RESUMO
BACKGROUND: Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. METHODS: We examined the protective effects of WYQ-C36D (C36D), a novel PDE9 inhibitor, against corticosterone-induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT-22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress-induced depression- and anxiety-like behaviors and memory deficits were also examined in mice. RESULTS: C36D significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp-8-Br-PET-cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant-like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic-like and memory-enhancing effects in the elevated plus-maze and novel object recognition tests. CONCLUSION: Our results show that inhibition of PDE9 by C36D produces antidepressant- and anxiolytic-like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD.
Assuntos
Corticosterona/toxicidade , GMP Cíclico/metabolismo , Depressão/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína de Ligação a CREB/metabolismo , Linhagem Celular Transformada , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Depressão/psicologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Elevação dos Membros Posteriores/psicologia , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Síndromes Neurotóxicas/etiologia , Reconhecimento Psicológico/efeitos dos fármacos , Restrição Física/efeitos adversos , Natação/psicologiaRESUMO
<p><b>AIM</b>To explore the effect of chronic hypoxic hypercapnia on learning-memory and the possible mechanisms involved.</p><p><b>METHODS</b>Fifty-eight male SD rats were randomly divided into three groups: Normal control group (NC, n=18), 2-week (2HH, n=18), and 4-week hypoxic hypercapnia (4HH, n=20) group. The rats, spatial learning-memory tasks were assessed by the Morris water maze. The expression of NMDAR1mRNA was determined by hybridization in situ.</p><p><b>RESULTS</b>Compared with NC group, rats exposed to chronic hypoxic hypercapnia displayed significant impairment in their performance assessed by two measures: mean escape latencies (2HH: 38.59 +/- 8.35 s, 4HH: 60.59 +/- 17.28 s) and swim path distances(2HH: 9893.45 +/- 1958.16 mm, 4HH: 18077.57 +/- 6878.85 mm). The expression level of NMDAR1mRNA in the hippocampus and cortex were lower than those in the NC group, especially, the NMDAR1mRNA expression of hippocampus CA1 in 4HH decreased by 21.4% (P < 0.01).</p><p><b>CONCLUSION</b>Chronic hypoxic hypercapnia could impair the rat spatial learning-memory and the decrease in expression of NMDAR1mRNA might be involved in.</p>
