Neuroprotective activity of antazoline against neuronal damage induced by limbic status epilepticus.
Imidazoline drugs exert neuroprotective effects in cerebral ischaemia models. They also have effects against mouse cerebellar and striatal neuronal death induced by N-methyl-D-aspartate (NMDA) through the blockade of NMDA currents. Here, we investigated the effects of antazoline on NMDA toxicity and current in rat hippocampal neuronal cultures, and on an in vivo model of status epilepticus. In hippocampal cultures, antazoline (30 microM) decreased NMDA-mediated neurotoxicity and also blocked the NMDA current with voltage-dependent and fast-reversible action (inhibition by 85+/-3% at -60 mV). Status epilepticus was induced by injecting pilocarpine (200 nmol) directly into the right pyriform cortex of male adult rats. The rats then received immediately three consecutive i.p. injections at 30-min intervals of either PBS (control group) or antazoline at 10 mg/kg (low-dose group) or at 45 mg/kg (high-dose group). During the 6-h recording, status epilepticus lasted more than 200 min in all groups. In the high-dose group only, seizures completely ceased 1 h after the third injection of antazoline, then started again 1 h later. Rats were killed 1 week later, and Cresyl Violet-stained sections of their brain were analysed for damage quantification. On the ipsilateral side to the pilocarpine injection, pyriform cortex and hippocampal CA1 and CA3 areas were significantly protected in both antazoline-treated groups, whilst prepyriform and entorhinal cortices were only in the high-dose group. On the contralateral side to the pilocarpine injection, only the hippocampal CA3 area was significantly protected in the low-dose group, but all investigated structures were in the high-dose group. In conclusion, antazoline is a potent neuroprotective drug in different models of neuronal primary culture, as previously shown in striatal and cerebellar granule neurons [Neuropharmacology 39 (2000) 2244], and here in hippocampal neurons. Antazoline is also neuroprotective in vivo in the intra-pyriform pilocarpine-induced status epilepticus model.
Milhaud
D
D
CNRS UPR 2580, Laboratoire de Génomique Fonctionnelle 141 rue de la Cardonille, F-34094 Montpellier 5, France.
Rondouin
G
G
Lerner-Natoli
M
M
Bockaert
J
J
Lafon-Cazal
M
M
D000818:Animals; D000831:Animals, Newborn; D000865:Antazoline / Q000627:therapeutic use*; D002452:Cell Count; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004553:Electric Conductivity; D004569:Electroencephalography / Q000295:instrumentation / Q000379:methods; D018690:Excitatory Amino Acid Agonists; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000008:administration & dosage; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010862:Pilocarpine / Q000008:administration & dosage; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications*; D013997:Time Factors; D020196:Trauma, Nervous System / Q000209:etiology / Q000517:prevention & control*
D018690:Excitatory Amino Acid Agonists; D006634:Histamine H1 Antagonists; D018721:Muscarinic Agonists; D010862:Pilocarpine; D016202:N-Methylaspartate; D000865:Antazoline