Mildronate exerts acute anticonvulsant and antihypnotic effects.
The effects of mildronate [3-(2,2,2-trimethylhydrazinium) propionate], an inhibitor of L-carnitine biosynthesis and an anti-ischaemic drug, were examined in various in-vivo conditions to investigate the neuropharmacological profile after acute administration. Mildronate (200 mg/kg, acute intraperitoneal administration) exerted anticonvulsant activity in a chemoconvulsant pentylenetetrazole-induced clonic and tonic seizure test but did not change the effects of a convulsion-inducing dose of (+)-bicuculline, a gamma-aminobutyric acid receptor antagonist. Mildronate also dose-dependently inhibited the sleeping time in ethanol-induced loss of righting reflex test. However, in a pentylenetetrazole-induced seizure test, mildronate significantly stimulated the anticonvulsant activity of ethanol. The anticonvulsant activity of mildronate was completely blocked after pre-treatment with alpha2-adrenergic receptor antagonist yohimbine (2 mg/kg) and nitric oxide synthase inhibitor N(G)-nitro-L-arginine (10 mg/kg). These results show that the acute administration of mildronate induces anticonvulsant and antihypnotic effects, which involve alpha2-adrenergic receptor and nitric oxide -dependent mechanisms. These findings indicate that the acute administration of mildronate could be beneficial for the treatment of seizures and alcohol intoxication.
Zvejniece
Liga
L
Latvian Institute of Organic Synthesis, Riga, Latvia. liga@biomed.lu
Svalbe
Baiba
B
Makrecka
Marina
M
Liepinsh
Edgars
E
Kalvinsh
Ivars
I
Dambrova
Maija
M
D000435:Alcoholic Intoxication / Q000188:drug therapy; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity; D008763:Methylhydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy*; D012890:Sleep / Q000187:drug effects*
D000927:Anticonvulsants; D008763:Methylhydrazines; D018341:Receptors, Adrenergic, alpha-2; D009569:Nitric Oxide; D000431:Ethanol; C050147:3-(2,2,2-trimethylhydrazine)propionate