Modulation of Cognitive Function by TRPM3 Channels in the Dentate Gyrus of a Menopausal Rat Model: Effects of Naringenin Treatment and Ciliary Neurotrophic Factor.

Abstract

Although transient receptor potential melastatin 3 (TRPM3) channels are primarily known for their role in spinal nociception, emerging evidence suggests their involvement in psychiatric conditions and central reward processing. Menopause, characterized by estrogen decline, induces neuroimmune activation and increases pro-inflammatory factors such as ciliary neurotrophic factor (CNTF). While a direct regulatory effect of CNTF on TRPM3 is not well established, both are involved in inflammation-related signaling, suggesting potential crosstalk. TRPM3 responds to neuroinflammatory and neurotrophic signals and may contribute to postmenopausal cognitive decline. However, this link remains unexplored. Naringenin, a natural flavonoid with estrogen-like properties, has been reported to inhibit TRPM3 channels and may help to alleviate postmenopausal memory impairment. This study aimed to investigate the role of elevated CNTF levels in increasing TRPM3 expression in the dentate gyrus (DG), contributing to cognitive deficits, and to assess the potential of naringenin in reversing these effects. Bilateral ovariectomy (OVX) was performed on female Sprague-Dawley rats, followed by treatment with naringenin (2.5, 5 and 10 mg/kg, intraperitoneal) for 14 days. Cognitive functions were assessed using the novel object recognition and passive avoidance tests. CNTF levels in the plasma and the DG, along with TRPM3 expression in the DG, were measured using ELISA and immunohistochemistry, respectively. Dendritic arborization in DG neurons was analyzed using Golgi-Cox staining. OVX rats showed impaired cognition, elevated CNTF and TRPM3 expression, and reduced dendritic complexity. Naringenin treatment reversed these changes, suggesting its potential to improve postmenopausal cognitive decline by modulating CNTF levels and TRPM3 activity in the DG.