Abstract
We have recently shown that pharmacological blockade of mGlu2 metabotropic glutamate receptors protects vulnerable neurons in the 4-vessel occlusion model of transient global ischemia, whereas receptor activation amplifies neuronal death. This raised the possibility that endogenous activation of mGlu2 receptors contributes to the pathophysiology of ischemic neuronal damage. Here, we examined this possibility using two models of transient focal ischemia: (i) the monofilament model of middle cerebral artery occlusion (MCAO) in mice, and (ii) the model based on intracerebral infusion of endothelin-1 (Et-1) in rats. Following transient MCAO, mGlu2 receptor knockout mice showed a significant reduction in infarct volume and an improved short-term behavioural outcome, as assessed by a neurological disability scale and the “grip test”. Following Et-1 infusion, Grm2 gene mutated Hannover Wistar rats lacking mGlu2 receptors did not show changes in the overall infarct volume as compared to their wild-type counterparts, although they showed a reduced infarct area in the agranular insular cortex. Interestingly, however, mGlu2 receptor-deficient rats performed better than wild-type rats in the adhesive tape test, in which these rats did not show the laterality preference typically observed after focal ischemia. These findings support the hypothesis that activation of mGlu2 receptors is detrimental in the post-ischemic phase, and support the use of mGlu2 receptor antagonists in the experimental treatment of brain ischemia.
Highlights
Metabotropic glutamate receptors have been implicated in mechanisms of neurodegeneration/neuroprotection, and are promising drug targets for the treatment of acute and chronic neurodegenerative disorders [1]
Using the 4-vessel occlusion model of transient global ischemia, we found that post-ischemic systemic treatment with a selective negative allosteric modulator (NAM) of mGlu2 receptors protected vulnerable hippocampal CA1 pyramidal neurons, whereas treatment with a positive allosteric modulator (PAM) of mGlu2 receptors extended the damage to resistant CA3 pyramidal neurons [12]
Our data suggest that endogenous activation of mGlu2 receptors is detrimental for the short-term outcome of transient focal ischemia, and support the hypothesis that pharmacological blockade of mGlu2 receptors is a valuable strategy for the treatment of brain ischemia
Summary
Metabotropic glutamate (mGlu) receptors have been implicated in mechanisms of neurodegeneration/neuroprotection, and are promising drug targets for the treatment of acute and chronic neurodegenerative disorders [1]. It is necessary to extend the study of mGlu receptors to models of transient focal ischemia that more closely mimic thromboembolic stroke in humans, such as the models of transient middle cerebral artery occlusion (MCAO) induced by filament insertion in mice [14] and intracerebral endothelin-1 (Et-1) infusion in rats [15]. We used these two models respectively in mGlu receptor knockout mice (mGlu2−/−) and in Hannover Wistar rats (Han Wistar rats) [16, 17] lacking mGlu receptors to examine the influence of mGlu receptors on the short-term histological and behavioural outcome of transient focal ischemia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
