Carnosine inhibits pentylenetetrazol-induced seizures by histaminergic mechanisms in histidine decarboxylase knock-out mice.
In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type (WT) mice to elucidate the possible role of carnosine in pentylenetetrazol (PTZ)-induced seizures. In the acute PTZ challenge study, PTZ (75 mg/kg) was injected intraperitoneally (i.p.) to induce seizures. Carnosine (200, 500 or 1000 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latency for myoclonic jerks in WT mice in a dose-dependent manner. The effects of carnosine (500 mg/kg) were time-dependent and reached a peak at 1h. However, it had no significant effect on HDC-KO mice. Carnosine (500 mg/kg) also significantly elevated the thresholds in WT mice but not HDC-KO mice following intravenous (tail vein) administration of PTZ. We also found that alpha-fluoromethylhistidine substantially reversed the protective effects of carnosine in WT mice. In addition, carnosine pretreatment reduced the cortical EEG activity induced by PTZ (75 mg/kg, i.p.). These results indicate that carnosine can protect against PTZ-induced seizures and its action is mainly through the carnosine-histidine-histamine metabolic pathway. This suggests that carnosine may be an endogenous anticonvulsant factor in the brain and may be used as a new antiepileptic drug in the future.
Zhu
Yuan-Yuan
YY
Department of Pharmacology, School of Medicine, Zhejiang University, and Department of Neurology, Second Affiliated Hospital, Hangzhou 310058, China.
Zhu-Ge
Zheng-Bing
ZB
Wu
Deng-Chang
DC
Wang
Shuang
S
Liu
Lu-Ying
LY
Ohtsu
Hiroshi
H
Chen
Zhong
Z
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002336:Carnosine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006632:Histamine / Q000502:physiology*; D006640:Histidine Decarboxylase / Q000172:deficiency*; D008297:Male; D008762:Methylhistidines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010433:Pentylenetetrazole; D011930:Reaction Time / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013997:Time Factors
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D008762:Methylhistidines; C028309:alpha-fluoromethylhistidine; D006632:Histamine; D002336:Carnosine; D006640:Histidine Decarboxylase; D010433:Pentylenetetrazole