Protection of focal ischemic infarction by rilmenidine in the animal: Evidence that interactions with central imidazoline receptors may be neuroprotective

Rilmenidine and idazoxan reduce the volume of focal ischemic infarctions produced by occlusion of the middle cerebral artery in the rat by 33% and 29%, respectively, by preserving neurons within the ischemic penumbra. In contrast, the α₂-selective antagonist SKF-86466 is without effect. The neuroprotective action of rilmenidine is dose dependent and parallels its antihypertensive actions. Neuroprotection cannot be attributed to changes in cerebral blood flow. We conclude that the neuroprotection produced by rilmenidine is attributable to an interaction with imidazoline receptors (IRs). However, the mechanism of action is not obvious. If it results from an action within the penumbra (direct), it is mediated by mitochondrial I-2 receptors on astrocytes, since cortical neurons are devoid of IRs. Neuroprotection might occur by selectively stimulating Ca²⁺ uptake into astrocytes, and thereby reducing Ca²⁺ uptake into neurons. Alternatively, rilmenidine may act indirectly to activate pathways in the brain that are neuroprotective. Neuroprotection may be a therapeutic target for rilmenidine and allied agents that act at central IRs.