RESUMO
RATIONALE: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 inhibitor Bay 60-7550. OBJECTIVES: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice. METHODS: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice. RESULTS: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress-induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823. CONCLUSION: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling.
Assuntos
Antidepressivos/uso terapêutico , Corticosterona/toxicidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Depressão/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Antidepressivos/química , Antidepressivos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/metabolismo , Depressão/metabolismo , Depressão/psicologia , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/psicologia , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologiaRESUMO
Two new heterocyclics, named hirudonucleodisulfide A (1) and hirudonucleodisulfide B (2), were isolated from the dried material of Whitmania pigra Whitman. Their structures were elucidated by various spectroscopic means in combination with X-ray crystallographic analysis. A biological assay in vitro against anoxic injury demonstrated that 1 and 2 have moderately anti-anoxic activity with EC (50) values of 27.01 +/- 2.23 microg/mL and 19.54 +/- 1.53 microg/mL, respectively.
Assuntos
Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Hipóxia/tratamento farmacológico , Sanguessugas/química , Animais , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Estrutura MolecularRESUMO
Two guaiane-type sesquiterpenoids named orientalol E (1) and orientalol F (3) were isolated from the rhizome of Alisma orientalis (SAM) JUZEP together with two known guaiane-type sesquiterpenoids alismol (2) and alismoxide (4). Their relative stereostructures were elucidated by spectroscopic methods, whereas absolute stereostructures were determined on the basis of chemical correlation.