Genetic deletion of mGlu2 metabotropic glutamate receptors improves the short-term outcome of cerebral transient focal ischemia

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.

Genetic Deletion of mGlu3 Metabotropic Glutamate Receptors Amplifies Ischemic Brain Damage and Associated Neuroinflammation in Mice

“…Using the four-vessel occlusion model of transient global ischemia in rats, we have shown that selective pharmacological activation of mGlu2 receptors amplified hippocampal damage, whereas mGlu2 receptor blockade was neuroprotective (19). Similar findings were obtained using mice lacking mGlu2 receptors, in which the infarct size was enhanced in response to transient focal ischemia (20). To our knowledge, there are no studies on mGlu3 receptors and brain ischemia, although the selective activation of mGlu3 receptors was shown to be neuroprotective in in vitro studies (17,(21)(22)(23)(24).…”

“…The infarct area was outlined at a magnification of ×2.5, and it was quantified using Scion Image software (NIH, Bethesda, MD, USA). Then, the volume was calculated by integrating the cross-sectional area of damage on each stained section and the distance between them (20,30).…”

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

“…Suboptimal neuroprotective effects of orthosteric mGlu2/3 receptor agonists have been observed in animal models of global and focal brain ischemia ( Bond et al, 1998 ; Bond et al, 2000 ), probably due to the involvement of mGlu2 receptors expressed in neurons ( Corti et al, 2007 ; Motolese et al, 2015 ; Mastroiacovo et al, 2017 ). However, the role of microglial mGlu2 receptor in stroke ischemia has not been fully elucidated.…”

Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1

“…PKD1 floxed and PKD1-KO mice littermates brain vascular anatomy was analyzed as described 61 . Briefly, mice were anesthetized by an i.p.…”