Protective effects of phosphodiesterase 5 inhibitor, mirodenafil, on traumatic brain injury-induced neuronal death

Traumatic brain injury (TBI) is a serious neurological condition caused by external physical forces that lead to extensive brain damage. The underlying pathological processes involve complex interactions, including neuronal death driven by cerebrovascular dysfunction, inflammation, and oxidative stress. A key contributor to these processes is the enzyme phosphodiesterase 5 (PDE5), which reduces cyclic guanosine monophosphate (cGMP) levels, leading to impaired vasodilation, reduced cerebral blood flow, and disruption of protective cellular pathways. Nitric oxide (NO) and zinc play significant roles in the progression of TBI-related damage. NO is a signaling molecule that supports cerebral blood flow and redox balance by boosting antioxidant defenses such as glutathione (GSH) levels. Zinc, an essential element for neural function, can become toxic in excess, contributing to oxidative stress and neuronal damage. During TBI, reduced NO availability and disrupted zinc homeostasis exacerbate these harmful effects, with increased PDE5 activity further depleting cGMP and limiting the activation of protective factors like Nrf2 and HO-1. This study explores the therapeutic potential of mirodenafil, a PDE5 inhibitor, in mitigating TBI-induced damage. Administered subcutaneously at 2 mg/kg, mirodenafil was evaluated through histological and biochemical techniques, including markers for neuronal degeneration, zinc accumulation, and NO synthesis. Results showed that mirodenafil reduced neuronal loss, regulated zinc levels, and restored NO signaling. These findings suggest that mirodenafil supports neuronal survival by preserving cGMP levels, enhancing NO function, and mitigating oxidative stress related to zinc dysregulation. This study highlights mirodenafil as a potential therapeutic option for limiting TBI-induced neuronal injury and preserving brain function.