Lack of alpha 1b-adrenergic receptor protects against epileptic seizures.
OBJECTIVE
The role of alpha 1b-adrenergic receptor (alpha 1b-AR) in relation with neuronal degeneration, drug addiction, and seizure susceptibility has recently emerged. In particular, mice that overexpress alpha 1b-AR undergo spontaneous epileptic seizures and progressive neuronal loss in a variety of brain areas. Therefore, one should expect that the blockade of alpha 1b-AR leads to anticonvulsant and neuroprotective effects. However, the lack of alpha 1b-AR antagonists does not allow testing of this hypothesis.


METHODS
The development of alpha 1b-AR knockout (KO) mice led us to measure seizure susceptibility and neurodegeneration following systemic excitotoxins in these mice.


RESULTS
We found that alpha 1b-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 alpha 1b-AR KO, neuronal degeneration never occurs.


CONCLUSIONS
These data indicate that alpha 1b-AR per se plays a fundamental role in the mechanisms responsible for seizure onset, severity, and duration, whereas the brain damage observed in alpha 1b-AR-overexpressing mice is likely to be a secondary phenomenon. In fact, the absence of alpha 1b-AR confers resistance to neurotoxicity induced by seizures/chemoconvulsants. These data, although confirming a pivotal role of alpha 1b-AR in modulating seizure threshold and neuronal death, offer a novel target, which may be used to develop novel anticonvulsants and neuroprotective agents.
Pizzanelli
Chiara
C
Unit of Neurophysiopathology, Hospital F. Lotti, Pontedera, Pisa, Italy.
Lazzeri
Gloria
G
Fulceri
Federica
F
Giorgi
Filippo S
FS
Pasquali
Livia
L
Cifelli
Giuseppe
G
Murri
Luigi
L
Fornai
Francesco
F
D000818:Animals; D001921:Brain / Q000473:pathology; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012720:Severity of Illness Index
C547717:Adra1b protein, mouse; D021122:Protein Subunits; D018340:Receptors, Adrenergic, alpha-1