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Glutamic‐Oxaloacetic Transaminase Combined with Metabolic Therapy in a Mouse Model of Amyotrophic Lateral Sclerosis
Author(s) -
Rogers Christopher Q.,
Ramirez Melissa,
Landon Carol S.,
DeBlasi Janine M.,
Koutnik Andrew P.,
D'Agostino Dominic P.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.545.5
Subject(s) - amyotrophic lateral sclerosis , excitotoxicity , riluzole , glutamate receptor , pharmacology , neuroprotection , medicine , citrate synthase , neurodegeneration , biochemistry , chemistry , disease , enzyme , receptor
Amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig's Disease is a progressive disease of neuronal degeneration in the spinal cord, brainstem and motor cortex resulting in impaired motor function and eventual demise. There is currently no widely accepted, effective treatment for this condition. Glutamate (Glu) excitotoxicity is a process in which excessive Glu‐induced stimulation of neurons can lead to their damage and death. The drug riluzole (Rilutek) is the only medication approved by the FDA for ALS. The drug appears to slow the disease's progression in some people, perhaps by reducing CNS Glu that is often present in elevated levels in ALS patients. Oxaloacetate (OX) is an anaplerotic molecule and initiation point for the activation of Kreb's Cycle. Previous work has demonstrated the ability of exogenous OX to reduce CNS Glu levels. Glutamic‐oxaloacetic transaminase (GOT) is an endogenous enzyme that catalyzes the following reaction: Glutamate + Oxaloacetate ↔ Alpha‐Ketoglutarate + Aspartate. GOT with OX has been shown to increase the removal of Glu from the blood and the CNS, thereby reducing excitotoxicity and improving neuronal health. A novel metabolic therapy known as the Deanna Protocol (DP) has been used effectively in ALS patients and mice. It consists of dietary supplements (arginine, alpha‐ketoglutarate, medium‐chain triglyceride oil, phenibut and coenzyme Q‐10) to support mitochondria and the Kreb's Cycle. Here we investigate the DP alone or in conjunction with GOT and OX as a potential therapy. Twenty ALS mice were randomly separated into four groups. Mice were singly‐housed. The control group received standard chow mash. The DP group received DP mixed with standard chow mash. The GOT/OX group received injections of GOT 3X/wk and OX mixed with standard chow mash. The DP + GOT/OX received injections of GOT 3X/wk and OX mixed in a DP‐containing chow mash. Compared to the control group, the three treatment groups each had significantly longer survival times, improved motor performance, and better neurological scores. The treatments were neither additive nor synergistic, suggesting unique therapeutic effects derived from each treatment. These findings suggest that the DP and/or GOT/OX treatment may have therapeutic application in patients with ALS and perhaps other neurologic disorders. Support or Funding Information This study was supported by Winning the Fight against Neurodegenerative Diseases grant #111990. Oxaloacetate kindly provided by Alan Cash. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .