Effects of cannabinoids and endocannabinoid hydrolysis inhibition on pentylenetetrazole-induced seizure and electroencephalographic activity in rats.
Cannabinoids and drugs that increase endocannabinoid levels inhibit neuronal excitability and restrain epileptic seizures through CB1 receptor activation. Nevertheless, the results have not been entirely consistent, since pro-convulsant effects have also been reported. The present study aimed to further investigate the effects of cannabinoid-related compounds on seizures induced by pentylenetetrazole (PTZ) in rats. Video-EEG recordings were used to determine both electrographic and behavioral thresholds to ictal activity. The animals received injections of WIN-55,212-2 (0.3-3 mg/kg, non-selective) or ACEA (1-4 mg/kg, CB1-selective), two synthetic cannabinoids, or URB-597 (0.3-3 mg/kg), an anandamide-hydrolysis inhibitor (FAAH enzyme inhibitor), followed by PTZ. Both WIN-55,212-2 (1 mg/kg) and ACEA (1-4 mg/kg) reduced the threshold for myoclonic seizures and enhanced epileptiform EEG activity, typical pro-convulsive effects. On the contrary, URB-597 (1 mg/kg) had an anti-convulsive effect, as it increased the threshold for the occurrence of minimal seizures and reduced EEG epileptiform activity. None of the drugs tested altered the tonic-clonic maximal seizure threshold. These data suggest that the effects of CB1 signaling upon seizure activity may depend on how this receptor is activated. Contrary to direct agonists, drugs that increase anandamide levels seem to promote an optimal tonus and represent a promising strategy for treating myoclonic seizures.
Graduate School in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais Av. Antônio Carlos 6627, 31270-901, Belo Horizonte, MG, Brazil.
Luciano R
LR
Vilela
Daniel C
DC
Medeiros
Gustavo H S
GH
Rezende
Antônio Carlos P
AC
de Oliveira
Marcio F D
MF
Moraes
Fabrício A
FA
Moreira
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use; D002186:Cannabinoids / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D003292:Convulsants / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000379:methods; D063388:Endocannabinoids / Q000627:therapeutic use*; D006868:Hydrolysis; D008297:Male; D009025:Morpholines / Q000627:therapeutic use; D009281:Naphthalenes / Q000627:therapeutic use; D010433:Pentylenetetrazole; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
D001549:Benzamides; D048588:Benzoxazines; D002186:Cannabinoids; D002219:Carbamates; D003292:Convulsants; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D010433:Pentylenetetrazole