Blood Glutamate Scavenger as a Novel Neuroprotective Treatment in Spinal Cord Injury

Abstract

Neurotrauma causes immediate elevation of extracellular glutamate (Glu) levels, which creates excitotoxicity and facilitates inflammation, glial scar formation, and consequently neuronal death. Finding factors that reduce the inflammatory response and glial scar formation, and increase neuronal survival and neurite outgrowth, are of major importance for improving the outcome after spinal cord injury (SCI). In the present study, we evaluated a new treatment aiming to remove central nervous system (CNS) Glu into the systemic blood circulation by intravenous (IV) administration of blood Glu scavengers (BGS) such as the enzyme recombinant glutamate-oxaloacetate transaminase 1 (rGOT1) and its co-substrate. In this study we induced in mice an SCI (hemisection), and 1 h post-injury started administering BGS treatment for 5 consecutive days. The treatment reduced the expression levels of p-p38, which regulates apoptosis and increased the expression of p-Akt, which mediates cell survival. Moreover, this treatment decreased pro-inflammatory cytokine expression and microglia activation, reduced astrocytes' reactivity, and facilitated expression of radial glia markers such as Pax6 and nestin. BGS treatment increased the survival of neurons at lesion site and enabled axonal regeneration into the injury site. These effects were correlated with improved functional recovery of the left paretic hindlimb. Thus, early pharmacological intervention with BGS following SCI may be neuroprotective and create a pro-regenerative environment by modulating glia cell response. In light of our results, the availability of the method to remove excess Glu from CNS without the need to deliver drugs across the blood-brain barrier (BBB) and with minimal or no adverse effects may provide a major therapeutic asset.

Sex Differences and Role of Gonadal Hormones on Glutamate Level, After Spinal Cord Injury in Rats: A Microdialysis Study

“…In other words, spinothalamic tract axons damage led to a large amount of glutamate release, in this model.The present results and the data obtained from other models of SCI in previous studies are in agreement, indicating an increase followed by a decrease in glutamate level that finally returns to near baseline level after injury. This shows the same effective mechanisms for secondary damage and glutamate release in this model and other SCI models such as contusion model (Goldshmit et al, 2018; McAdoo & Wu, 2008; Smith et al, 2002; Steward, Popovich, Dietrich, & Kleitman, 2012). Previous studies indicate a correlation between sex differences and central mechanism of feelings, pain processing, and perceptions (Mousavi et al, 2007; Naderi et al, 2014; Taylor, Tio, Paydar, & Sutton, 2018).…”

Inhibition of astrocyte hemichannel improves recovery from spinal cord injury

“…These processes elicit increased levels of extracellular molecules and ions, which include glutamate, lactate, K + , nitric oxide, arachidonate, reactive oxygen species, and ammonia. The increased extracellular levels of these species in turn create a cytotoxic postinjury environment (3,4). These factors are known to contribute to increased lesion size after SCI (5,6).…”

“…While strategies that promote axonal growth are limited, other treatment paradigms that limit secondary damage in incomplete SCIs can potentially allow patients to retain greater function postinjury. Additionally, secondary injury results in glial scar formation and neuronal cell death (3). These can be detrimental to axon regeneration and contribute to other complications that arise from SCI, such as neuropathic pain and spasticity (9).…”

Role of Ginkgolides in the Inflammatory Immune Response of Neurological Diseases: A Review of Current Literatures

“…Extracellular glutamate increased significantly after ischemia (Hsieh et al, 2017 ). And this extracellular glutamate can result in microglial activation and production of inflammatory mediators such as pro-inflammatory cytokines, adhesion molecules, and chemokines (Goldshmit et al, 2018 ). These inflammatory mediators can increase the severity of primary brain damages (Huang et al, 2018 ).…”