Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment

Abstract

Background/Aim: The sporadic form of the disease affects the majority of amyotrophic lateral sclerosis (ALS) patients. The role of glutamate (Glu) excitotoxicity in ALS has been extensively documented and remains one of the prominent hypotheses of ALS pathogenesis. In light of this evidence, the availability of a method to remove excess Glu from brain and spinal cord extracellular fluids without the need to deliver drugs across the blood-brain barrier and with minimal or no adverse effects may provide a major therapeutic asset, which is the primary aim of this study. Methods: The therapeutic efficacy of the combined treatment with recombinant Glu-oxaloacetate-transaminase (rGOT) and its co-factor oxaloacetic acid (OxAc) has been tested in an animal model of sporadic ALS. Results: We found that OxAc/rGOT treatment provides significant neuroprotection to spinal cord motor neurons. It also slows down the development of motor weakness and prolongs survival. Conclusion: In this study we bring evidence that the administration of Glu scavengers to rats with sporadic ALS inhibited the massive death of spinal cord motor neurons, slowed the onset of motor weakness and prolonged survival. This treatment may be of high clinical significance for the future treatment of chronic neurodegenerative diseases.

Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: Longitudinal studies

“…experiments this system was supplemented by systemic injection of both oxaloacetate and rGOT, neither of which cross the blood brain barrier to any significant extent (Boyko et al, 2012;Hassel et al, 2002). Blood-based glutamate scavengers preferentially promote excess glutamate clearance from the brain by increasing the concentration gradient between the blood and luminal side of endothelial cells in cerebral blood vessels, which in turn promotes removal of any excess glutamate in the brain's interstitial fluid (Castillo et al, 2016;Cohen-Kashi-Malina et al, 2012;Gottlieb et al, 2003;Ruban et al, 2015). (Castillo et al, 2016;Gottlieb et al, 2003;Zlotnik et al, 2007).…”

“…The dose of recombinant glutamate-oxaloacetate transaminase type 1 (rGOT) (Megazyme, Bray, Ireland) given (0.39 mg/rat i.v.) was previously reported to significantly increase GOT serum concentration for over 20 h (Ruban et al, 2015). Treatment (s.c.) with rGOT started immediately after i.c.v.…”

“…Next we attempted to enhance the blood-scavenging effect of oxaloacetate by increasing the blood concentration of GOT using recombinant protein type 1 (rGOT) (Perez-Mato et al, 2014;Ruban et al, 2015;Zlotnik et al, 2007). We previously reported that co-treatment with rGOT (0.39 mg/rat) prolonged the oxaloacetate-mediated reduction in serum glutamate clearance and the abrogation of the acute deleterious effect of Aß on LTP (Zhang et al, 2016).…”

“…15 excitotoxicity in an amyotrophic lateral sclerosis model (Ruban et al, 2015). Therefore in addition to acutely injecting blood-based glutamate scavengers i.v.…”

“…Consistent with a key role for glutamate-mediated synaptotoxic mechanisms, postmortem glutamatergic synaptic loss is a very strong morphological correlate of cognitive impairment in Alzheimer's disease (Davies et al, 1987;DeKosky and Scheff, 1990;Overk and Masliah, 2014;Terry et al, 1991). Indeed, there is now convincing evidence for a causal role for amyloid-ß (Aß) at the early stages of Alzheimer's disease and oligomeric Aß, which is a potent synaptotoxin, associates with disease (Bilousova et al, 2016;Cohen et al, 2015;Dohler et al, 2014;Lesne et al, 2013;Mc Donald et al, 2010).…”