RESUMO
In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective α7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-ß-erythroidine, a selective α4ß2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-ß-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal α7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via α7 nAChR and α4ß2 nAChR, and also enhances hippocampal neurogenesis.
Assuntos
Antineoplásicos/efeitos adversos , Ansiedade/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Nicotina/uso terapêutico , Animais , Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Diazepam/farmacologia , Interações Medicamentosas , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Nicotina/farmacologia , Antagonistas Nicotínicos/farmacologia , RNA Mensageiro/metabolismo , Ratos Wistar , Receptores Nicotínicos/genética , Memória Espacial/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Receptor Nicotínico de Acetilcolina alfa7/genéticaRESUMO
Many patients who have received chemotherapy to treat cancer experience depressive- and anxiety-like symptoms or cognitive impairment. However, despite the evidence for this, the underlying mechanisms are still not understood. This study investigated behavioral and biochemical changes upon treatment with doxorubicin and cyclophosphamide, focusing on mental and cognitive systems, as well as neurogenesis in male rats. Doxorubicin (2 mg/kg), cyclophosphamide (50 mg/kg), and the combination of doxorubicin and cyclophosphamide were injected intraperitoneally once per week for 4 weeks. In particular, the co-administration of doxorubicin and cyclophosphamide produced anhedonia-like, anxiety-like, and spatial cognitive impairments in rats. It also reduced both the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus and their survival. Serum brain-derived neurotrophic factor (BDNF) levels were decreased along with chemotherapy-induced decreases in platelet levels. However, hippocampal BDNF levels and Bdnf mRNA levels were not decreased by this treatment. On the other hand, hippocampal cyclin D1 levels were significantly decreased by chemotherapy. These results suggest that the co-administration of doxorubicin and cyclophosphamide induces psychological and cognitive impairment, in addition to negatively affecting hippocampal neurogenesis, which may be related to hippocampal cyclin D1 levels, but not hippocampal BDNF levels.