Abstract
Glutamate (Glu) plays a key role in excitotoxicity-related injury in cerebral ischemia. In the brain, Glu homeostasis depends on Glu transporters, including the excitatory amino acid transporters and the cysteine/Glu antiporter (xc-). We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia. We compared the effects of these drugs on brain infarct volume, neurological deficits and the mRNA and protein expression of the Glu transporter-1 (GLT-1) and xc- with the effects of ischemic preconditioning and chemical preconditioning using 3-nitropropionic acid. Administration of CEF and NAC significantly reduced infarct size and neurological deficits caused by a 90-min MCAO. These beneficial effects were accompanied by changes in GLT-1 expression caused by a 90-min MCAO at both the mRNA and protein levels in the frontal cortex, hippocampus, and dorsal striatum. Thus, the results of this study suggest that the regulation of GLT-1 and xc- plays a role in the development of cerebral tolerance to ischemia and that this regulation may be a novel approach in the therapy of brain ischemia.
Highlights
IntroductionExcitotoxicity related to excessive glutamate (Glu) release plays an important role in the pathophysiology of brain ischemia (Globus et al 1991)
We hypothesized that drugs acting on Glu transporters, such as ceftriaxone (CEF, 200 mg/kg, i.p.) and N-acetylcysteine (NAC, 150 mg/kg, i.p.), administered repeatedly for 5 days before focal cerebral ischemia in rats and induced by a 90-min middle cerebral artery occlusion (MCAO), may induce brain tolerance to ischemia
Excitotoxicity related to excessive glutamate (Glu) release plays an important role in the pathophysiology of brain ischemia (Globus et al 1991)
Summary
Excitotoxicity related to excessive glutamate (Glu) release plays an important role in the pathophysiology of brain ischemia (Globus et al 1991). The glial high-affinity glutamate transporter 1 (GLT-1) and the cysteine/Glu antiporter xc- cooperate to actively regulate the concentration of extracellular Glu (Danbolt 2001; Sato et al 1999). Brain ischemia is accompanied by a massive release of Glu; the role of both GLT-1 and xc- in this phenomenon is important. Modulation of the glutaminergic system is associated with ischemic preconditioning (IP). In this process, the brain develops a tolerance to severe, damaging ischemia by previous exposure to lowintensity and potentially damaging agents such as shortterm ischemia. But deleterious, global brain ischemia decreased GLT-1 protein expression (Raghavendra Rao et al 2000), whereas IP upregulated GLT-1
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