Lack of α1b‐adrenergic receptor protects against epileptic seizures

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.