development and axon guidance.While TRPC4 and C5 channels were reported to be HC-030031 supplier involved in various physiological and pathophysiological processes, such as vascular smooth muscle, endothelial function, adiponectin regulation, and oxidative stress. The protein kinase calcium/calmodulin-dependent kinase II beta was found to be a critical effector of TRPC5 function in neurons. TRPC5 has been reported to negatively regulate neurite outgrowth, dendrite morphogenesis and connectivity. The role of TRPC4 in axonal regeneration and epileptiform burst firing were also reported. Both TRPC4 and TRPC5 have been shown to be involved in anxiety-like behavior in the mouse model of fear conditioning test. Studies also suggest that TRPCs may be targeted for therapeutic treatment of neurological diseases. Recently, a new class of TRPC4/C5 inhibitors was identified using a cell-based high throughput screening assay. The lead compound, M084, exhibited very good selectivity on TRPC4, TRPC5, and TRPC1/C4 channels as compared to several other TRP channels as well as voltage-gated Ca2+, Na+ and K+ channels tested. In the present study, we investigated whether M084 has antidepressant and anti-anxiety effects. Our results show remarkable beneficial effects by a single treatment of mice with M084 for as short as 2 hours in multiple depression/ anxiety-related behavioral tests both under normal conditions and after long-term chronic unpredictable stress exposure. Accompanied with the antidepressant-like and anxiolytic-like effects and similar to other antidepressants, theM084 treatment caused increased signaling by brain-derived neurotrophic factor in prefrontal cortex. These results highlight TRPC4 and TRPC5 as new potential targets for the treatment of mood-related disorders. The compound M084, n-butyl-1h-benzimidazol-2-amine , was synthesized as described and dissolved in a water solution containing 10 of DMSO. The antidepressant amitriptyline and antianxiety drug diazepam were also dissolved in the water solution containing 10 of DMSO. Animals NVP-LBH589 received intraperitoneal injection of either the solvent control , or M084 or amitriptyline or diazepam two hours before the behavioral tests. The
