Neuroprotection against ischemic/hypoxic brain damage: blockers of ionotropic glutamate receptor and voltage sensitive calcium channels.
The growing number of cellular and molecular pathways believed to be involved in mechanisms of ischemic cell death in the brain has spurred a similar growth in the number of potential neuroprotective modalities, the majority of which are pharmacological in nature. Preventing or minimizing the first few steps in the cascade of events leading to ischemic cell death would have a more profound effect on the postischemic outcome than intervention at later steps in that cascade. This logic is, of course, at the heart of the urgency in providing the stroke or cardiac arrest patient with the earliest possible neuroprotective treatment. For the purpose of assessing potential neuroprotective modalities, the use of a well-established cerebral hypoxic/ischemic model system is a prerequisite. In our studies, we have used two major approaches, in vitro and in vivo. We evaluated both agonists and antagonists of ionotropic glutamate receptor channels (IGRC) and their effects in exacerbating and attenuating, respectively, the posthypoxic/ischemic outcome. Other drugs were tested for their ability to block the L-type voltage-sensitive calcium channels (VSCC), which are responsible for calcium influx and overload upon hypoxia/ischemia. These two membrane protein entities, the IGRC and the VSCC, are believed to be involved in the early stages of the cellular cascade that leads to the demise of neurons posthypoxia/ischemia. Some of the drugs were also tested for possible interaction with each other searching for possible synergy. These and other published studies in the field are reviewed here.