Compounds that seem to improve brain hypometabolism

[apod]

I've been doing a little more digging around on pubmed, primary looking at natural compounds that seem to improve some metric of cerebral hypometabolism. Raising BDNF / NAD+ / AMPK / Ketones was a common theme, where intermittent fasting and exercise seem to check a lot of these boxes from the lifestyle front. I figured it might be nice to put these all in one spot.

* Creatine
* Pyruvate
* CDP-Choline
* DHA
* Phosphatidylserine
* Alpha Lipoic Acid
* Acetyl-L-Carnitine
* Benfotiamine
* Oxaloacetate
* Vinpocetine
* Piracetam
* L-Carnosine
* Resveratrol
* Citrus Bioflavonoids
* Quercetin
* Cinnamon
* Black Seed
* Nicotinamide Riboside / NMN
* Reishi Mushrooms
* Curcumin
* CBD
* Idebenone

Metabolic Agents that Enhance ATP can Improve Cognitive Functioning: A Review of the Evidence for Glucose, Oxygen, Pyruvate, Creatine, and L-Carnitine: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257700/
Laakso et al. demonstrated that compared with non-carriers, the levels of creatine were significantly lower in ε4 carriers. This finding may suggest increased metabolic demands in the brain of the ε4 carriers. They also observed that the levels of creatine correlated significantly with age and performance on the Mini-Mental State Examination test in the ε4 carriers, but not in the non-carriers.

Effect of Phosphatidylserine on Cerebral Glucose Metabolism in Alzheimer's Disease: https://www.karger.com/Article/Abstract/107142
Global metabolic rate increased by 14.8% following treatment. A repeated-measures ANOVA demonstrated significant increases (p < 0.01) of glucose metabolism in defined cortical and subcortical structures ranging up to 20.3% in basal ganglia/thalamus and 19.3% in visual cortex. Metabolism was also increased in areas most involved in AD (13.5–16%).

Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer's disease: a 13C NMR study: https://www.ncbi.nlm.nih.gov/pubmed/24220168
"Several clinical studies have shown Alzheimer's disease to be associated with disturbances in glucose metabolism... this hypometabolism was partially or completely restored by lipoic acid feeding. The ability of lipoic acid to restore glucose metabolism and subsequent TCA cycle-related metabolites further substantiates its role in overcoming the hypometabolic state inherent in early stages of Alzheimer's disease."

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567484/
We hypothesized that disruption of thiamine metabolism directly contributes to AD pathogenesis by perturbing glucose utilization and by activating multiple pathophysiological cascades in the brain. Based on this hypothesis, a strategy of simultaneously correcting the abnormal thiamine metabolism while treating other pathogenic factors may be a viable approach to modify the progression of AD.

Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer’s disease, whereas amyloid deposition does not: https://alzres.biomedcentral.com/articl ... 018-0354-2
To our knowledge, our study is the first to disclose that TDP reduction is a potential mediator of brain glucose hypometabolism in AD.

Trial of oxaloacetate in Alzheimer's disease (TOAD): interim FDG PET analysis: https://www.neurologyadvisor.com/aaic-2 ... le/783762/
Brain bioenergetic function is defective in AD, and may contribute to reduced glucose utilization on fluorodeoxyglucose positron emission tomography (FDG PET) scans,” the investigators reported. “Preclinical studies found oxaloacetate (OAA) enhanced brain bioenergetics and glucose flux

Brain fuel metabolism, aging and Alzheimer's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478067/
Dietary supplementation with DHA increases GLUT1 expression in the rat brain endothelial cells and astrocytes, suggesting a positive correlation between DHA level in brain membranes and glucose transporter expression in the brain. This is confirmed by in vitro studies performed on primary cultures of rat brain endothelial cells in which glucose uptake is positively correlated to DHA levels in these cells

Metabolism of acetyl-L-carnitine for energy and neurotransmitter synthesis in the immature rat brain: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949601/
A number of studies have shown that intravenous ALCAR modulates brain energy metabolism leading to increased cerebral glucose metabolism (CMRglc) in adult rats within 10–30 min of administration, and decreased brain lactate after ischemia. Although investigators have proposed that ALCAR stimulates cerebral energy metabolism by providing acetyl CoA as an oxidizable substrate to the TCA cycle, direct evidence of the metabolism of ALCAR for energy and neurotransmitter synthesis has not been reported.

27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation: http://jem.rupress.org/content/214/3/699
Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory.

The effect of vinpocetine on brain glucose uptake in mice: https://www.ncbi.nlm.nih.gov/pubmed/7152391
These results indicate that vinpocetine increases cerebral energy metabolism in mice after oral administration as well as intraperitoneal injection.

Effect of Piracetam on electrocorticogram and local cerebral glucose utilization in the rat: https://www.ncbi.nlm.nih.gov/pubmed/3569848
As this anti-hypoxidotic property could be linked to Piracetam influence on energy-metabolic processes in the brain, we studied the effect of this nootropic drug on local cerebral glucose utilization (LCGU) by means of a variant of the Sokoloff's technique. Our results showed that Piracetam enhances LCGU

Effects of various cerebral metabolic activators on glucose metabolism of brain: https://www.ncbi.nlm.nih.gov/pubmed/1098982
Citicoline enhances the incorporation of blood glucose into the brain and its metabolism in the brain

Dual effects of carnosine on energy metabolism of cultured cortical astrocytes under normal and ischemic conditions.: https://www.ncbi.nlm.nih.gov/pubmed/25195162
Carnosine may be an endogenous regulator of astrocyte energy metabolism and a clinically safe therapeutic agent for promoting brain energy metabolism recovery after ischemia/reperfusion injury.

Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats: https://www.ncbi.nlm.nih.gov/pubmed/20868700
This study provides in vivo evidence that resveratrol could exert neuroprotective effect against ischemia injury by improving brain energy metabolism

NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency: https://www.ncbi.nlm.nih.gov/pubmed/29432159
This suggests that NAD+ up-regulation can reverse the impaired brain-energy metabolism and possibly oxidative stress that are implicated in cognitive decline.

Neurometabolic Effect of Altaian Fungus Ganoderma lucidum (Reishi Mushroom) in Rats Under Moderate Alcohol Consumption: https://www.ncbi.nlm.nih.gov/pubmed/26058418
Regular administration of the Reishi suspension improved the energy supply to the brain cortex

Curcumin regulates insulin pathways and glucose metabolism in the brains of APPswe/PS1dE9 mice: https://www.ncbi.nlm.nih.gov/pubmed/28124574
Our study found that curcumin improved spatial learning and memory, at least in part, by increasing glucose metabolism and ameliorating the impaired insulin signalling pathways in the brain.

CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885828/
Additional benefits of the activation of CB2 receptors in AD may derive from the ability of these receptors to mediate glucose uptake in brain

Effects of idebenone on neurological deficits, local cerebral blood flow, and energy metabolism in rats with experimental cerebral ischemia: https://www.ncbi.nlm.nih.gov/pubmed/2764637
These results suggest that idebenone ameliorates the neurological deficits related to cerebral ischemia, and that this effect is mediated by improving cerebral energy metabolism.

Long-term naringin consumption reverses a glucose uptake defect and improves cognitive deficits in a mouse model of Alzheimer's disease: https://www.ncbi.nlm.nih.gov/pubmed/22741174

Naringin ameliorates cognitive deficits in streptozotocin-induced diabetic rats: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887715/

Naringin reverses a glucose uptake defect and improves cognitive function in the APPswe/PSΔE9 transgenic mouse model of Alzheimer’s disease

Cytoprotective effects of hesperetin and hesperidin against amyloid β-induced impairment of glucose transport through downregulation of neuronal autophagy: https://www.ncbi.nlm.nih.gov/pubmed/22383310

Treatment with hesperetin and hesperidin improved Aβ-impaired glucose utilization

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874707/
Thus hippocampal GLUT4 overexpression could be a target to improve the cognitive process in AD. This could be the case of quercetin which improves cognitive dysfunction mediated by chronic unpredicted stress, through upregulation of GLUT4 expression in the hippocampus

Cinnamon Counteracts the Negative Effects of a High Fat/High Fructose Diet on Behavior, Brain Insulin Signaling and Alzheimer-Associated Changes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862724/
The negative effects of a HF/HFr diet on brain insulin signaling and behavior were alleviated by CN suggesting neuroprotective effects of CN associated with whole body improved insulin sensitivity and related changes in the brain.

Oxidative stress and expression of insulin signaling proteins in the brain of diabetic rats: Role of Nigella sativa oil and antidiabetic drugs.: https://www.ncbi.nlm.nih.gov/pubmed/28505155
These data suggest that NSO or its combined treatments with anti-diabetic drugs have a possible benefit as disease modifying agents for the insulin resistance in the brain through enhancing brain insulin signaling pathway.

Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention: https://www.ncbi.nlm.nih.gov/pubmed/29967007
Therefore, pyruvate may provide a more efficient energy source for the ApoE4 brain by circumventing a sustained impairment in neuronal glucose utilization due to defects in glucose uptake and glycolysis

[Plumster]

Great list, apod! Thanks.

Also, I found this study on anserine and carnosine supplementation that was specifically/possibly beneficial to apoe4:

This study is the first RCT concerning the effects of ACS [anserine/carnosine supplementation] in MCI subjects. The results did not indicate that ACS has significant efficacy on cognitive change of MCI subjects but might suggest that beneficial effect in APOE4(+) MCI subjects exists, and thereby, ACS might help to prevent a transition from MCI to AD as a secondary effect in APOE4 (+) MCI subjects. Furthermore, changes in sNAT scores, which are based on the EEG analysis, may be a useful biomarker for assessing these benefits.

Full text: https://www.mdpi.com/2072-6643/11/7/1626/htm

[aphorist]

I'm partial to salsalate or acetyl-salicylic acid, found in aspirin.

Fleischman, A., Shoelson, S., Bernier, R., & Goldfine, A. (2007). Salsalate Improves Glycemia and Inflammatory Parameters in Obese Young Adults. Diabetes Care, 31(2), 289-294. doi: 10.2337/dc07-1338

Min SW, Chen X, Tracy TE, et al. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015;21(10):1154-1162. doi:10.1038/nm.3951

Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG. The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 2012 May 18;336(6083):918-22. doi: 10.1126/science.1215327. Epub 2012 Apr 19. PMID: 22517326; PMCID: PMC3399766.

Pietrocola F, Castoldi F, Markaki M, Lachkar S, Chen G, Enot DP, Durand S, Bossut N, Tong M, Malik SA, Loos F, Dupont N, Mariño G, Abdelkader N, Madeo F, Maiuri MC, Kroemer R, Codogno P, Sadoshima J, Tavernarakis N, Kroemer G. Aspirin Recapitulates Features of Caloric Restriction. Cell Rep. 2018 Feb 27;22(9):2395-2407. doi: 10.1016/j.celrep.2018.02.024. PMID: 29490275; PMCID: PMC5848858.

Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory
Dhruv Patel, Avik Roy, Madhuchhanda Kundu, Malabendu Jana, Chi-Hao Luan, Frank J. Gonzalez, Kalipada Pahan
Proceedings of the National Academy of Sciences Jul 2018, 115 (31) E7408-E7417; DOI: 10.1073/pnas.1802021115


https://www.fightaging.org/archives/201 ... lzheimers/

[TheBrain]

Wow. You've done a ton of great work here. Thanks, apod!