Putative mechanisms of cortical spreading depression-induced neuroprotection.

Abstract

Cortical spreading depression (CSD) has been shown to infer protection against ischemia, though the mechanism by which it acts has yet to be determined. It is hypothesized that the reversal of the glial glutamate transporters are primarily responsible for the majority of glutamate release in an ischemic situation and that the down regulation of these glutamate transporters induced by CSDs would lead to a neuroprotective effect. To determine whether or not the metabotropic glutamate receptors (mGluR) play a role in the CSD-induced down regulation of the glutamate transporters, we have pharmacologically antagonized the specific groups of mGluRs prior to the elicitation of CSD. Neither group I antagonism with AIDA, group I and II antagonism with MCPG nor group III antagonism with MAP4 prior to CSD induction revealed any effect on the plasma membrane content of GLT-1. These studies have also revealed that no down regulation of the GLT-1 transporter was seen three days post-CSD, as was previously reported (Douen et al., 2000). Though a number of factors may have contributed to these differing results, our examination of our techniques could find no conclusive evidence to either support or refute the CSD-induced down regulation of GLT-l. An examination of the molecular mechanisms that may underlie the neuroprotective effect of CSD has revealed that immediately after 2 hours of CSD, there is a significant increase in ERK phosphorylation while at the same time, no MEK, c-raf or SAPK phosphorylation was observed. These findings may lead to greater insight into the pathway by which CSD may mediate its neuroprotective effect, especially in light of the fact that ERK phosphorylation has been seen to be neuroprotective in both in vivo (Shamloo et al., 1999) and in vitro (Parrizas et al., 1997) models of neuroprotection.