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Keywords:

  • Epilepsy;
  • α1b-Adrenergic receptor;
  • Noradrenaline;
  • Neurodegeneration;
  • Sensitization;
  • Methylenedioxymethamphetamine

Summary

Purpose: The role of α1b-adrenergic receptor (α1b-AR) in relation with neuronal degeneration, drug addiction, and seizure susceptibility has recently emerged. In particular, mice that overexpress α1b-AR undergo spontaneous epileptic seizures and progressive neuronal loss in a variety of brain areas. Therefore, one should expect that the blockade of α1b-AR leads to anticonvulsant and neuroprotective effects. However, the lack of α1b-AR antagonists does not allow testing of this hypothesis.

Methods: The development of α1b-AR knockout (KO) mice led us to measure seizure susceptibility and neurodegeneration following systemic excitotoxins in these mice.

Results: We found that α1b-AR KO mice are markedly resistant to kainate- and pilocarpine-induced seizures. Moreover, when marked seizure duration and severity are obtained by doubling the dose of chemoconvulsants in α1b-AR KO, neuronal degeneration never occurs.

Conclusions: These data indicate that α1b-AR per se plays a fundamental role in the mechanisms responsible for seizure onset, severity, and duration, whereas the brain damage observed in α1b-AR–overexpressing mice is likely to be a secondary phenomenon. In fact, the absence of α1b-AR confers resistance to neurotoxicity induced by seizures/chemoconvulsants. These data, although confirming a pivotal role of α1b-AR in modulating seizure threshold and neuronal death, offer a novel target, which may be used to develop novel anticonvulsants and neuroprotective agents.