RESUMEN
Although accumulating evidence indicates that the immunomodulatory medication thalidomide exerts anticonvulsant properties, the mechanisms underlying such effects of thalidomide are still unknown. Our previous preclinical study suggested that nitric oxide (NO) signaling may be involved in the anticonvulsant effects of thalidomide in a mouse model of clonic seizure. Additionally, several studies have shown a modulatory interaction between thalidomide and opioids in opioids intolerance, nociception and neuropathic pain. However, it is unclear whether opioidergic transmission or its interaction with NO signaling is involved in the anticonvulsant effects of thalidomide. Given the fact that both opioidergic and nitrergic transmissions have bimodal modulatory effects on seizure thresholds, in the present study we explored the involvement of these signaling pathways in the possible anticonvulsant effects of thalidomide on the pentylenetetrazole (PTZ)-induced clonic seizure in mice. Our data showed that acute administration of thalidomide (5-50 mg/kg, i.p., 30 min prior PTZ injection) dose-dependently elevated PTZ-induced clonic seizure thresholds. Acute administration of low doses (0.5-3 mg/kg, i.p., 60 min prior PTZ) of morphine exerted anticonvulsant effects (P < 0.001), whereas higher doses (15-60 mg/kg, 60 min prior PTZ) had proconvulsant effects (P < 0.01). Acute administration of a non-effective anticonvulsant dose of morphine (0.25 mg/kg) prior non-effective dose of thalidomide (5 mg/kg) exerted a robust (P < 0.01) anticonvulsant effect. Administration of a non-effective proconvulsant dose of morphine (7.5 mg/kg) prior thalidomide (5 mg/kg) didn't affect clonic seizure thresholds. Acute administration of a non-effective dose of the opioid receptor antagonist naltrexone (1 mg/kg, i.p.) significantly prevented anticonvulsant effects of thalidomide (10 mg/kg, i.p.). Pretreatment with non-effective dose of the NO precursor L-arginine (60 mg/kg, i.p.) significantly (P < 0.01) reduced the anticonvulsant effects of combined low doses of morphine (0.25 mg/kg) and thalidomide (5 mg/kg). Conversely, pretreatment with non-effective doses of either non-selective (L-NAME, 5 mg/kg, i.p.) or selective neuronal (7-nitroindazole, 30 mg/kg, i.p.) NO synthase (NOS) inhibitors significantly augmented the anticonvulsant effects of combined low doses of thalidomide and morphine, whereas the inducible NOS inhibitor aminoguanidine (100 mg/kg, i.p.) did not exert such effect. Our results indicate that opioidergic transmission and its interaction with neuronal NO signaling may contribute to the anti-seizure activity of thalidomide in the mice PTZ model of clonic seizure.
Asunto(s)
Analgésicos Opioides/farmacología , Anticonvulsivantes/farmacología , Convulsiones/tratamiento farmacológico , Talidomida/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Masculino , Ratones , Óxido Nítrico Sintasa/antagonistas & inhibidores , Pentilenotetrazol/farmacología , Convulsiones/inducido químicamente , Talidomida/efectos adversosRESUMEN
The neuro-protective effects of rubidium and lithium as alkali metals have been reported for different central nervous system dysfunctions including mania and depression. The aim of this study was evaluating as well as comparing the effects of rubidium chloride (RbCl) and lithium chloride (LiCl) on different seizures paradigms in mice and determining the involvement of NMDA receptors and nitrergic pathway. To assess the seizures threshold, animals received intravenous pentylenetetrazole (PTZ, 0.5%; 1â¯mL/min). Male NMRI mice (6-8 weeks) received intraperitoneal (i.p.) injections of different doses of RbCl and LiCl. Doses greater than 10â¯mg/kg of RbCl showed a significant anticonvulsant activity 60â¯min after administration; the anticonvulsant effects of LiCl was observed at the doses more than 5â¯mg/kg and after 30â¯min in PTZ-induced seizure threshold. But, RbCl (10, 20â¯mg/kg, i.p) or LiCl (5, 10â¯mg/kg, i.p) injection did not induce protection against maximal electroshock (MES) or intraperitoneal injection of PTZ lethal dose (80â¯mg/kg)-induced seizure models. Pre-treatment with L-NAME (non-selective nitric oxide synthase (NOS) inhibitor, 10â¯mg/kg; i.p.) and 7-nitroindazole (selective neuronal NOS inhibitor, 30â¯mg/kg; i.p.) enhanced the anticonvulsive effects of both RbCl (5â¯mg/kg, i.p.) and LiCl (1â¯mg/kg, i.p.) in PTZ-induced seizure threshold model. Injection of MK-801 (NMDA receptor antagonist, 0.05â¯mg/kg; i.p.) before RbCl (5â¯mg/kg, i.p.; Pâ¯<â¯0.001) and LiCl (1â¯mg/kg, i.p.; Pâ¯<â¯0.001) administration increased the anti-seizure activity. But, treatment with L-arginine (precursor of nitric oxide, 100â¯mg/kg; i.p.) decreased the seizure threshold of both RbCl (20â¯mg/kg, i.p.; Pâ¯<â¯0.001) and LiCl (10â¯mg/kg, i.p.; Pâ¯<â¯0.001). Measurement of nitrite levels in hippocampus of animals revealed a remarkable reduction after treatment with RbCl (20â¯mg/kg, i.p; Pâ¯<â¯0.05) and LiCl (10â¯mg/kg, i.p; Pâ¯<â¯0.01). To conclude, rubidium may protect central nervous system against seizures in PTZ-induced seizures threshold model through NMDA/nitrergic pathways with a similarity to lithium effects in mice.