RESUMO
Clinical observations indicate that seizures induced by hypoxia are common kind of convulsive activity in both infants and elderly patients. The occurrence of seizure episode during hypoxia is important risk factor of epilepsy development in the future. Experimental hypoxia was obtained by exposure of adult (20-23 g) Albino Swiss mice to spontaneous breathing in gas mixture composed of 5% oxygen and 95% nitrogen. The latency time to convulsive activity was determined. Single sublethal episode of seizures induced by hypoxia (HS) resulted in higher susceptibility to pentetrazol (PTZ), bicuculline (BCC), N-methyl-D-aspartic acid (NMDA) but not in electrically induced convulsions. Adenosine A1 receptor agonist, R(-)N6-(2-phenyl-isopropyl)adenosine (R-PIA) (0.01; 0.05; 0.1 mg/kg, i.p.) prolonged the latency to HS-induced convulsions. A1 receptor antagonist, 8-cyclopentyltheophylline (CPT), reversed the protective action of R-PIA. A2 receptor agonist, N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyladenosine (DPMA), only at the highest dose (5 mg/kg i.p.) prolonged the latency time to convulsive activity. This effect was only partially reversed by A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). Administered immediately after episode of HS R-PIA diminished the higher susceptibility to PTZ, BCC, NMDA at 3rd day after HS, while DPMA appeared to be ineffective. These results confirm the important role of adenosine A1 receptor agonist in protection against acute and chronic epileptogenic effect of hypoxia. The role of adenosine A2 receptors seems to be of minor importance.
Assuntos
Adenosina/análogos & derivados , Envelhecimento/fisiologia , Anticonvulsivantes/farmacologia , Hipóxia/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Agonistas do Receptor Purinérgico P1 , Convulsões/fisiopatologia , Teobromina/análogos & derivados , Adenosina/farmacologia , Animais , Anticonvulsivantes/uso terapêutico , Bicuculina/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Convulsivantes/farmacologia , Modelos Animais de Doenças , Eletrochoque , Feminino , Hipóxia/tratamento farmacológico , Camundongos , N-Metilaspartato/efeitos adversos , N-Metilaspartato/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Pentilenotetrazol/farmacologia , Antagonistas de Receptores Purinérgicos P1 , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Teobromina/farmacologia , Fatores de TempoRESUMO
Preconditioning is defined as an adaptive mechanism produced by short periods of hypoxia/ischemia, resulting in protection against subsequent ischemic insult, and development of seizures. Results of the present study demonstrate that an episode of normobar hypoxia reduces the susceptibility to convulsions induced by pentylenetetrazol (PTZ) 30 min, 24 h, as well as 4 and 7 days later. Administration of morphine showed similar effects after 24 h. Naloxone, given before ischemic preconditioning, as well as morphine, blocked the development of the protection. Administration of D-Ala-Met-enkephalin-Gly-ol (DAMGO - a selective mu-opioid receptor agonist), as well as trans-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloexilbenzeneacetamide ethane sulfonate] (U-69,593 - a selective kappa-opioid receptor agonist), mimicked the effects of hypoxic preconditioning (HPC). (-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (cyprodime - a selective mu-opioid receptor antagonist, as well as nor-binaltorphimine dihydrochloride (nor-BNI - selective kappa-opioid receptors antagonist), given before HPC as well as before respective opioid receptor agonists, blocked the development of the protection. This study provides evidence that mu- and kappa-opioid receptors are involved in HPC against seizures in the brain.
Assuntos
Hipóxia/fisiopatologia , Precondicionamento Isquêmico , Receptores Opioides/fisiologia , Convulsões/prevenção & controle , Animais , Relação Dose-Resposta a Droga , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Feminino , Camundongos , Morfina/farmacologia , Naloxona/farmacologiaRESUMO
As an extension of our previous work we describe the synthesis and pharmacological investigation of a new series of derivatives of pyrrole-3,4-dicarboximide possessing the 4-substituted-piperazin-1-ylalkyl group linked to the imide nitrogen. The products were evaluated for acute toxicity, and effectiveness in a series of CNS and arterial blood pressure tests. The preliminary pharmacological screening was determined in animal models. Several compounds demonstrated moderate to high analgesic activity in the 'writhing syndrome' test (5f-1/640 LD50). Some of the structure-activity relationships are also discussed.