The effect of CGP-40116 on pilocarpine evoked seizures in mice exposed to transient episode of brain ischemia.
The objective of the study was to examine the role of N-methyl-D-aspartate (NMDA) receptors in the modulation of a brain tolerance after a transient cerebral ischemia. Adult mice were exposed for 30 min to bilateral clamping of common carotid arteries (BCCA) under anaesthesia. The competitive NMDA antagonist CGP-40116 was administered intraperitoneally (i.p.) in two experimental paradigms, (a) acute treatment: twice, 4.0 mg/kg; 1.5 h before the clamping of vessels and 6 h after re-circulation and (b) chronic treatment in a dose of 1.0 mg/kg; started 24 h after re-circulation and continued once daily for 13 days with the last injection 24 h before the induction of convulsions. Seizures were evoked with pilocarpine (400 mg/kg, i.p.) 14 days after BCCA. The preliminary study showed that BCCA induced protection against pilocarpine toxicity. The acute treatment with CGP-40116 partially diminished the anticonvulsant phenomenon. In contrast, the chronic treatment with the drug led to a marked potentiation of the effect. The whole brain gamma-aminobutyric acid (GABA) analysis performed 14 days after BCCA showed a moderate increase in vehicle-treated mice and a significant elevation after chronic treatment with CGP-40116. It can be concluded that NMDA antagonists may exert the opposite effects on the brain tolerance against pilocarpine toxicity after BCCA. The acute treatment with CGP-40116 diminished its induction while the chronic low-dose treatment enhanced a brain tolerance, possibly through the mechanism of chemical preconditioning.
Rejdak
K
K
Department of Hygiene, Medical University, 11 Radziwillowska Str., 20-080, Lublin, Poland.
Rejdak
R
R
Stelmasiak
Z
Z
Czuczwar
S J
SJ
Kleinrok
Z
Z
Sieklucka-Dziuba
M
M
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D017536:Carotid Artery, Common / Q000502:physiology; D002546:Ischemic Attack, Transient / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D019194:Ischemic Preconditioning; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists; D010862:Pilocarpine; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D018721:Muscarinic Agonists; D010862:Pilocarpine; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D005680:gamma-Aminobutyric Acid; D015763:2-Amino-5-phosphonovalerate