ABSTRACT
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.
Subject(s)
Corticosterone/toxicity , Cyclic GMP/metabolism , Depression/drug therapy , Neurotoxicity Syndromes/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Signal Transduction/drug effects , Animals , CREB-Binding Protein/metabolism , Cell Line, Transformed , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Depression/psychology , Disease Models, Animal , Dose-Response Relationship, Drug , Hindlimb Suspension/psychology , Locomotion/drug effects , Male , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Neurotoxicity Syndromes/etiology , Recognition, Psychology/drug effects , Restraint, Physical/adverse effects , Swimming/psychologyABSTRACT
AIMS: Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) signaling by phosphodiesterase (PDE) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE2 inhibitor, in HT-22 cells and antidepressant-like effects in mouse models of depression. METHODS: Hcyb1 was synthesized and its selectivity upon PDE2 was tested. Moreover, HT-22 hippocampal cells were used to determine the effects of Hcyb1 on cell viability, cyclic nucleotide levels, and the downstream molecules related to cAMP/cGMP signaling by neurochemical, enzyme-linked immunosorbent, and immunoblot assays in vitro. The antidepressant-like effects of Hcyb1 were also determined in the forced swimming and tail suspension tests in mice. RESULTS: Hcyb1 had a highly selective inhibition of PDE2A (IC50 = 0.57 ± 0.03 µmol/L) and over 250-fold selectivity against other recombinant PDE family members. Hcyb1 at concentrations of 10-10 and 10-9 mol/L significantly increased cell viability after treatment for 24 hours. At concentrations of 10-9 ~10-7 mol/L, Hcyb1 also increased cGMP levels by 1.7~2.3 folds after 10-minute treatment. Furthermore, Hcyb1 at the concentrations of 10-9 mol/L increased both cGMP and cAMP levels 24 hours after treatment. The levels of phosphorylation of CREB and BDNF were also increased by Hcyb1 treatment in HT-22 cells for 24 hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2 mg/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity. CONCLUSION: These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant-like effects most likely mediated by cAMP/cGMP-CREB-BDNF signaling.
Subject(s)
Antidepressive Agents/therapeutic use , Depression/drug therapy , Guanine/analogs & derivatives , Naphthalenes/therapeutic use , Neurons/drug effects , Neuroprotective Agents/therapeutic use , Phosphodiesterase Inhibitors/therapeutic use , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , CREB-Binding Protein/genetics , CREB-Binding Protein/metabolism , Cell Line, Transformed , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Disease Models, Animal , Guanine/chemistry , Guanine/pharmacology , Guanine/therapeutic use , Hindlimb Suspension/methods , Inhibitory Concentration 50 , Locomotion/drug effects , Male , Mice , Mice, Inbred ICR , N-Methylaspartate/toxicity , Naphthalenes/chemistry , Naphthalenes/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacology , SwimmingABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Moutan Cortex (MC, family: Paeonia suffruticosa Andr.) is a well-known traditional herbal medicine that has been shown to hold a protective effect on inflammation in several diseases. However, its anti-inflammatory activity on diabetic nephropathy (DN) has been less reported. The present study was conducted to evaluate the potential attenuation activities of MC on inflammation in AGEs-induced rat mesangial cells dysfunction and high-glucose-fat diet and streptozotocin (STZ)-induced DN rats and explore the possible mechanism underlying its DN effect. MATERIALS AND METHODS: The inflammation in mesangial cells (HBZY-1) was induced by 200 µg/ml advanced glycation end products (AGEs). DN rats model was established by an administration high-glucose-fat diet and an intraperitoneal injection of STZ (30 mg/kg). Interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) level in cell supernatant and rats serum were detected by appropriate kits. A co-culture system of mesangial cells and macrophages was performed to evaluate the migration of macrophages. Immunohistochemical assay was applied to examine transforming growth factor beta1 (TGF-ß1), IL-6, MCP-1 and intercellular adhesion molecule-1 (ICAM-1) expression in kidney tissues of rats. Furthermore, western blot analysis was carried out to examine TGF-ß1, IL-6, MCP-1, ICAM-1 and RAGE protein expressions in mesangial cells. RESULTS: Pretreatment with MC could significantly inhibit AGEs-induced migration of macrophages in the co-culture system of mesangial cell and macrophage. MC could decrease IL-6 and MCP-1 levels in serum of DN rats in a dose-dependent manner. Furthermore, MC also improved the blood glucose, serum creatinine and urine protein levels. Both immunocytochemistry analysis and western blot analysis showed that MC decreased significantly the over-expression of IL-6, MCP-1, TGF-ß1, ICAM-1 and RAGE in mesangial cells or kidney tissues. Additionally, the protein expression of proinflammatory cytokine could also be down-regulated by the pretreatment of RAGE-Ab (5 µg/ml). CONCLUSION: These findings indicated that the extract of MC had an amelioration activity on the inflammation in AGEs-induced mesangial cells dysfunction and high-glucose-fat diet and STZ-induced DN rats. The protective effect might be associated with the intervention of MC via target of RAGE. These findings suggested that MC might be a benefit agent for the prevention and treatment of DN.
Subject(s)
Diabetes Mellitus, Experimental/complications , Dietary Fats/adverse effects , Drugs, Chinese Herbal/pharmacology , Glucose/adverse effects , Glycation End Products, Advanced/toxicity , Mesangial Cells/drug effects , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Cell Line , Diabetic Nephropathies/drug therapy , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/chemistry , Gene Expression Regulation/drug effects , Glucose/administration & dosage , Mesangial Cells/metabolism , Paeonia/chemistry , Random Allocation , RatsABSTRACT
OBJECTIVE: To examine the self-reported scale of brief psychopathological symptoms (SBPS) to detect malingering in forensic psychiatric cases. METHODS: Two hundred and six cases with different types of psychiatric problems were tested by SBPS. All cases were separately evaluated by two experts. RESULTS: About 34.5% cases (71/206) were classified as malingering by the cut-off 13 scores of SBPS. Compared with expert's evaluation, SBPS showed a false negative rate of 19.8% and a false positive rate of 1.7%, respectively, with a total accuracy rate of 90.8%. Cases involved in compensations including working injury and traffic accidence showed the highest rate of malingering (51%). CONCLUSION: SBPS is useful for detecting malingering psychopathological symptoms.
