Oxaloacetate Activates Brain Mitochondrial Biogenesis, Enhances the Insulin Pathway, Reduces Inflammation, and Stimulates Neurogenesis

All these good things happening to strokes in mice. Whom is going to test this out in humans? Or are survivors going to have to become their own guinea pigs because the stroke medical world is too afraid to do anything other that the failed status quo?
http://hmg.oxfordjournals.org/content/early/2014/07/14/hmg.ddu371.abstract

1. Heather M. Wilkins1,2,
2. Janna L. Harris3,
3. Steven M. Carl2,
4. E Lezi4,
5. Jianghua Lu1,
6. J. Eva Selfridge5,
7. Nairita Roy5,
8. Lewis Hutfles2,
9. Scott Koppel2,
10. Jill Morris1,2,
11. Jeffrey M. Burns1,2,5,
12. Mary L. Michaelis2,6,
13. Elias K. Michaelis2,6,
14. William M. Brooks1,2,3 and
15. Russell H. Swerdlow1,2,5,7,*

+ Author Affiliations

1. ¹Department of Neurology
2. ²University of Kansas Alzheimer's Disease Center
3. ³Hoglund Brain Imaging Center
4. ⁴Department of Rehabilitation Medicine
5. ⁵Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160 USA
6. ⁶Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045 USA
7. ⁷Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA

1. ↵*Corresponding author: Russell H. Swerdlow, MD, University of Kansas School of Medicine, MS 2012, Landon Center on Aging, 3901 Rainbow Blvd, Kansas City, KS 66160, E-mail: rswerdlow@kumc.edu

• Received May 31, 2014.
• Revision received July 2, 2014.
• Accepted July 8, 2014.

Abstract

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies, and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA), affects brain bioenergetics, insulin signaling, inflammation, and neurogenesis we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions, or post-translational modifications of mRNA and proteins (PGC1α, PRC, NRF1, TFAM, COX4I1, CREB, p38 MAPK, and AMPK) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mTOR, and P70S6K phosphorylation. OAA lowered NFκB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal VEGF mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts, and neurite length increased in OAA-treated mice. ¹H-MRS showed OAA increased brain lactate, GABA, and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation, and activates hippocampal neurogenesis.