Supplementing with oxaloacetate, low-carb diets, and fasting may be neuroprotective against glutamate excitotoxicity, neuroinflammation, and neurodegeneration due in part to their increased usage of the malate-aspartate shuttle in and out of the mitochondrion.
Excess glutamate is one possible cause of excitotoxicity, which is basically where you overstimulate your neuron’s NMDA receptors so much that they die. A mild version of this happens when you eat monosodium glutamate (MSG) at that dodgy Chinese restaurant. The resulting headache, anxiety, and irritability that some people feel as a result of MSG exposure is an example of mild, acute excitotoxicity.
Chronic excitotoxicity can lead to chronic neuroinflammation and neurodegeneration eventually. Preventing it is a therapeutic target for preventing and slowing the progression of many disorders, including Parkinson’s, Alzheimer’s, bipolar disorders, depressive disorders, anxiety disorders like GAD and PTSD, and many others.
The kynurenine pathway can also contribute to excitotoxicity. As discussed in another post, the kynurenine pathway is triggered by stress and, if left unchecked, can lead to the accumulation of excitotoxic metabolites in the brain. Although these strategies won’t affect the kynurenine pathway directly, they should decrease the overall load of excitatory neurotransmitters, thus protecting against stress-induced excitotoxicity indirectly.
Supplementing with Oxaloacetate or Malate
In the cell’s cytosol, oxaloacetate is reduced by malate dehydrogenase and NADH to malate. An antiporter in the mitochondrial membrane then imports the malate into the mitochondrial matrix and exports an alpha-ketoglutarate out into the cytosol.
Alpha-ketoglutarate is a key intermediate in the citric acid cycle. Glutamate, the main excitatory neurotransmitter in the brain, can be converted to and from alpha-ketoglutarate. By Le Chatelier’s principle, decreasing the amount of alpha-ketoglutarate in the matrix should shunt more glutamate towards becoming alpha-ketoglutarate to maintain normal levels in the TCA cycle. If this does indeed happen in neurons, supplementing with exogenous oxaloacetate should be neuroprotective against glutamate excitotoxicity in theory.
Supplementing with malate could do the same thing in theory. However, the whole reason for the malate-aspartate shuttle is that malate is more reduced and more hydrophilic than oxaloacetate, which is more hydrophobic. That makes it easier for malate to go through the antiporter in the mitochondrial membrane, which evolved to transport hydrophilic substances. As far as I know though, there is no specific transport protein in the cell’s plasma membrane for malate, and large hydrophilic molecules can’t diffuse across a membrane without a transporter. The more hydrophobic oxaloacetate has a better chance of diffusing across the plasma membrane into the cytosol.
Indeed, Swerdlow et al. found that supplementing Alzheimer’s patients with 100mg of oxaloacetate daily was safe and appeared to raise serum levels modestly, but it wasn’t clear how significant that increase was or whether that meant any of it was getting into cells where it matters (Swerdlow 2016).
That being said, oxaloacetate probably isn’t hydrophobic enough to diffuse easily. An effective therapeutic strategy would probably require a drug delivery device like a liposome to get it across the plasma membrane, in which case you could put either oxaloacetate or malate in the liposome.
However, oxaloacetate still has the slight advantage that it oxidizes one more NADH to get turned into malate. In today’s Calorie-saturated environment, it’s important to take every chance possible to burn extra energy.
Triggering Gluconeogenesis via Fasting or Low-Carb & Ketogenic Diets
Fasting, low-carb diets, and ketogenic diets probably may achieve the same effect without supplementation. In situations of low blood glucose, the hormone glucagon is released. Glycolysis slows down and gluconeogenesis, the creation of new glucose, speeds up.
To perform gluconeogenesis, malate is converted into aspartate. To do this, a molecule of glutamate must donate its amino group and be converted into an alpha-ketoglutarate.
Doing this in the brain (by inducing glutamate oxaloacetate aminotransferase 1, aka GOT) may prevent brain damage after an ischemic stroke. This is partly because it would reduce toxic extraneuronal glutamate levels, but also because it would regenerate TCA cycle intermediates, helping to provide the brain with enough energy from an alternative fuel source (Khanna 2015).
This hypothesis was supported by evidence in neuronal cell cultures and a transgenic mouse model of ischemic stroke. Mice that overexpressed the GOT enzyme had “not only reduced ischemic stroke lesion volume but also attenuated neurodegeneration and improved poststroke sensorimotor function (Khanna 2017).”
For now though, let’s assume that we’re not going to genetically engineer ourselves with CRISPR to overexpress the GOT enzyme like those mice. Can we hack our metabolism naturally to achieve a similar result?
Gluconeogenesis is performed almost exclusively in the liver and the to a lesser extent in the kidney, not the brain. So by triggering gluconeogenesis with fasting or a low-carb diet, you would actually be decreasing peripheral glutamate concentrations, not in the brain directly. However, glutamate is transported across the blood brain barrier (Smith 2000). So in theory, it’s plausible that decreasing peripheral glutamate would pull glutamate out of the brain to equilibrate the concentrations on either side of the blood brain barrier slightly. There is evidence that brain-to-blood glutamate efflux does increase if you administer oxaloacetate to stroke victims intravenously (Nagy 2009).
A slight decrease in glutamate is all we want in most cases anyway, since too little glutamate is also a problem (think narcolepsy). Like most things in biology, the goal is balance.
If this line of reasoning holds up (which most of it appears to from my preliminary look at the literature), anything that increases gluconeogenesis should be mildly protective against excitotoxicity.
Have any evidence for or against this hypothesis? Want to call shenanigans on my speculations? Leave and comment and let me know!
- Swerdlow RH, Bothwell R, Hutfles L, Burns JM, Reed GA. Tolerability and pharmacokinetics of oxaloacetate 100mg capsules in Alzheimer’s subjects. BBA Clin. 2016;5:120-123. doi:10.1016/j.bbacli.2016.03.005.
- Smith QR. Transport of glutamate and other amino acids at the blood-brain barrier. J Nutr. 2000;130(4S Suppl):1016S-22S.
- Nagy D, Marosi M, Kis Z, et al. Oxaloacetate Decreases the Infarct Size and Attenuates the Reduction in Evoked Responses after Photothrombotic Focal Ischemia in the Rat Cortex. Cell Mol Neurobiol. 2009;29(6-7):827-835. doi:10.1007/s10571-009-9364-8.
- http://www.ncbi.nlm.nih.gov/pubmed/10736373. Accessed May 14, 2017.
- Rink C, Gnyawali S, Stewart R, et al. Glutamate oxaloacetate transaminase enables anaplerotic refilling of TCA cycle intermediates in stroke-affected brain. FASEB J. 2017;31(4):1709-1718. doi:10.1096/fj.201601033R.
- Khanna S, Briggs Z, Rink C. Inducible Glutamate Oxaloacetate Transaminase as a Therapeutic Target Against Ischemic Stroke. Antioxid Redox Signal. 2015;22(2):175-186. doi:10.1089/ars.2014.6106.
Disclaimer: As always, none of this should be construed as medical advice. Consult your primary healthcare provider before changing any aspect of your medical care.