Abstract
Stroke is a major cause of morbidity, mortality, and disability. During ischemic stroke, a marked and prolonged rise of glutamate concentration in the brain causes neuronal cell death. This study explores the protective effect of a bioconjugate form of glutamate oxaloacetate transaminase (hrGOT), which catalyzes the depletion of blood glutamate in the bloodstream for ~6 days following a single administration. When treated with this bioconjugate, a significant reduction of the infarct volume and a better retention of sensorimotor function was observed for ischemic rats compared to those treated with saline. Moreover, the equivalent dose of native hrGOT yielded similar results to the saline treated group for some tests. Targeting the bioconjugate to the blood-brain-barrier did not improve its performance. The data suggest that the bioconjugates draw glutamate out of the brain by displacing homeostasis between the different glutamate pools of the body.
Highlights
Stroke is a major cause of morbidity, mortality, and disability
Angiopep-2 is a 19-amino acid peptide derived from the common sequence of the low-density lipoprotein receptor-related protein-1 (LRP1) ligands
GOT catalyzes the reversible reaction of L-aspartate and αketoglutarate into oxaloacetate and L-glutamate via a ping–pong mechanism, with pyridoxal 5-phosphate as an essential cofactor[17]
Summary
Stroke is a major cause of morbidity, mortality, and disability. During ischemic stroke, a marked and prolonged rise of glutamate concentration in the brain causes neuronal cell death. This study explores the protective effect of a bioconjugate form of glutamate oxaloacetate transaminase (hrGOT), which catalyzes the depletion of blood glutamate in the bloodstream for ~6 days following a single administration When treated with this bioconjugate, a significant reduction of the infarct volume and a better retention of sensorimotor function was observed for ischemic rats compared to those treated with saline. One such approach relies on exploiting the natural diffusion of cerebral glutamate across the blood–brain barrier (BBB) for therapeutic purposes This is an emerging, conceptually novel protective strategy to reduce the excitotoxic effect of excess extracellular glutamate that accumulates in the brain after ischemic damage. One major shortcoming of this approach is that the effect of hrGOT administration is short-lived (~3 h), compared with the therapeutic time window required to attenuate glutamate toxicity in brain (~6–9 h after stroke), mainly because of its rapid degradation in the body[12]. Insight into the mechanism of protection (glutamate efflux) as well as factors for improving the therapy are assessed by examining glutamate levels in the blood and cerebrospinal fluid (CSF), as well as by targeting the hrGOT bioconjugates to the BBB in order to explore a possible localized effect on the brain
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