Blood Glutamate Scavenging as a Novel Neuroprotective Treatment for Paraoxon Intoxication

Abstract

Organophosphate-induced brain damage is an irreversible neuronal injury, likely because there is no pharmacological treatment to prevent or block secondary damage processes. The presence of free glutamate (Glu) in the brain has a substantial role in the propagation and maintenance of organophosphate-induced seizures, thus contributing to the secondary brain damage. This report describes for the first time the ability of blood glutamate scavengers (BGS) oxaloacetic acid in combination with glutamate oxaloacetate transaminase to reduce the neuronal damage in an animal model of paraoxon (PO) intoxication. Our method causes a rapid decrease of blood Glu levels and creates a gradient that leads to the efflux of the excess brain Glu into the blood, thus reducing neurotoxicity. We demonstrated that BGS treatment significantly prevented the peripheral benzodiazepine receptor (PBR) density elevation, after PO exposure. Furthermore, we showed that BGS was able to rescue neurons in the piriform cortex of the treated rats. In conclusion, these results suggest that treatment with BGS has a neuroprotective effect in the PO intoxication. This is the first time that this approach is used in PO intoxication and it may be of high clinical significance for the future treatment of the secondary neurologic damage post organophosphates exposure.

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

“…In the past years we have developed the novel neuroprotective treatment termed BGS, which has been shown to reduce the levels of the Glu in the blood, which in turn results in an efflux of excess Glu from the CNS into the blood [10,16,29,30]. The mechanism of this process has been shown both in vitro as well as in various animal models where Glu levels were reduced in the CNS upon BSG treatment.…”

“…We have previously proven this using a rat model, where only animals whose blood Glu levels were reduced as a result of treatment with the oxaloacetate showed an efflux of radiolabeled Glu from the brain into the blood [31]. Similarly, in our recent studies that used a paraoxon intoxication model, and in an ischemic stroke model, the levels of Glu in the blood have been shown to be substantially reduced upon treatment with BGS [16,29]. …”

“…This approach turned out to be extremely effective in providing neuroprotection in animal models of acute excitotoxic conditions such as traumatic brain injury [30], stroke [13] and paraoxon intoxication [29,30]. The neuroprotection was detected in terms of neurological and behavioral tests, as well as in histological sections.…”

“…Therefore, we developed an alternative strategy in which excess Glu is removed from the brain interstitial fluid into the systemic blood circulation following the administration of a blood Glu scavenger (BGS) such as oxaloacetic acid (OxAc) [29,30]. BGS activate the blood resident enzyme Glu-oxaloacetate transaminase (GOT), thereby decreasing the levels of blood Glu and increasing the driving force for the efflux of excess and deleterious Glu from the brain interstitial fluid into the blood.…”

Glutamate Efflux at the Blood–Brain Barrier: Cellular Mechanisms and Potential Clinical Relevance

“…This study represents cerebrospinal fluid-to-blood transport and cannot be directly related to glutamate efflux across the BBB. However, the study inspired several investigations of the effects of blood-glutamate scavenging during pathological conditions such as ischemia (19,53e55), subarachnoid hemorrhage (56), closed head injury (57,58), traumatic brain injury (59) and paraoxon intoxication (60). The studies utilized different approaches to lower blood L-glutamate levels, all based on increasing L-glutamate metabolism either by inducing GOT or GPT and/or by direct intravenous injection of the same enzymes.…”