Oxaloacetate Reduces Neuroinflammation

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Neuroinflammation is inflammation of the brain and nervous tissue. The common causes of chronic neuroinflammation include:

  • Aging
  • Air pollution
  • Autoimmunity
  • Microbes
  • Passive smoke
  • Toxic metabolites
  • Traumatic brain injury
  • Viruses

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls:

  • cell survival
  • cytokine production
  • transcription of DNA

NF-kB is an important factor in the inflammation pathway and if there is excessive or overly activated NF-kB, then this reaction can result in chronic inflammation not only in the nervous tissue but throughout the body.

NF-κB is involved in cellular responses to stimuli such as:

  • bacterial or viral antigens
  • cocaine
  • cytokines
  • free radicals
  • isoproterenol
  • oxidized LDL
  • stress
  • ultraviolet irradiation
  • tumor necrosis factor alpha (TNFα),
  • interleukin 1-beta (IL-1β)

NF-κB has been shown to have diverse functions in the nervous system.  Activated NF-κB can be transported retrogradely from activated synapses to the nucleus to translate short-term processes to long-term changes such as axon growth, which is important for long-term memory. 1

In glia, NF-κB is inducible and regulates inflammatory processes that exacerbate diseases such as autoimmune encephalomyelitis, ischemia, and Alzheimer’s disease. In summary, inhibition of NF-κB in glia might ameliorate disease. 2

NF-KBPathway

Abating or lowering the NF-kB protein trans-location to the nucleus when inflammation is present is one of the strategies to reducing neuroinflammation and chronic inflammation in general.

A study from December 2014 published in the Journal Human Molecular Genetics, entitled “Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis”, found among other things, that oxaloacetate reduces neuroinflammation.

Oxaloacetic acid (also known as oxalacetic acid or oxaloacetate ) is a metabolic intermediate in many processes that occur in humans and other animals. Oxaloacetate takes part in many systems within the body, such as:

  • amino acid synthesis
  • citric acid cycle
  • fatty acid synthesis
  • gluconeogenesis
  • glyoxylate cycle
  • urea cycle
Oxaloacetic_acid

Oxaloacetic acid molecule

In the December 2014 study, the researchers assessed the effects of Oxaloacetate (OAA) administration on brain inflammation.  They measured the mRNA levels for two inflammation-related genes, tumor necrosis factor α (TNFα) and C–C motif chemokine 11 (CCL11).

While hippocampal TNFα levels were comparable across the groups, hippocampal CCL11 mRNA levels were 44% lower in the group receiving 2 g/kg/day than they were in the control group (Figure 1).

The amount of nuclear factor κB (NFκB) protein was lower in the nucleus of the combined OAA treatment group (by 50%), after two weeks of OAA supplementation, and in both OAA treatment groups the nucleus-to-cytoplasm ratio was ∼70% lower than it was in the control group.  3 

 

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Figure 1:  Effect on inflammation. (A) TNFα mRNA levels were comparable. (B) CCL11 mRNA was lower in the 2 g/kg/day OAA group. (C) Nuclear NFκB protein was lower in the combined OAA group. Although the ANOVA was not significant, on post hoc analysis nuclear NFκB protein was lower in the 1 g/kg/day OAA group. (D) The NFκB nucleus:cytoplasm ratio was lower in the 1 g/kg/day, 2 g/kg/day and combined OAA groups. Values shown are relative group means ± SEM. *P < 0.05; **P < 0.005; #ANOVA comparison was not significant, but the post hoc LSD test between the specified treatment group and the control group was significant at P < 0.05.  (Source:  Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis, Hum Mol Genet. 2014 Dec 15; 23(24): 6528–6541. Published online 2014 Jul 15. doi:  10.1093/hmg/ddu371)

The researchers concluded that:

When activated, NFκB’s restraint is removed and it moves to the nucleus. Since NFκB promotes the CCL11 gene, reduced NFκB may account for lower CCL11 expression. OAA, therefore, could prove useful for treating brain diseases in which neuroinflammation occurs.”  4


 

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