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Post‐ischemic administration of nimodipine following focal cerebral ischemic‐reperfusion injury in rats alleviated excitotoxicity, neurobehavioural alterations and partially the bioenergetics
Author(s) -
Babu Chidambaram Saravana,
Ramanathan Muthiah
Publication year - 2011
Publication title -
international journal of developmental neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.761
H-Index - 88
eISSN - 1873-474X
pISSN - 0736-5748
DOI - 10.1016/j.ijdevneu.2010.08.001
Subject(s) - excitotoxicity , neuroprotection , bioenergetics , ischemia , glutamate receptor , anesthesia , pharmacology , medicine , brain ischemia , reperfusion injury , nimodipine , endocrinology , chemistry , calcium , biochemistry , mitochondrion , receptor
The present study focuses on the temporal calcium significance in middle cerebral artery occluded (2 h ischemia)–reperfused (70 h reperfusion) rats treated with nimodipine (NM) through concurrent measurements of excitotoxicity, bioenergetics and neurobehavioural paradigms. Further, the suitable therapeutic time window of calcium channel antagonism in stroke was also ascertained. NM (5 mg/kg, i.p.) was administered at pre (30 min before the induction of ischemia), during (1 h following occlusion of MCA) and post‐ischemic (3 h after begin of reperfusion) states. The magnitude of neuroprotection in terms of excitotoxicity (glutamate, glutamine synthetase, Na + K + ATPase), bioenergetics (ATP, NAD + ) and neurobehavioural paradigms (neurological score and open field exploratory behaviour) were measured and compared to ensure the therapeutic time‐window of NM in stroke. Middle cerebral artery occlusion‐reperfusion (MCAO/R) was found to elevate glutamate, glutamine synthetase levels and deplete Na + K + ATPase activity in the vehicle treated group (IR group). Significant decrease in bioenergetics such as ATP and NAD + levels was also observed. Further, IR group demonstrated grievous oxidative stress (increase in lipid peroxidation, protein carbonyl content, nitrite/nitrate levels and decrease in superoxide dismutase and glutathione levels) along with anxiogenic behaviour, neurological deficits and neuronal damage and decreased nuclear to cytoplasm ratio in CA1 hippocampal region. Post‐ischemic NM administration reversed the excitotoxicity, neurobehavioural and histopathological alterations significantly, but it restored bioenergetics level in MCAO/R rats only partially. These findings were further confirmed with the combination treatment (CT) of post‐ischemic NM and pre‐ischemic memantine (MN) administration, since MN showed protective effect in the pre‐ischemic administration (Babu and Ramanathan, 2009). The failure of NM to forefend the neurodegeneration on pre‐ and during‐ischemic administration suggests that the initial phase damages in ischemic‐reperfusion (IR) might be mediated through other mechanism(s) such as glutamergic overstimulation or reverse operation of glutamate transporters. From the present study, it is concluded that calcium plays a crucial role in post‐ischemic status and the suitable therapeutic time window of calcium antagonism is the post‐ischemic state.