Amelioration of scopolamine-induced learning and memory impairment by the TRPV4 inhibitor HC067047 in ICR mice

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. Cholinergic dysfunction is one of the pathological hallmarks of AD and leads to learning and memory impairment. Transient receptor potential vanilloid 4 (TRPV4), a nonselective cation channel, is involved in learning and memory functions. HC067047, a TRPV4 specific inhibitor, has been reported to protect neurons against cerebral ischemic injury and amyloid-13-(A13) 40-induced hippocampal cell death. However, whether HC067047 could improve scopolamine (SCP)-induced cognitive dysfunction in mice is still unknown. The aims of this study were to verify whether HC067047 could ameliorate the SCP-induced learning and memory impairments in mice and to elucidate its underlying mechanisms of action. In this study, we examined the neuroprotective effect of the HC067047 against cognitive dysfunction induced by SCP (5 mg/kg, i.p.), a muscarinic receptor antagonist. The results showed that administration of HC067047 (10 mg/kg, i.p.) significantly ameliorated SCP-induced cognitive dysfunction as assessed by the novel place recognition test (NPRT) and novel object recognition test (NORT). In the Y-maze test, HC067047 significantly enhanced the time spent in the novel arm in SCP mice. To further investigate the molecular mechanisms underlying the neuroprotective effect of HC067047, expression of several proteins involved in apoptosis was examined. The results demonstrated that HC067047 treatment decreased the protein levels of proapoptotic proteins such as Bax and caspase-3 in the hippocampus of SCP mice. In addition, HC067047 enhanced expression of the neurogenesis marker DCX and improved levels of the mature neuronal marker NeuN in SCP mice. These findings suggest the neuroprotective potential of the TRPV4 inhibitor HC067047 for the management of dementia with learning and memory loss.