. Green, Joan S. Steffan, Hilda Martinez-Coria, Xuemin Sun, Steven S. Schreiber, Leslie Michels Thompson and Frank M. LaFerla. “Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau” Journal of Neuroscience (2008): 28 (45) 11500-11510.

Vitamin B6 (Pyridoxine HCl)

Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by a folate, vitamin B6 and B12-deficient diet ^*

Abstract

Epidemiological and clinical studies indicate that elevated circulating level of homocysteine (Hcy) is a risk factor for developing Alzheimer’s disease (AD). Dietary deficiency of folate, vitamin B6 and B12 results in a significant increase of Hcy levels, a condition also known as hyperhomocysteinemia (HHcy).

In the present study we tested the hypothesis that a diet deficient for these three important factors when administered to a mouse model of AD, i.e. Tg2576, will result in HHcy and in an acceleration of their amylodotic phenotype.

Compared with Tg2576 mice on regular chow, the ones receiving the diet deficient for folate, B6 and B12 developed HHcy. This condition was associated with a significant increase in Aβ levels in the cortex and hippocampus, and an elevation of Aβ deposits in the same regions. No significant changes were observed for steady-state levels of total APP, BACE-1, ADAM-10, PS1 and nicastrin in the brains of mice with HHcy. No differences were observed for the main Aβ catabolic pathways, i.e. IDE and neprilysin proteins, or the Aβ chaperone apolipoprotein E. Our findings demonstrate that a dietary condition which leads to HHcy may also result in increased Aβ levels and deposition in a transgenic mouse model of AD-like amylodosis. They further support the concept that dietary factors can contribute to the development of AD neuropathology.

Source: Jia-Min Zhuo Domenico Praticò. “Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by a folate, vitamin B6 and B12-deficient diet” Experimental Gerontology (2010): Volume 45, Issue 3, Pages 195-201.

Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time ^*

Abstract

Background: B-vitamin deficiencies have been associated with depression; however, there is very little prospective evidence from population-based studies of older adults. Objective: We examined whether dietary intakes of vitamins B-6, folate, or vitamin B-12 were predictive of depressive symptoms over an average of 7.2 y in a community-based population of older adults.

Design: The study sample consisted of 3503 adults from the Chicago Health and Aging project, an ongoing, population-based, biracial (59% African American) study in adults aged ≥65 y. Dietary assessment was made by food-frequency questionnaire. Incident depression was measured by the presence of ≥4 depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale.

Results: The logistic regression models, which used generalized estimating equations, showed that higher total intakes, which included supplementation, of vitamins B-6 and B-12 were associated with a decreased likelihood of incident depression for up to 12 y of follow-up, after adjustment for age, sex, race, education, income, and antidepressant medication use. For example, each 10 additional milligrams of vitamin B-6 and 10 additional micrograms of vitamin B-12 were associated with 2% lower odds of depressive symptoms per year. There was no association between depressive symptoms and food intakes of these vitamins or folate. These associations remained after adjustment for smoking, alcohol use, widowhood, caregiving status, cognitive function, physical disability, and medical conditions.

Conclusion: Our results support the hypotheses that high total intakes of vitamins B-6 and B-12 are protective of depressive symptoms over time in community-residing older adults.

Source: Kimberly A Skarupski, Christine Tangney, Hong Li, Bichun Ouyang, Denis A Evans, Martha Clare Morris. “Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time” The American Journal of Clinical Nutrition (2010): Volume 92, Issue 2, Pages 330–335.

Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by a folate, vitamin B6 and B12-deficient diet ^*

Abstract

Epidemiological and clinical studies indicate that elevated circulating level of homocysteine (Hcy) is a risk factor for developing Alzheimer’s disease (AD). Dietary deficiency of folate, vitamin B6 and B12 results in a significant increase of Hcy levels, a condition also known as hyperhomocysteinemia (HHcy).

In the present study we tested the hypothesis that a diet deficient for these three important factors when administered to a mouse model of AD, i.e. Tg2576, will result in HHcy and in an acceleration of their amylodotic phenotype.

Compared with Tg2576 mice on regular chow, the ones receiving the diet deficient for folate, B6 and B12 developed HHcy. This condition was associated with a significant increase in Aβ levels in the cortex and hippocampus, and an elevation of Aβ deposits in the same regions. No significant changes were observed for steady-state levels of total APP, BACE-1, ADAM-10, PS1 and nicastrin in the brains of mice with HHcy. No differences were observed for the main Aβ catabolic pathways, i.e. IDE and neprilysin proteins, or the Aβ chaperone apolipoprotein E. Our findings demonstrate that a dietary condition which leads to HHcy may also result in increased Aβ levels and deposition in a transgenic mouse model of AD-like amylodosis. They further support the concept that dietary factors can contribute to the development of AD neuropathology.

Source: Jia-Min Zhuo Domenico Praticò. “Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by a folate, vitamin B6 and B12-deficient diet” Experimental Gerontology (2010): Volume 45, Issue 3, Pages 195-201.

Vitamin B6 Is Associated with Depressive Symptomatology in Massachusetts Elders ^*

Abstract

Objective: We examined the cross-sectional relationship between dietary vitamin B6 and plasma pyridoxyl-5′-phosphate concentrations (PLP) with depressive symptomatology among a representative sample of 618 elderly Caribbean Hispanics, and a neighborhood based comparison group of 251 non-Hispanic white (NHW) older adults in Massachusetts.

Methods: Depressive symptomatology was assessed with the Center for Epidemiologic Studies Depression Scale (CES-D). 41% of Hispanics and 22.6% of NHWs had CES-D scores greater than 16, indicating depressive caseness. Dietary intake was calculated from a semi-quantitative food frequency questionnaire (FFQ) designed for this population.

Results: PLP was significantly associated with CES-D score and depressive caseness in the total sample and in non-supplement users. Deficient levels of plasma PLP (plasma PLP < 20 nmol/L) approximately doubled the likelihood of depressive caseness. Total intake (diet + supplement) of vitamin B6 was not associated with these outcomes. However, dietary vitamin B6 was significantly associated with CES-D score and depressive caseness.

Conclusion: Longitudinal studies are needed to clarify the direction of causality between vitamin B6 and depressive symptoms.

Source: Cristina Merete, MS, Luis M. Falcon, PhD & Katherine L. Tucker, PhD. “Vitamin B6 Is Associated with Depressive Symptomatology in Massachusetts Elders” Received 19 Jul 2006, Accepted 24 Jan 2007, Published online: 14 Jun 2013.

Vitamin B6‐dependent seizures

Abstract

A 131/2h-year-old child died with vitamin B6-dependent seizures in progress. Microscopic findings in the brain included an abnormally sparse quantity of central myelinated fibers in the cerebral hemispheres. Glutamic acid concentrations were elevated and GABA concentrations reduced in the frontal and occipital cortices but not in the spinal cord. All other amino acid concentrations were normal, except for increased cystathionine in the occipital cortex. Pyridoxal-5-phosphate (PLP) was reduced in the frontal cortex. Glutamic acid decarboxylase activity comparable to that of controls was detected when the PLP concentration was greater than 0.05 mM. These findings suggest that pyridoxine-dependent seizures in man are associated with reduced GABA concentrations in the brain and with diminished central white matter structures.

Source: LOTT, IRA T., et al. “Vitamin B6‐dependent seizures: pathology and chemical findings in the brain.” Neurology 28.1 (1978): 47-47.

Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer’s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.

Source: Smith, A. David, et al. “Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial.” PloS one 5.9 (2010): e12244.

Green Tea Extract (leaf)

The Effects of Green Tea Extract on Working Memory in Healthy Women ^*

Abstract

Objectives: This study aimed to examine the effects of green tea extract on working memory in healthy younger (21 - 29 y) and older (50 - 63 y) women.

Design: A single-blind, placebo-controlled, crossover design was used.

Setting: A university laboratory.

Participants: Twenty non-smoking Caucasian women were recruited in the younger (10) and older (10) age group.

Intervention: Subjects received 5.4 g green tea extract (at least 45% epigallocatechin-3-gallate) or placebo (cornstarch) within a 24-hour period.

Measurements: Working memory was measured by reading span and N-back task paradigm. Blood sample (20 mL) was collected and measured for plasma malondialdehyde (MDA) and total antioxidant capacity (TEAC) concentration. A 24-hour recall was conducted for each treatment period to ensure similar dietary patterns.

Results: Green tea extract significantly improved reading span performance in older women, indicated by higher absolute and partial scores of reading span. No significant changes were observed in the younger group. N-back latencies and accuracies were not significantly different after green tea treatment in either age group. Plasma concentration of MDA and TEAC were not different after green tea extract in either group.

Conclusion: Acute supplementation of decaffeinated green tea extract may enhance working memory capacity of women between 50 to 63 years of age. This study provides preliminary evidence that consumption of green tea extract may enhance the cognitive performance in older adults and thus provide potential chemopreventive benefits in this group. The mechanism should be explored in future research.

Source: Y Liu, A D Fly, Z Wang, J E Klaunig. “The Effects of Green Tea Extract on Working Memory in Healthy Women” Journal of Nutrition, Health and Aging (2018): 22(3):446-450.

Daily consumption of green tea catechin delays memory regression in aged mice ^*

Abstract

Almost all elderly people show brain atrophy and cognitive dysfunction, even if they are saved from illness, such as cardiac disease, malignancy and diabetes. Prevention or delay of brain senescence would therefore enhance the quality of life for older persons. Because oxidative stress has been implicated in brain senescence, we investigated the effects of green tea catechin (GT-catechin), a potential antioxidant, in senescence-accelerated (SAMP10) mice. The mouse is a model of brain senescence with short life span, cerebral atrophy and cognitive dysfunction. Mice were fed water containing 0.02% GT-catechin from 1- to 15-month-old. The mean dose was about 35 mg/kg/day. We found that daily consumption of GT-catechin prevented memory regression and DNA oxidative damage in these mice. GT-catechin did not prolong the lifetime of SAMP10 mice, but it did delay brain senescence. These findings suggest that continued intake of GT-catechin might promote healthy ageing of the brain in older persons.

Source: Keiko Unno, Fumiyo Takabayashi, Hirotoshi Yoshida, Daisuke Coba, Rei Fukutomi, Naomi Kikunaga, Takahairo Kishido, Naoto Oku, Minoru Hoshino. “Daily consumption of green tea catechin delays memory regression in aged mice” Biogerontology (2006): volume 8, 89–95.

A Combination of Green Tea Extract and l-Theanine Improves Memory and Attention in Subjects with Mild Cognitive Impairment: A Double-Blind Placebo-Controlled Study ^*

Abstract

A combination of green tea extract and l-theanine (LGNC-07) has been reported to have beneficial effects on cognition in animal studies. In this randomized, double-blind, placebo-controlled study, the effect of LGNC-07 on memory and attention in subjects with mild cognitive impairment (MCI) was investigated. Ninety-one MCI subjects whose Mini Mental State Examination-K (MMSE-K) scores were between 21 and 26 and who were in either stage 2 or 3 on the Global Deterioration Scale were enrolled in this study. The treatment group (13 men, 32 women; 57.58 ± 9.45 years) took 1,680 mg of LGNC-07, and the placebo group (12 men, 34 women; 56.28 ± 9.92 years) received an equivalent amount of maltodextrin and lactose for 16 weeks. Neuropsychological tests (Rey–Kim memory test and Stroop color–word test) and electroencephalography were conducted to evaluate the effect of LGNC-07 on memory and attention. Further analyses were stratified by baseline severity to evaluate treatment response on the degree of impairment (MMSE-K 21–23 and 24–26). LGNC-07 led to improvements in memory by marginally increasing delayed recognition in the Rey–Kim memory test (P = .0572). Stratified analyses showed that LGNC-07 improved memory and selective attention by significantly increasing the Rey–Kim memory quotient and word reading in the subjects with MMSE-K scores of 21–23 (LGNC-07, n = 11; placebo, n = 9). Electroencephalograms were recorded in 24 randomly selected subjects hourly for 3 hours in eye-open, eye-closed, and reading states after a single dose of LGNC-07 (LGNC-07, n = 12; placebo, n = 12). Brain theta waves, an indicator of cognitive alertness, were increased significantly in the temporal, frontal, parietal, and occipital areas after 3 hours in the eye-open and reading states. Therefore, this study suggests that LGNC-07 has potential as an intervention for cognitive improvement.

Source: Sang-Ki Park, In-Chul Jung, Won Kyung Lee, Young Sun Lee, Hyoung Kook Park, Hyo Jin Go, Kiseong Kim, Nam Kyoo Lim, Jin Tae Hong, Sun Yung Ly, Seok Seon Rho. “A Combination of Green Tea Extract and l-Theanine Improves Memory and Attention in Subjects with Mild Cognitive Impairment: A Double-Blind Placebo-Controlled Study” Journal of Medicinal Food (2011): Vol. 14, No. 4.

Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Aβ_1-42 oligomers and upregulating synaptic plasticity–related proteins in the hippocampus ^*

Abstract

The senescence-accelerated mouse prone-8 (SAMP8) is characterized by early onset of learning and memory deficits along with spontaneous overproduction of soluble β-amyloid peptide (Aβ) in the brain. In our study, 4 month old male SAMP8 mice were orally administered 0.05% and 0.1% green tea catechins (GTC, w/v) in drinking water for 6 months. We found that a supplementation with 0.05% or 0.1% GTC prevented spatial learning and memory impairments of mice in the Morris water maze. Better performance of GTC-treated mice was associated with decreased levels of Aβ_1-42 oligomers in the hippocampus. The activity of the protein kinase A/cAMP-response element binding protein (PKA/CREB) pathway, one of the molecular targets of Aβ oligomers which is crucial for late long-term potentiation and long-term memory formation, was significantly increased after GTC administration. We also found that chronic 0.05% or 0.1% GTC consumption prevented the reductions of three representative proteins of synaptic function and synaptic structure, including brain-derived neurotrophic factor(BDNF), post-synaptic density protein-95 (PSD95) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). These results demonstrated that long-term 0.05% or 0.1% green tea catechin administration may prevent spatial learning and memory decline of SAMP8 mice by decreasing Aβ1-42 oligomers and upregulating synaptic plasticity–related proteins in the hippocampus.

Source: Q. Li, H.F. Zhao, Z.F. Zhang, Z.G. Liu, X.R. Pei, J.B. Wang, Y. Li. “Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Aβ1-42 oligomers and upregulating synaptic plasticity–related proteins in the hippocampus” Behavioral Neuroscience (2009): Volume 163, Issue 3, Pages 741-749.

Green tea effects on cognition, mood and human brain function: A systematic review ^*

Abstract

Background: Green tea (Camellia sinensis) is a beverage consumed for thousands of years. Numerous claims about the benefits of its consumption were stated and investigated. As green tea is experiencing a surge in popularity in Western culture and as millions of people all over the world drink it every day, it is relevant to understand its effects on the human brain.

Purpose: To assess the current state of knowledge in the literature regarding the effects of green tea or green tea extracts, l-theanine and epigallocatechin gallate both components of green tea-on general neuropsychology, on the sub-category cognition and on brain functions in humans.

Methods: We systematically searched on PubMed database and selected studies by predefined eligibility criteria. We then assessed their quality and extracted data. We structured our effort according to the PRISMA statement.

Outcome: We reviewed and assessed 21 studies, 4 of which were randomised controlled trials, 12 cross-over studies (both assessed with an adapted version of the DELPHI-list), 4 were cross-sectional studies and one was a cohort study (both assessed with an adapted version of the Newcastle-Ottawa assessment scale). The average study quality as appraised by means of the DELPHI-list was good (8.06/9); the studies evaluated with the Newcastle-Ottawa-scale were also good (6.7/9).

Conclusions: The reviewed studies presented evidence that green tea influences psychopathological symptoms (e.g. reduction of anxiety), cognition (e.g. benefits in memory and attention) and brain function (e.g. activation of working memory seen in functional MRI). The effects of green tea cannot be attributed to a single constituent of the beverage. This is exemplified in the finding that beneficial green tea effects on cognition are observed under the combined influence of both caffeine and l-theanine, whereas separate administration of either substance was found to have a lesser impact.

Source: Edele Mancini, Christoph Beglinger, Jürgen Drewe, Davide Zanchi, Undine E Lang, Stefan Borgwardt. “Green tea effects on cognition, mood and human brain function: A systematic review” Journal of Phytomedicine (2017): 34:26-37.

Effect of green tea consumption on human brain function in resting-state functional MRI ^*

Abstract

Background: Green tea (Camellia sinensis) is a beverage consumed for thousands of years. Numerous claims about the benefits of its consumption were stated and investigated. As green tea is experiencing a surge in popularity in Western culture and as millions of people all over the world drink it every day, it is relevant to understand its effects on the human brain. Purpose To assess the current state of knowledge in the literature regarding the effects of green tea or green tea extracts, L-theanine and epigallocatechin gallate both components of green tea—on general neuropsychology, on the sub-category cognition and on brain functions in humans.

Methods: We systematically searched on PubMed database and selected studies by predefined eligibility criteria. We then assessed their quality and extracted data. We structured our effort according to the PRISMA statement.

Outcome: We reviewed and assessed 21 studies, 4 of which were randomised controlled trials, 12 cross-over studies (both assessed with an adapted version of the DELPHI-list), 4 were cross-sectional studies and one was a cohort study (both assessed with an adapted version of the Newcastle–Ottawa assessment scale). The average study quality as appraised by means of the DELPHI-list was good (8.06/9); the studies evaluated with the Newcastle–Ottawa-scale were also good (6.7/9).

Conclusions: The reviewed studies presented evidence that green tea influences psychopathological symptoms (e.g. reduction of anxiety), cognition (e.g. benefits in memory and attention) and brain function (e.g. activation of working memory seen in functional MRI). The effects of green tea cannot be attributed to a single constituent of the beverage. This is exemplified in the finding that beneficial green tea effects on cognition are observed under the combined influence of both caffeine and L-theanine, whereas separate administration of either substance was found to have a lesser impact.

Source: Hui Wang, Wei Sun, Yan Chang, Zhenzhou Wu, Yajie Xu, Erlei Wang, Lei Wang, Peiwei Yi. “Effect of green tea consumption on human brain function in resting-state functional MRI” Asia Pacific Journal of Clinical Nutrition (2019): 28(4):740-746.

Caffeine Anhydrous

Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling ^*

Abstract

Caffeine has cognitive-enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor-independent form of LTP (CAF LTP) in the CA1 region of the hippocampus by promoting calcium-dependent secretion of BDNF, which subsequently activates TrkB-mediated signaling required for the expression of _CAF LTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAF LTP, a process that requires cytosolic free Ca²⁺. Consistent with the involvement of IRS2 signals in caffeine-mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2^-/- mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3-kinase (PI3K) pathway. These findings indicate that TrkB-IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

Source: Cristina Lao-Peregrín , Jesús Javier Ballesteros , Miriam Fernández , Alfonsa Zamora-Moratalla , Ana Saavedra, María Gómez Lázaro , Esther Pérez-Navarro , Deborah Burks , Eduardo D Martín. “Caffeine-mediated BDNF release regulates long-term synaptic plasticity through activation of IRS2 signaling” Addiction Biology (2017): 1706-1718.

Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotrophic factor in healthy subjects ^*

Abstract

The present single-dose study was performed to assess the effect of whole coffee fruit concentrate powder (WCFC), green coffee caffeine powder (N677), grape seed extract powder (N31) and green coffee bean extract powder (N625) on blood levels of brain-derived neurotrophic factor (BDNF). Randomly assorted groups of fasted subjects consumed a single, 100 mg dose of each material. Plasma samples were collected at time zero (T0) and at 30 min intervals afterwards, up to 120 min. A total of two control groups were included: subjects treated with silica dioxide (as placebo) or with no treatment. The collected data revealed that treatments with N31 and N677 increased levels of plasma BDNF by about 31 % under these experimental conditions, whereas treatment with WCFC increased it by 143 % (n 10), compared with baseline. These results indicate that WCFC could be used for modulation of BDNF-dependent health conditions. However, larger clinical studies are needed to support this possibility.

Source: Tania Reyes-Izquierdo, Boris Nemzer, Cynthia Shu, Lan Huynh. “Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotrophic factor in healthy subjects” British Journal of Nutrition (2013): Volume 110, Issue 3, 420-425.

Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects ^*

Abstract

Caffeine is the most widely consumed central-nervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonin neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.

Source: A Nehlig, J L Daval, G Debry. “Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects” Brain Research (1992): 17(2):139-70.

20 Effects of Caffeine on Cognitive Performance, Mood, and Alertness in Sleep-Deprived Humans

Abstract

The demands and pace of continuous military operations produce sleep fragmentation and varying degrees of sleep deprivation in soldiers. The observable effects of this sleep disruption include decreased alertness, slowed thinking, lapses in attention, decreased motivation, and a performance phenomenon called the speed-accuracy-tradeoff. Several studies have documented performance and mood changes during periods of sleep deprivation (Babkoff et al., 1989a,b; Mikulincer et al., 1989; Thorne et al., 1983). There is a decline in the performance of accuracy tasks involving attention, reasoning abilities, and reaction time. Alertness decreases, and there are changes in self-reported fatigue (increases) and vigor (decreases). Sustaining optimum soldier performance relates to the prevention or amelioration of these changes. Three categories of solutions include the following: (1) Doctrinal solutions involve the overtraining of soldiers to perform their tasks with a minimum of cognitive effort; ensuring that soldiers are cross-trained so that crew members can substitute for each other when necessary; developing and adhering to appropriate work-rest cycles, including rotating crews as the mission permits; developing efficient leadership tactics so that unnecessary demands are not placed on subordinates; and modifying equipment and systems so that the likelihood of making errors is as small as possible. (2) Behavioral solutions make sure that soldiers sleep as much as they can, whenever they can (sleep discipline), while paying attention to where and how they sleep (sleep hygiene), that is, in as comfortable a position as possible, away from the noise and bustle of other soldiers and equipment. (3) Pharmacological solutions may be warranted in special circumstances, when adherence to doctrinal and behavioral solutions is not possible or breaks down. This last category of solutions for preventing or ameliorating sleep deprivation effects is the topic of the research reported in this chapter.

The characteristics of stimulant drugs useful in specific military situations are not only effectiveness but low therapeutic toxicity and low abuse potential, d-Amphetamine was tested for its ability to reverse changes in mood, alertness, and cognitive performance after an extended period of sleep deprivation (Newhouse et al., 1989). Although effective, its restricted legal status and the psychological side effects associated with long-term use, coupled with its abuse potential, almost certainly prohibit large-scale use. Caffeine is a universally available, legal, and socially accepted and used stimulant with low toxicity and low abuse potential. It is believed to reverse the performance and mood effects seen during sleep deprivation, although it has not been tested systematically.

Caffeine has a long history of use and can be found in many common foods, drinks, and medications. Although caffeine has been the subject of pharmacological studies for several decades, the mechanism of action of its effects on the central nervous system have only recently been defined as a blockade of adenosine receptors (Choi et al., 1988; Fredholm, 1985; Snyder, 1984). Extensive reviews of caffeine (Dews, 1984; Weiss and Laties, 1962) conclude that its stimulant properties are weak in comparison with those of other drugs (e.g., amphetamine) and that its effects are modest, making detection of these effects difficult and generalizations cumbersome. Dews (1984), however, states that the following three effects are clear: (1) it has the tendency to postpone sleep; (2) it reduces the degradation of performance because of fatigue and boredom; and (3) it decreases hand steadiness. The interpretation distilled from these and other reviews is that caffeine’s effects are significant primarily when performance of repetitive, nonintellectual tasks is partially degraded. What is lacking in the literature and of importance to military operations is a systematic study of caffeine’s effects on sleep-deprived individuals and the assessment of caffeine’s effectiveness in reversing the changes caused by sleep deprivation.

Source: David M.Penetar, Una McCann, David Thorne, Aline Schelling, Cynthia Galinski, Helen Sing, Maria Thomas, Gregory Belenky. “20 Effects of Caffeine on Cognitive Performance, Mood, and Alertness in Sleep-Deprived Humans” Food Components to Enhance Performance: An Evaluation of Potential Performance-Enhancing Food Components for Operational Rations - Institute of Medicine (US) Committee on Military Nutrition Research (1994).

Gamma-Aminobutyric Acid (GABA)

Neurotransmitters as food supplements: the effects of GABA on brain and behavior ^*

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. The food supplement version of GABA is widely available online. Although many consumers claim that they experience benefits from the use of these products, it is unclear whether these supplements confer benefits beyond a placebo effect. Currently, the mechanism of action behind these products is unknown. It has long been thought that GABA is unable to cross the blood–brain barrier (BBB), but the studies that have assessed this issue are often contradictory and range widely in their employed methods. Accordingly, future research needs to establish the effects of oral GABA administration on GABA levels in the human brain, for example using magnetic resonance spectroscopy. There is some evidence in favor of a calming effect of GABA food supplements, but most of this evidence was reported by researchers with a potential conflict of interest. We suggest that any veridical effects of GABA food supplements on brain and cognition might be exerted through BBB passage or, more indirectly, via an effect on the enteric nervous system. We conclude that the mechanism of action of GABA food supplements is far from clear, and that further work is needed to establish the behavioral effects of GABA.

Source: Evert Boonstra, Roy de Kleijn, Lorenza S. Colzato, Anneke Alkemade, Birte U. Forstmann and Sander Nieuwenhuis. “Neurotransmitters as food supplements: the effects of GABA on brain and behavior” Frontiers in Psychology (2015): 6: 1520.

GABA ‐producing Bifidobacterium dentium modulates visceral sensitivity in the intestine ^*

Abstract

Background: Recurrent abdominal pain is a common and costly health‐care problem attributed, in part, to visceral hypersensitivity. Increasing evidence suggests that gut bacteria contribute to abdominal pain perception by modulating the microbiome‐gut‐brain axis. However, specific microbial signals remain poorly defined. γ‐aminobutyric acid (GABA ) is a principal inhibitory neurotransmitter and a key regulator of abdominal and central pain perception from peripheral afferent neurons. Although gut bacteria are reported to produce GABA , it is not known whether the microbial‐derived neurotransmitter modulates abdominal pain.

Methods: To investigate the potential analgesic effects of microbial GABA , we performed daily oral administration of a specific Bifidobacterium strain (B. dentium ATCC 27678) in a rat fecal retention model of visceral hypersensitivity, and subsequently evaluated pain responses.

Key Results: We demonstrate that commensal Bifidobacterium dentium produces GABA via enzymatic decarboxylation of glutamate by GadB. Daily oral administration of this specific Bifidobacterium (but not a gadB deficient) strain modulated sensory neuron activity in a rat fecal retention model of visceral hypersensitivity.

Conclusions & Inferences: The functional significance of microbial‐derived GABA was demonstrated by gadB‐dependent desensitization of colonic afferents in a murine model of visceral hypersensitivity. Visceral pain modulation represents another potential health benefit attributed to bifidobacteria and other GABA ‐producing species of the intestinal microbiome. Targeting GABA ergic signals along this microbiome‐gut‐brain axis represents a new approach for the treatment of abdominal pain.

Source: K. Pokusaeva, C. Johnson, B. Luk, G. Uribe, Y. Fu, N. Oezguen, R. K. Matsunami, M. Lugo, A. Major, Y. Mori‐Akiyama, E. B. Hollister, S. M. Dann, X. Z. Shi, D. A. Engler, T. Savidge, J. Versalovic. “GABA ‐producing Bifidobacterium dentium modulates visceral sensitivity in the intestine” Neurogastroenterology & Motility (2016).

Inhibitory role for GABA in autoimmune inflammation ^*

Abstract

GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA. Thus, the immune system harbors all of the necessary constituents for GABA signaling, and GABA itself may function as a paracrine or autocrine factor. These observations led us to ask further whether manipulation of the GABA pathway influences an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Increasing GABAergic activity ameliorates ongoing paralysis in EAE via inhibition of inflammation. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins.

Source: Roopa Bhat, Robert Axtell, Ananya Mitra, Melissa Miranda, Christopher Lock, Richard W. Tsien, and Lawrence Steinman. “Inhibitory role for GABA in autoimmune inflammation” Proceedings of the National Academy of Sciences (2010): 107 (6) 2580-2585.

The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells ^*

Abstract

Systemic gamma-aminobutyric acid (GABA) therapy prevents or ameliorates type 1 diabetes (T1D), by suppressing autoimmune responses and stimulating pancreatic beta cells. In beta cells, it increases insulin secretion, prevents apoptosis, and induces regeneration. It is unclear how GABA mediates these effects. We hypothesized that Klotho is involved. It is a multi-functional protein expressed in the kidneys, brain, pancreatic beta cells, other tissues, and is cell-bound or soluble. Klotho knockout mice display accelerated aging, and in humans Klotho circulating levels decline with age, renal disease and diabetes. Here, we report that GABA markedly increased circulating levels of Klotho in streptozotocin (STZ)-induced diabetes. GABA also increased Klotho in the islet of Langerhans of normal mice, as well as the islets and kidneys of STZ-treated mice. In vitro, GABA stimulated production and secretion of Klotho by human islet cells. Knockdown (KD) of Klotho with siRNA in INS-1E insulinoma cells abrogated the protective effects of GABA against STZ toxicity. Following KD, soluble Klotho reversed the effects of Klotho deficiency. In human islet cells soluble Klotho protected against cell death, and stimulated proliferation and insulin secretion. NF-κB activation triggers beta-cell apoptosis, and both GABA and Klotho suppress this pathway. We found Klotho KD augmented NF-κB p65 expression, and abrogated the ability of GABA to block NF-κB activation. This is the first report that GABAergic stimulation increases Klotho expression. Klotho protected and stimulated beta cells and lack of Klotho (KD) was reversed by soluble Klotho. These findings have important implications for the treatment of T1D.

Source: Gérald J Prud'homme , Yelena Glinka , Merve Kurt , Wenjuan Liu , Qinghua Wang. “The anti-aging protein Klotho is induced by GABA therapy and exerts protective and stimulatory effects on pancreatic beta cells” Biochemical and Biophysical Research Communications (2017): 493(4):1542-1547.

Bacopa Aerial Part Extract (20% Bacoside)

Neurocognitive Effect of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer's Disease ^*

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the elderly. The rapid increase in its incidence has necessitated development of newer drugs. Ayurvedic herbal medications are increasingly researched due to their biosafety profile and usefulness in cognitive impairment. In this article, we critically reviewed one such Medhya Rasayana (nootropic drug) Brahmi-derived from extract of Bacopa monnieri (EBm). Studies have shown that EBm promotes free radical scavenger mechanisms and protects cells in prefrontal cortex, hippocampus, and striatum against cytotoxicity and DNA damage implicated in AD. It also reduces lipoxygenase activity reducing lipid peroxidation, increases glutathione peroxidase and chelates iron. Administration of EBm was seen to protect the cholinergic neurons and reduce anticholinesterase activity comparable to donepezil, rivastigmine, and galantamine. It also reduces hippocampal β-amyloid deposition and stress-induced hippocampal damage. The neuroprotective effect of EBm is also due to nitric oxide-mediated cerebral vasodilation. EBm improved the total memory score and maximum improvement was seen in logical memory and paired associate learning in humans and reversed phenytoin-induced memory impairment in experimental model. EBm has not shown any serious clinical, neurological, hematological complications, or vital organs damage in experimental studies. Rats showed marked reduction in fertility; however, libido was unaffected. There is no experimental evidence of genotoxicity or teratogenesis by use of EBm. Mild nausea and gastrointestinal upset are seen in humans. Brahmi promises to be a novel agent in AD; however, further human trials are recommended to verify the efficacy and rule out any side effects as evidenced by the experimental models.

Source: Kaustubh S. Chaudhari, Nishant R. Tiwari, Rakesh R. Tiwari, and Rohan S. Sharma. “Neurocognitive Effect of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer's Disease” Annals of Neuroscience (2017): 111–122.

Bacopa monnieri as an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain ^*

Abstract

The detrimental effect of neuronal cell death due to oxidative stress and mitochondrial dysfunction has been implicated in age-related cognitive decline and neurodegenerative disorders such as Alzheimer's disease. The Indian herb Bacopa monnieri is a dietary antioxidant, with animal and in vitro studies indicating several modes of action that may protect the brain against oxidative damage. In parallel, several studies using the CDRI08 extract have shown that extracts of Bacopa monnieri improve cognitive function in humans. The biological mechanisms of this cognitive enhancement are unknown. In this review we discuss the animal studies and in vivo evidence for Bacopa monnieri as a potential therapeutic antioxidant to reduce oxidative stress and improve cognitive function. We suggest that future studies incorporate neuroimaging particularly magnetic resonance spectroscopy into their randomized controlled trials to better understand whether changes in antioxidant status in vivo cause improvements in cognitive function.

Source: Tamara Simpson, Matthew Pase, and Con Stough. “Bacopa monnieri as an Antioxidant Therapy to Reduce Oxidative Stress in the Aging Brain” Evidence-Based Complementary and Alternative Medicine (2015): 615384.

Bacopa monniera, a reputed nootropic plant: an overview ^*

Abstract

Bacopa monniera (BM), a traditional Ayurvedic medicine, used for centuries as a memory enhancing, anti-inflammatory, analgesic, antipyretic, sedative and antiepileptic agent. The plant, plant extract and isolated bacosides (the major active principles) have been extensively investigated in several laboratories for their neuropharmacological effects and a number of reports are available confirming their nootropic action. In addition, researchers have evaluated the anti-inflammatory, cardiotonic and other pharmacological effects of BM preparations/extracts. Therefore, in view of the important activities performed by this plant, investigation must be continued in the recently observed actions described in this paper. Moreover, other clinical studies have to be encouraged, also to evidence any side effects and possible interactions between this herbal medicine and synthetic drugs.

Source: A Russo , F Borrelli. “Bacopa monniera, a reputed nootropic plant: an overview” Phytomedicine: International Journal of Phytotherapy and Phytopharmacology (2005): 305-17.

Antimicrobial activity of various fractions of ethanol extract of Bacopa monnieri Linn. aerial parts

Abstract

The ethyl acetate and n-butanol fractions of ethanol extract of Bacopa monnieri Linn. aerial parts were screened for antibacterial and antifungal activities by both zones of inhibition study and determination of minimum inhibitory concentration (MIC). The ethyl acetate fraction was found to be more potent than the n-butanol fraction, though both of them were endowed with antimicrobial activity. The present study reveals the potential usefulness of B. monnieri aerial parts in the treatment of various pathogenic diseases as mentioned in the Ayurvedic literature.

Source: Ghosh, T., et al. “Antimicrobial activity of various fractions of ethanol extract of Bacopa monnieri Linn. aerial parts.” Indian Journal of Pharmaceutical Sciences 69.2 (2007): 312.

Phytotoxic and antimicrobial constituents of Bacopa monnieri and Holmskioldia sanguinea

Abstract

The phytochemicals betulinic acid (1), wogonin (2) and oroxindin (3) isolated from the aerial parts of Bacopa monnieri and Holmskioldia sanguinea showed significant antifungal activity against the two fungi Alternaria alternata and Fusarium fusiformis. Inhibition of root growth germination of wheat seeds was observed for all three compounds which showed 100% inhibition at 10 µg/mL. Compounds (1) and (2) showed potent inhibition of Alternaria alternata compared with oroxindin at a concentration of 4 µg/mL, whereas compound (2) was an effective inhibitor of both fungi. The structures of the compounds were established by spectral and chemical studies. Copyright © 2004 John Wiley & Sons, Ltd.

Source: Chaudhuri, P. K., et al. “Phytotoxic and antimicrobial constituents of Bacopa monnieri and Holmskioldia sanguinea.” Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives 18.2 (2004): 114-117.

Alpha-GPC – (Alpha Glycerylphosphorylcholine)

A multicentre trial to evaluate the efficacy and tolerability of alpha-glycerylphosphorylcholine versus cytosine diphosphocholine in patients with vascular dementia ^*

Abstract

An open clinical trial was carried out to compare the efficacy and the tolerability of 1 g/day alpha-glycerylphosphorylcholine (alpha-GPC) with 1 g/day cytosine diphosphocholine (CDP) both given intramuscularly for 90 days in 120 patients with mild to moderate vascular dementia. The clinical evaluation, carried out at the start as well as halfway through (45 days) and at the end of treatment (90 days), was expressed by psychometric tests (modified Parkside behaviour rating scale, Sandoz clinical assessment geriatric scale, word fluency test, Hamilton's rating scale of depression, narration subtest of Wechsler memory scale). Both treatments produced a definite symptomatic improvement and showed a very good tolerability. The results suggest that in most tests alpha-GPC possessed a statistical higher efficacy and an overall more satisfactory activity assessed by both patients and investigators compared with CDP.

Source: R Di Perri , G Coppola, L A Ambrosio, A Grasso, F M Puca, M Rizzo. “A multicentre trial to evaluate the efficacy and tolerability of alpha-glycerylphosphorylcholine versus cytosine diphosphocholine in patients with vascular dementia” The Journal of International Medical Research (1991): 19(4):330-41.

Alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial ^*

Abstract

The clinical efficacy and the tolerability of alpha-glycerophosphocholine (alpha-GPC), a drug able to provide high levels of choline for the nervous cells of the brain and to protect their cell walls, have been tested in a clinical open multicenter trial on 2044 patients suffering from recent stroke or transient ischemic attacks. alpha-GPC was administered after the attack at the daily dose of 1000 mg im for 28 days and orally at the dose of 400 mg tid during the following 5 months after the first phase. The evaluation of the efficacy on the psychic recovery was done by the Mathew Scale (MS) during the period of im drug administration, and using the Mini Mental State Test (MMST), the Crichton Rating Scale (CRS), and the Global Deterioration Scale (GDS) during the following period of oral administration. The MS mean increased 15.9 points in 28 days in a statistically significant way (p < 0.001) from 58.7 to 74.6. At the end of the 5 month oral administration, the CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 (p < 0.001); the MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the trial, reaching the "normality" score at the 3rd month assessment. The GDS score at the end of the trial corresponded to "no cognitive decline" or "forgetfulness" in 71% of the patients. Adverse events were complained of by 44 patients (2.14%); in 14 (0.7%) the investigator preferred to discontinue therapy. The most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation (0.4%), and headache (0.2%). The trial confirms the therapeutic role of alpha-GPC on the cognitive recovery of patients with acute stroke or TIA, and the low percentage of adverse events confirms its excellent tolerability.

Source: G Barbagallo Sangiorgi , M Barbagallo, M Giordano, M Meli, R Panzarasa. “alpha-Glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial” Annals of the New York Academy of Sciences (1994): 717:253-69.

Effect of a new cognition enhancer, alpha-glycerylphosphorylcholine, on scopolamine-induced amnesia and brain acetylcholine

Abstract

The present study investigates the effect of the administration of alpha-glycerylphosphorylcholine (alpha-GPC) on scopolamine-induced amnesia and on brain acetylcholine (ACh) levels and release in rats. The results indicate that alpha-GPC, when administered orally, reverses the amnesia caused by scopolamine in passive avoidance. The peak effect is observed using 600 mg/kg IG, 5 h before training. The effect of the drug is long lasting (up 30 h) in accordance with its pharmacokinetic characteristics. Since, alpha-GPC administered IG is cleaved within the gut mucosal cells to glycerophosphate and free choline, it is tempting to speculate that this drug acts by increasing the ACh precursor pool. This view is supported also by the observation that alpha-GPC partially counteracts the decrease of brain ACh levels elicited by scopolamine administration. The effect is observed in the hippocampus and cortex, but not in the striatum. Moreover, in ex vivo experiments, alpha-GPC is able to increase the amount of ACh released by rat hippocampus slices following potassium stimulation.

Source: Lopez, C. M., et al. "Effect of a new cognition enhancer, alpha-glycerylphosphorylcholine, on scopolamine-induced amnesia and brain acetylcholine." Pharmacology Biochemistry and Behavior 39.4 (1991): 835-840.

A Multicentre Trial to Evaluate the Efficacy and Tolerability of α-Glycerylphosphorylcholine versus Cytosine Diphosphocholine in Patients with Vascular Dementia

Abstract

An open clinical trial was carried out to compare the efficacy and the tolerability of 1 g/day α-glycerylphosphorylcholine (α-GPC) with 1 g/day cytosine diphosphocholine (CDP) both given intramuscularly for 90 days in 120 patients with mild to moderate vascular dementia. The clinical evaluation, carried out at the start as well as halfway through (45 days) and at the end of treatment (90 days), was expressed by psychometric tests (modified Parkside behaviour rating scale, Sandoz clinical assessment geriatric scale, word fluency test, Hamilton's rating scale of depression, narration subtest of Wechsler memory scale). Both treatments produced a definite symptomatic improvement and showed a very good tolerability. The results suggest that in most tests α-GPC possessed a statistical higher efficacy and an overall more satisfactory activity assessed by both patients and investigators compared with CDP.

Source: Perri, R. Di, et al. "A multicentre trial to evaluate the efficacy and tolerability of α-glycerylphosphorylcholine versus cytosine diphosphocholine in patients with vascular dementia." Journal of international medical research 19.4 (1991): 330-341.

Huperzine-A

Huperzine-A response to cognitive impairment and task switching deficits in patients with Alzheimer's disease ^*

Abstract

Background: Alzheimer's Disease (AD) is associated with cognitive decline due to various pathological mechanisms. There are several acetylcholinesterase inhibitor compounds which can improve cognition, but Huperzine-A is a natural sesquiterpene alkaloid extracted from Chinese herb (Huperzia Serrata) which has rapid action.

Methods: Double blind study was conducted. Participants included 50 patients with AD and 50 healthy individuals. Patients were recruited from Civil and BV hospital Bahawalpur and Nishter hospital Multan, Pakistan during May 2017 until February 2018 who were stable on Huperzine-A medication. Patients were tested twice. First, at the time of diagnosis to determine baseline scores. Second, post eight weeks of Huperzine-A treatment. Healthy individuals had single testing session. Participants completed Addenbrooke's Cognitive Examination and Trail Making Test.

Results: Patients with AD showed cognitive and task switching deficits in contrast with healthy individuals. There was significant improvement in cognition and task switching abilities post Huperzine-A treatment compared with baseline performance.

Conclusion: Huperzine-A is effective in reducing cognitive and task switching deficits in patients with AD.

Source: Amara Gul , Jehan Bakht , Farah Mehmood. “Huperzine-A response to cognitive impairment and task switching deficits in patients with Alzheimer's disease” Journal of the Chinese Medical Association (2019): 82(1):40-43.

Huperzine A as a neuroprotective and antiepileptic drug: a review of preclinical research ^*

Abstract

Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor extracted from Huperzia Serrata, a firmoss, which has been used for various diseases in traditional Chinese medicine for fever and inflammation. More recently, it has been used in Alzheimer's disease and other forms of dementia with a presumed mechanism of action via central nicotinic and muscarinic receptors. HupA is marketed as a dietary supplement in the U.S. This article reviews newly proposed neuroprotective and anticonvulsant HupA properties based on animal studies. HupA exerts its effects mainly via α7nAChRs and α4β2nAChRs, thereby producing a potent anti-inflammatory response by decreasing IL-1β, TNF-α protein expression, and suppressing transcriptional activation of NF-κB signaling. Thus, it provides protection from excitotoxicity and neuronal death as well as increase in GABAergic transmission associated with anticonvulsant activity.

Source: U Damar , R Gersner , J T Johnstone , S Schachter , A Rotenberg. “Huperzine A as a neuroprotective and antiepileptic drug: a review of preclinical research” Expert Review of Neurotherapeutics (2016): 16(6):671-80.

Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease

Abstract

In recent years, the most common pharmacological treatment for Alzheimer’s disease (AD) has been acetylcholinesterase (AChE) inhibition. However, this single-target approach has limited effectiveness and there is evidence that a multitarget approach might be more effective. Huperzine A (HupA), a novel alkaloid isolated from a Chinese herb, has neuroprotective effects that go beyond the inhibition of AChE. Recent data have demonstrated that HupA can ameliorate the learning and memory deficiency in animal models and AD patients. Its potentially beneficial actions include modification of β-amyloid peptide processing, reduction of oxidative stress, neuronal protection against apoptosis, and regulation of the expression and secretion of nerve growth factor (NGF) and NGF signaling.

Source: Zhang, Hai Yan, and Xi Can Tang. “Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease.” Trends in pharmacological sciences 27.12 (2006): 619-625.

Comparison of the effects of natural and synthetic huperzine-A cholinergic function in vitro and in vivo

Abstract

(−)-Huperzine-A has been shown to be a promising agent for the treatment of dementia of the Alzheimer type. This substance is rare in nature. We have been able to prepare a racemic mixture of (±)-huperzine-A in quantity. In the absence of a chiral synthetic procedure for (−)-huperzine-A, this study sought to determine whether the racemic mixture would yield an in vitro and in vivo pharmacological profile of activity similar to that of the natural compound. The synthetic racemic mixture (±)-huperzine-A was 3 times less potent than (−)-huperzine-A in vitro (IC50s of 3 × 10−7 M and 10−7 M, respectively) because the former consisted of a racemic mixture of the compound in which the (+)-huperzine component was considerably less potent (IC50 = 7 × 10−6M). A comparable magnitude of effect was also observed in studies conducted in vivo, in which, over a range of 0.1–2.0 mg/kg administered intraperitoneally (i.p.), both (−)-huperzine-A and (±)-huperzine-A exerted significant inhibition of acetylcholinesterase activity, in all brain regions tested (hippocampus, striatum, hypothalamus, and frontal cortex). This inhibition of acetylcholinesterase activity was inversely related to levels of acetylcholine measured in the hippocampus and followed the same time course of effect. (−)-Huperzine-A and (±)-huperzine-A were shown to be more potent than physostigmine as inhibitors of acetylcholinesterase in vitro (IC50 = 6 × 10−7M). Moreover, their inhibitory effect on acetylcholinesterase in vivo was of a longer duration (peak activity of 20 min for physostigmine versus 60 min for the huperzine variants), at the doses tested. Finally, no effect was exerted by either of the huperzine variants on choline acetyltransferase activity in cortex or hippocampus, over a wide range of doses tested (0.1–1.0 mg/kg, i.p.). These findings demonstrate that (±)- huperzine-A compares in its activity and biological effects with the natural product, (−)-huperzine-A, both in vitro and in vivo.

Source: Xi-Can, Tang, et al. “Comparison of the effects of natural and synthetic huperzine-A cholinergic function in vitro and in vivo.” Journal of Ethnopharmacology 44.3 (1994): 147-155.

L-theanine

L-theanine, a natural constituent in tea, and its effect on mental state ^*

Abstract

Tea is the most widely consumed beverage in the world after water. Tea is known to be a rich source of flavonoid antioxidants. However tea also contains a unique amino acid, L-theanine that may modulate aspects of brain function in humans. Evidence from human electroencephalograph (EEG) studies show that it has a direct effect on the brain (Juneja et al. Trends in Food Science & Tech 1999;10;199-204). L-theanine significantly increases activity in the alpha frequency band which indicates that it relaxes the mind without inducing drowsiness. However, this effect has only been established at higher doses than that typically found in a cup of black tea (approximately 20mg). The aim of the current research was to establish this effect at more realistic dietary levels. EEG was measured in healthy, young participants at baseline and 45, 60, 75, 90 and 105 minutes after ingestion of 50mg L-theanine (n=16) or placebo (n=19). Participants were resting with their eyes closed during EEG recording. There was a greater increase in alpha activity across time in the L-theanine condition (relative to placebo (p+0.05). A second study replicated this effect in participants engaged in passive activity. These data indicate that L-theanine, at realistic dietary levels, has a significant effect on the general state of mental alertness or arousal. Furthermore, alpha activity is known to play an important role in critical aspects of attention, and further research is therefore focussed on understanding the effect of L-theanine on attentional processes.

Source: Anna C Nobre , Anling Rao, Gail N Owen. “L-theanine, a natural constituent in tea, and its effect on mental state” Asia Pacific Journal of Clinical Nutrition (2008): 17 Suppl 1:167-8.

L-Theanine reduces psychological and physiological stress responses

Abstract

L-Theanine is an amino acid contained in green tea leaves which is known to block the binding of l-glutamic acid to glutamate receptors in the brain. Because the characteristics of l-Theanine suggest that it may influence psychological and physiological states under stress, the present study examined these possible effects in a laboratory setting using a mental arithmetic task as an acute stressor. Twelve participants underwent four separate trials: one in which they took l-Theanine at the start of an experimental procedure, one in which they took l-Theanine midway, and two control trials in which they either took a placebo or nothing. The experimental sessions were performed by double-blind, and the order of them was counterbalanced. The results showed that l-Theanine intake resulted in a reduction in the heart rate (HR) and salivary immunoglobulin A (s-IgA) responses to an acute stress task relative to the placebo control condition. Moreover, analyses of heart rate variability indicated that the reductions in HR and s-IgA were likely attributable to an attenuation of sympathetic nervous activation. Thus, it was suggested that the oral intake of l-Theanine could cause anti-stress effects via the inhibition of cortical neuron excitation.

Source: Kimura, Kenta, et al. "L-Theanine reduces psychological and physiological stress responses." Biological psychology 74.1 (2007): 39-45.

L-theanine—a unique amino acid of green tea and its relaxation effect in humans

Abstract

Since ancient times, it has been said that drinking green tea brings relaxation. The substance that is responsible for a sense of relaxation, is theanine. Theanine is a unique amino acid found almost solely in tea plants and the main component responsible for the exotic taste of ‘green’ tea. It was found that L-theanine administered intraperitoneally to rats reached the brain within 30 min without any metabolic change. Theanine also acts as a neurotransmitter in the brain and decreases blood pressure significantly in hypertensive rats. In general, animals always generate very weak electric pulses on the surface of the brain, called brain waves. Brain waves are classified into four types, namely α,β,δ and θ-waves, based on mental conditions. Generation of α-waves is considered to be an index of relaxation. In human volunteers, α-waves were generated on the occipital and parietal regions of the brain surface within 40 min after the oral administration of theanine (50–200 mg), signifying relaxation without causing drowsiness. With the successful industrial production of L-theanine, we are now able to supply Suntheanine™ (trade name of L-theanine) which offers a tremendous opportunity for designing foods and medical foods targeting relaxation and the reduction of stress. Taiyo Kagaku Co., Ltd, Japan won the 1998 ‘Food Ingredient Research Award’ for development of Suntheanine™ at Food Ingredients in Europe (Frankfurt). The judges felt it was a particularly well-documented and fascinating piece of research.

Source: Juneja, Lekh Raj, et al. "L-theanine—a unique amino acid of green tea and its relaxation effect in humans." Trends in Food Science & Technology 10.6-7 (1999): 199-204.

The effects of L-theanine, caffeine and their combination on cognition and mood

Abstract

L-Theanine is an amino acid found naturally in tea. Despite the common consumption of l-theanine, predominantly in combination with caffeine in the form of tea, only one study to date has examined the cognitive effects of this substance alone, and none have examined its effects when combined with caffeine. The present randomised, placebo-controlled, double-blind, balanced crossover study investigated the acute cognitive and mood effects of l-theanine (250 mg), and caffeine (150 mg), in isolation and in combination. Salivary caffeine levels were co-monitored. l-Theanine increased ‘headache’ ratings and decreased correct serial seven subtractions. Caffeine led to faster digit vigilance reaction time, improved Rapid Visual Information Processing (RVIP) accuracy and attenuated increases in self-reported ‘mental fatigue’. In addition to improving RVIP accuracy and ‘mental fatigue’ ratings, the combination also led to faster simple reaction time, faster numeric working memory reaction time and improved sentence verification accuracy. ‘Headache’ and ‘tired’ ratings were reduced and ‘alert’ ratings increased. There was also a significant positive caffeine × l-theanine interaction on delayed word recognition reaction time. These results suggest that beverages containing l-theanine and caffeine may have a different pharmacological profile to those containing caffeine alone.

Source: Haskell, Crystal F., et al. "The effects of L-theanine, caffeine and their combination on cognition and mood." Biological psychology 77.2 (2008): 113-122.

The Neuropharmacology of L-Theanine (N-Ethyl-L-Glutamine)

Abstract

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotropic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

Source: Nathan, Pradeep J., et al. "The neuropharmacology of L-theanine (N-ethyl-L-glutamine) a possible neuroprotective and cognitive enhancing agent." Journal of Herbal Pharmacotherapy 6.2 (2006): 21-30.

The acute effects of L‐theanine in comparison with alprazolam on anticipatory anxiety in humans

Abstract

L‐Theanine (δ‐glutamylethylamide) is one of the predominant amino acids ordinarily found in green tea, and historically has been used as a relaxing agent. The current study examined the acute effects of L‐theanine in comparison with a standard benzodiazepine anxiolytic, alprazolam and placebo on behavioural measures of anxiety in healthy human subjects using the model of anticipatory anxiety (AA). Sixteen healthy volunteers received alprazolam (1 mg), L‐theanine (200 mg) or placebo in a double‐blind placebo‐controlled repeated measures design. The acute effects of alprazolam and L‐theanine were assessed under a relaxed and experimentally induced anxiety condition. Subjective self‐reports of anxiety including BAI, VAMS, STAI state anxiety, were obtained during both task conditions at pre‐ and post‐drug administrations. The results showed some evidence for relaxing effects of L‐theanine during the baseline condition on the tranquil–troubled subscale of the VAMS. Alprazolam did not exert any anxiolytic effects in comparison with the placebo on any of the measures during the relaxed state. Neither L‐theanine nor alprazolam had any significant anxiolytic effects during the experimentally induced anxiety state. The findings suggest that while L‐theanine may have some relaxing effects under resting conditions, neither L‐theanine nor alprazolam demonstrate any acute anxiolytic effects under conditions of increased anxiety in the AA model.

Source: Lu, Kristy, et al. "The acute effects of L‐theanine in comparison with alprazolam on anticipatory anxiety in humans." Human Psychopharmacology: Clinical and Experimental 19.7 (2004): 457-465.

L-Tyrosine

Neuro-Cognitive Effects of Acute Tyrosine Administration on Reactive and Proactive Response Inhibition in Healthy Older Adults ^*

The aging brain is characterized by altered dopamine signaling. The amino acid tyrosine, a catecholamine precursor, is known to improve cognitive performance in young adults, especially during high environmental demands. Tyrosine administration might also affect catecholamine transmission in the aging brain, thereby improving cognitive functioning. In healthy older adults, impairments have been demonstrated in two forms of response inhibition: reactive inhibition (outright stopping) and proactive inhibition (anticipatory response slowing) under high information load. However, no study has directly compared the effects of a catecholamine precursor on reactive and load-dependent proactive inhibition. In this study we explored the effects of tyrosine on reactive and proactive response inhibition and signal in dopaminergically innervated fronto-striatal regions. Depending on age, tyrosine might lead to beneficial or detrimental neurocognitive effects. We aimed to address these hypotheses in 24 healthy older human adults (aged 61–72 years) using fMRI in a double blind, counterbalanced, placebo-controlled, within-subject design. Across the group, tyrosine did not alter reactive or proactive inhibition behaviorally but did increase fronto-parietal proactive inhibition-related activation. When taking age into account, tyrosine affected proactive inhibition both behaviorally and neurally. Specifically, increasing age was associated with a greater detrimental effect of tyrosine compared with placebo on proactive slowing. Moreover, with increasing age, tyrosine decreased fronto-striatal and parietal proactive signal, which correlated positively with tyrosine’s effects on proactive slowing. Concluding, tyrosine negatively affected proactive response slowing and associated fronto-striatal activation in an age-dependent manner, highlighting the importance of catecholamines, perhaps particularly dopamine, for proactive response inhibition in older adults.

Source: Mirjam Bloemendaal, Monja Isabel Froböse, Joost Wegman, Bram Bastiaan Zandbelt, Ondine van de Rest, Roshan Cools, and Esther Aarts. “Neuro-Cognitive Effects of Acute Tyrosine Administration on Reactive and Proactive Response Inhibition in Healthy Older Adults” eNeurologicalSci (2018): 5(2): ENEURO.0035-1.7.2018.

L-Tyrosine to alleviate the effects of stress? ^*

Stress is an inescapable part of human existence and in extreme forms can cause or exacerbate psychiatric disorders, including depression, schizophrenia and posttraumatic stress disorder. Many people feel that their level of stress is above the optimal level, and this probably accounts for the large number of herbal and “natural” compounds sold over the counter in supermarkets and drug stores and sold on the web to help counteract the effects of stress. For many of these compounds, there is little or no evidence of efficacy. However, for one, L-tyrosine, the claims cannot be dismissed summarily. Any patient with even modest Web-searching skills can discover that the ability of L-tyrosine (often referred to on the Web as simply tyrosine) to alleviate the effects of stress is the subject of several publications in respectable journals over the past decade. Most of these articles originated from research units attached to the US military; other publications originated from universities and the Dutch military.

L-Tyrosine is the precursor of the catecholamines; alterations in the availability of L-tyrosine to the brain can influence the synthesis of both dopamine and norepinephrine in experimental animals and probably in humans. In animals, stress increases the release of catecholamines, which can result in the depletion of their levels, an effect that can be corrected by giving L-tyrosine. L-Tyrosine does not seem to enhance the release of catecholamines when neurons are firing at their basal rates, but it does when firing rates are increased by stress. This is the basis for studying the effect of L-tyrosine on the stress response of humans.

The main effects of L-tyrosine that have been reported are acute effects in preventing a decline in cognitive function in response to physical stress. The physical stressors include those of interest to the military, such as cold stress, the combination of cold stress and high-altitude stress (i.e., mild hypoxia), extended wakefulness and lower body negative pressure stress (designed to simulate some of the effects of space flight). Doses of L-tyrosine in these studies ranged up to 20 g, many times the normal daily dietary intake. In one study, L-tyrosine was given at a dosage of 2 g per day for 5 days during a demanding military combat training course; it improved various aspects of cognitive function relative to placebo.

Some of the papers have titles that include the words “dietary tyrosine,” even though L-tyrosine is given without the amino acids that accompany it when it is ingested as part of protein. The use of L-tyrosine in purified form ensures that it is metabolized less via protein synthesis and more by catecholamine synthesis. Given that purified L-tyrosine is handled metabolically in a somewhat different way from ingesting it as part of the diet, calling it a dietary or natural remedy is misleading. Effectively, it is being used as a drug. Safety data on long-term L-tyrosine use in healthy people is lacking. In one of the longest studies, 2.5 g L-tyrosine 3 times daily had no beneficial or adverse effects when given to people with mild essential hypertension for 2 weeks. The measures in this study were limited to heart rate and blood pressure.

Patients or healthy people feeling somewhat stressed may read claims that L-tyrosine alleviates the effects of stress. They probably imagine that L-tyrosine will help them to feel less stressed in response to the psychosocial stressors of everyday life. What has been shown is that L-tyrosine prevents some of the cognitive decline in response to physical stressors, an effect of interest to almost noone outside the military. The use of L-tyrosine cannot be recommended for patients. Patients who are already taking it need to be educated about what it has actually been shown to do and about the lack of evidence for long-term safety.

Source: Simon N. Young. “L-Tyrosine to alleviate the effects of stress?” Journal of Psychiatry and Neuroscience (2007): 32(3): 224.

Tyrosine, Phenylalanine, and Catecholamine Synthesis and Function in the Brain ^*

Abstract

Aromatic amino acids in the brain function as precursors for the monoamine neurotransmitters serotonin (substrate tryptophan) and the catecholamines [dopamine, norepinephrine, epinephrine; substrate tyrosine (Tyr)]. Unlike almost all other neurotransmitter biosynthetic pathways, the rates of synthesis of serotonin and catecholamines in the brain are sensitive to local substrate concentrations, particularly in the ranges normally found in vivo. As a consequence, physiologic factors that influence brain pools of these amino acids, notably diet, influence their rates of conversion to neurotransmitter products, with functional consequences. This review focuses on Tyr and phenylalanine (Phe). Elevating brain Tyr concentrations stimulates catecholamine production, an effect exclusive to actively firing neurons. Increasing the amount of protein ingested, acutely (single meal) or chronically (intake over several days), raises brain Tyr concentrations and stimulates catecholamine synthesis. Phe, like Tyr, is a substrate for Tyr hydroxylase, the enzyme catalyzing the rate-limiting step in catecholamine synthesis. Tyr is the preferred substrate; consequently, unless Tyr concentrations are abnormally low, variations in Phe concentration do not affect catecholamine synthesis. Unlike Tyr, Phe does not demonstrate substrate inhibition. Hence, high concentrations of Phe do not inhibit catecholamine synthesis and probably are not responsible for the low production of catecholamines in subjects with phenylketonuria. Whereas neuronal catecholamine release varies directly with Tyr-induced changes in catecholamine synthesis, and brain functions linked pharmacologically to catecholamine neurons are predictably altered, the physiologic functions that utilize the link between Tyr supply and catecholamine synthesis/release are presently unknown. An attractive candidate is the passive monitoring of protein intake to influence protein-seeking behavior.

Source: John D. Fernstrom, Madelyn H. Fernstrom. “Tyrosine, Phenylalanine, and Catecholamine Synthesis and Function in the Brain” Journal of Nutrition (2007): Volume 137, Issue 6, Pages 1539S.

Effect of tyrosine on cognitive function and blood pressure under stress ^*

Abstract

The effects of tyrosine on mood, performance, heart rate and blood pressure of 16 healthy young subjects were assessed. Subjects were tested on two separate days, one test session after ingestion of 100 mg/kg tyrosine and the other test session after placebo, in random order. While performing a number of stress sensitive tasks, subjects were exposed to a Stressor consisting of 90 dB noise. Tyrosine was found to improve the performance on two cognitive tasks, which were performed l h after administration of the medication and which could be characterized as highly sensitive to stress. In addition, tyrosine decreased diastolic blood pressure 15 min after ingestion, while l h after ingestion diastolic blood pressure was the same with tyrosine and placebo. No effects on mood, systolic blood pressure and heart rate were found.

Source: J.B Deijen, J.F Orlebeke. “Effect of tyrosine on cognitive function and blood pressure under stress” Brain Research Bulletin (1994): Volume 33, Issue 3, Pages 319-323.

 

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