RESUMO
Chronic cerebral hypoperfusion (CCH) is a common condition associated with the development and/or worsening of age-related dementia.We previously reported persistent memory loss and neurodegeneration after CCH in middle-aged rats. Statin-mediated neuroprotection has been reported after acute cerebral ischemia. Unknown, however, is whether statins can alleviate the outcome of CCH. The present study investigated whether atorvastatin attenuates the cognitive and neurohistological outcome of CCH. Rats (1215 months old) were trained in a non-food-rewarded radial maze, and then subjected to CCH. Atorvastatin (10 mg/kg, p.o.) was administered for 42 days or 15 days, beginning 5 h after the first occlusion stage. Retrograde memory performance was assessed at 7, 14, 21, 28, and 35 days of CCH, and expressed by "latency," "number of reference memory errors" and "number of working memory errors." Neurodegeneration was then examined at the hippocampus and cerebral cortex. Compared to sham, CCH caused profound and persistent memory loss in the vehicle-treated groups, as indicated by increased latency (91.2% to 107.3%) and number of errors (123.5% to 2508.2%), effects from which the animals did not spontaneously recover across time. This CCH-induced retrograde amnesia was completely prevented by atorvastatin (latency: −4.3% to 3.3%; reference/working errors: −2.5% to 45.7%), regardless of the treatment duration. This effect was sustained during the entire behavioral testing period (5 weeks), even after discontinuing treatment. This robust and sustained memory-protective effect of atorvastatin occurred in the absence of neuronal rescue (39.58% to 56.45% cell loss). We suggest that atorvastatin may be promising for the treatment of cognitive sequelae associated with CCH.
Assuntos
Amnésia Retrógrada/tratamento farmacológico , Atorvastatina/farmacologia , Encéfalo/efeitos dos fármacos , Transtornos Cerebrovasculares/tratamento farmacológico , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Amnésia Retrógrada/etiologia , Amnésia Retrógrada/patologia , Amnésia Retrógrada/fisiopatologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/patologia , Transtornos Cerebrovasculares/fisiopatologia , Doença Crônica , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/fisiologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Células Piramidais/fisiologia , Ratos Wistar , Resultado do TratamentoRESUMO
We previously reported that the phosphodiesterase-5 (PDE5) inhibitor sildenafil prevented neurodegeneration but not learning deficits in middle-aged rats that were subjected to the permanent, three-stage, four-vessel occlusion/internal carotid artery (4-VO/ICA) model of chronic cerebral hypoperfusion (CCH). In the present study, we examined whether the PDE3 inhibitor cilostazol alleviates the loss of long-term memory (i.e., retrograde amnesia) caused by CCH. The effect of sildenafil was then compared to cilostazol. Naive rats (12-15 months old) were trained in a non-food-rewarded eight-arm radial maze and subjected to CCH. One week later, retrograde memory was assessed for 5 weeks. Cilostazol (50mg/kg, p.o.) was administered for 42 days or 15 days, beginning approximately 45 min after the first occlusion stage. Sildenafil (3mg/kg, p.o.) was similarly administered for 15 days only. Histological examination was performed after behavioral testing. Chronic cerebral hypoperfusion caused persistent retrograde amnesia, which was reversed by cilostazol after both short-term and long-term treatment. This antiamnesic effect of cilostazol was sustained throughout the experiment, even after discontinuing treatment (15-day treatment group). This effect occurred in the absence of neuronal rescue. Sildenafil failed to prevent CCH-induced retrograde amnesia, but it reduced hippocampal cell death. Extending previous findings from this laboratory, we conclude that sildenafil does not afford memory recovery after CCH, despite its neuroprotective effect. In contrast, cilostazol abolished CCH-induced retrograde amnesia, an effect that may not depend on histological neuroprotection. The present data suggest that cilostazol but not sildenafil represents a potential strategy for the treatment of cognitive sequelae associated with CCH.