RESUMEN
Consumption of caffeine, an adenosine receptor antagonist, was found to be inversely associated with the incidence of Alzheimer's disease. Moreover, caffeine protects cultured neurons against beta-amyloid-induced toxicity, an effect mimicked by adenosine A(2A) but not A(1) receptor antagonists. We now tested if caffeine administration would prevent beta-amyloid-induced cognitive impairment in mice and if this was mimicked by A(2A) receptor blockade. One week after icv administration of the 25-35 fragment of beta-amyloid (Abeta, 3 nmol), mice displayed impaired performance in both inhibitory avoidance and spontaneous alternation tests. Prolonged treatment with caffeine (1 mg/ml) had no effect alone but prevented the Abeta-induced cognitive impairment in both tasks when associated with acute caffeine (30 mg/kg) 30 min treatment before Abeta administration. The same protective effect was observed after subchronic (4 days) treatment with daily injections of either caffeine (30 mg/kg) or the selective adenosine A(2A) receptor antagonist SCH58261 (0.5 mg/kg). This provides the first direct in vivo evidence that caffeine and A(2A) receptor antagonists afford a protection against Abeta-induced amnesia, which prompts their interest for managing Alzheimer's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Péptidos beta-Amiloides/antagonistas & inhibidores , Cafeína/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Fragmentos de Péptidos/antagonistas & inhibidores , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Amnesia/fisiopatología , Péptidos beta-Amiloides/efectos adversos , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Cafeína/uso terapéutico , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/fisiopatología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fragmentos de Péptidos/efectos adversos , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptor de Adenosina A2A/metabolismo , Resultado del Tratamiento , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
RATIONALE: Flunarizine is known as a calcium channel blocker commonly used in many countries to treat migraine and vertigo. Parkinsonism has been described as one of its side-effects in the elderly, which is in agreement with its recently characterized moderate D2 receptor antagonism. OBJECTIVES: To perform a pre-clinical evaluation of flunarizine as a potential antipsychotic. METHODS: We evaluated the action of orally administered flunarizine in mice against hyperlocomotion induced by amphetamine and dizocilpine (MK-801) as pharmacological models of schizophrenia, induction of catalepsy as a measure for extrapyramidal symptoms and impairment induced by dizocilpine on the delayed alternation task for working memory. RESULTS: Flunarizine robustly inhibited hyperlocomotion induced by both amphetamine and dizocilpine at doses that do not reduce spontaneous locomotion (3-30 mg/kg). Mild catalepsy was observed at 30 mg/kg, being more pronounced at 50 mg/kg and 100 mg/kg. Flunarizine (30 mg/kg) improved dizocilpine-induced impairment on the delayed alternation test. CONCLUSIONS: These results suggest a profile comparable to atypical antipsychotics. The low cost, good tolerability and long half-life (over 2 weeks) of flunarizine are possible advantages for its use as an atypical antipsychotic. These results warrant clinical trials with flunarizine for the treatment of schizophrenia.