Effects of α2-Adrenoceptor Agonists on Perinatal Excitotoxic Brain Injury

Abstract

Background: A growing number of children have severe neurologic impairment related to very premature birth. Experimental data suggest that overstimulation of cerebral N-methylD-aspartate (NMDA) receptors caused by excessive glutamate release may be involved in the genesis of perinatal hypoxic–ischemic brain injury. ␣2-Adrenoceptor agonists are protective in models of brain ischemia in adults. The authors sought to determine whether they prevent perinatal excitotoxic neuronal damage. Methods: Five-day-old mice were allocated at random to clonidine (4 – 400 ␮g/kg), dexmedetomidine (1–30 ␮g/kg), or saline injected intraperitoneally before an intracerebral stereotactic injection of the NMDA receptor agonist ibotenate; cortical and white matter lesions were quantified 5 days later by histopathologic examination. Cortical neuron cultures exposed to 300 ␮M NMDA were used to evaluate the effects of clonidine or dexmedetomidine on neuronal death assessed by counting the number of pycnotic nuclei after fluorescent chromatin staining. Results: In vivo, both clonidine and dexmedetomidine induced significant concentration-dependent reductions in the size of ibotenate-induced lesions in the cortex and white matter. In vitro, the number of neurons damaged by NMDA exposure was significantly decreased by both dexmedetomidine (؊28 ؎ 12% at 10 ␮M; P <0.01) and clonidine (؊37 ؎ 19% at 100 ␮M; P <0.01) as compared with controls. In both models, the selective ␣2-adrenoceptor antagonist yohimbine abolished the neuroprotective effect of clonidine and dexmedetomidine. Conclusions: Clonidine and dexmedetomidine are potent neuroprotectors that act by stimulating the ␣2 adrenoceptors. These results obtained in a murine model of perinatal excitotoxic injury may be relevant to some forms of neonatal brain damage in humans.