Effects of alpha(2)-adrenoceptor agonists on perinatal excitotoxic brain injury: comparison of clonidine and dexmedetomidine.
BACKGROUND
A growing number of children have severe neurologic impairment related to very premature birth. Experimental data suggest that overstimulation of cerebral N-methyl-d-aspartate (NMDA) receptors caused by excessive glutamate release may be involved in the genesis of perinatal hypoxic-ischemic brain injury. alpha(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 microg/kg), dexmedetomidine (1-30 microg/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 microm 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 microm; P < 0.01) and clonidine (-37 +/- 19% at 100 microm; P < 0.01) as compared with controls. In both models, the selective alpha2-adrenoceptor antagonist yohimbine abolished the neuroprotective effect of clonidine and dexmedetomidine.


CONCLUSIONS
Clonidine and dexmedetomidine are potent neuroprotectors that act by stimulating the alpha(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.
Laudenbach
Vincent
V
Laboratoire de Neurologie du Développement, Institut National de la Santé de la Recherche Médicale E9935, Hôpital Robert Debré, Paris, France. vlaudenb@infobiogen.fr
Mantz
Jean
J
Lagercrantz
Hugo
H
Desmonts
Jean-Marie
JM
Evrard
Philippe
P
Gressens
Pierre
P
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology*; D020927:Dexmedetomidine / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005260:Female; D007051:Ibotenic Acid / Q000494:pharmacology; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy
D000316:Adrenergic alpha-Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D020927:Dexmedetomidine; D003000:Clonidine