ABSTRACT
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.
Subject(s)
Antidepressive Agents/therapeutic use , Corticosterone/toxicity , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Depression/drug therapy , Neurotoxicity Syndromes/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Animals , Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Depression/metabolism , Depression/psychology , Hindlimb Suspension/adverse effects , Hindlimb Suspension/psychology , Male , Mice , Mice, Inbred ICR , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Neurotoxicity Syndromes/metabolism , Neurotoxicity Syndromes/psychology , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacologyABSTRACT
A series of novel rutaecarpine derivatives were synthesized and subjected to pharmacological evaluation as PDE5 inhibitors. The structure-activity relationships were discussed and their binding conformation and simultaneous interaction mode were further clarified by the molecular docking studies. Among the 25 analogues, compound 8i exhibited most potent PDE5 inhibition with IC50 values about 0.086 µM. Moreover, it also produced good effects against scopolamine-induced cognitive impairment in vivo. These results might bring significant instruction for further development of potential PDE5 inhibitors derived from rutaecarpine as a good candidate drug for the treatment of Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Cognitive Dysfunction/chemically induced , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Indole Alkaloids/chemistry , Phosphodiesterase 5 Inhibitors/chemical synthesis , Phosphodiesterase 5 Inhibitors/pharmacology , Quinazolines/chemistry , Animals , Cholinergic Antagonists/toxicity , Cognitive Dysfunction/drug therapy , Dose-Response Relationship, Drug , Mice , Models, Molecular , Molecular Structure , Morris Water Maze Test , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/chemistry , Protein Conformation , Scopolamine/toxicityABSTRACT
Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders. Herein, based on the existing PDE2 inhibitors and their binding modes, a series of purin-6-one derivatives were designed, synthesized and evaluated for PDE2 inhibitory activities, which led to the discovery of the best compounds 6p and 6s with significant inhibitory potency (IC50: 72 and 81â¯nM, respectively). Docking simulation was performed to insert compound 6s into the crystal structure of PDE2 at the active site to determine the binding mode. Furthermore, compound 6s significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cAMP and cGMP levels. It also produced anxiolytic-like effect in the elevated plus-maze test and exhibited favorable pharmacokinetic properties in vivo. These results might bring significant instruction for further development of potent PDE2 inhibitors.
Subject(s)
Anti-Anxiety Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Drug Design , Neuroprotective Agents/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Purinones/pharmacology , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Cell Line , Cell Survival/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Purinones/chemical synthesis , Purinones/chemistry , Structure-Activity RelationshipABSTRACT
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.
