The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates

Abstract

Sildenafil is a recognized treatment for patients suffering from erectile dysfunction and pulmonary hypertension. However, new evidence suggests that it may have a neuroprotective and a neurorestorative role in the central nervous system of both adults and neonates. Phosphodiesterase type 5—the target of sildenafil—is distributed in many cells throughout the body, including neurons and glial cells. This study is a comprehensive review of the demonstrated effects of sildenafil on the brain with respect to its function, extent of injury, neurons, neuroinflammation, myelination, and cerebral vessels.

Effects of Sildenafil on the Recovery of Cognitive Function and the Protection of Neuronal Cell Death Following Transient Global Cerebral Ischemia in Gerbils

“…This finding aligns with previous research indicating the anti-inflammatory and neuroprotective properties of sildenafil [21]. Sildenafil inhibits microglia activation and the death of oligodendrocytes through the mitogenactivated protein kinase (MAPK) signaling pathway, while increases in the production of proinflammatory cytokines via PKG signaling affects the activation of astrocytes and microglia [20,[33][34][35]. The downregulation of GFAP and AQP-4 co-expression implies mitigation of the astrocytic reaction and potential reductions in edema formation, supporting the hypothesis that sildenafil contributes to neuroprotection in the context of global cerebral ischemia.…”

“…According to the current study results, spontaneous alternations in short-term spatial working memory were significantly impaired in the ischemic group, while the group treated with 20mg/kg of sildenafil demonstrated significant improvements compared to the ischemic group (Figure 6B). The inhibition of the PDE5 effect by sildenafil increases intracellular cGMP levels by breaking down the phosphodiester bond of cGMP and inhibiting the hydrolysis of cGMP to GMP [20]. Previous studies have proposed that sildenafil activates the PI3K/Akt pathway via the NO-cGMP-PKG signaling pathway, enhancing neurogenesis and synaptic plasticity [48,49].…”

“…The increased blood flow by sildenafil is effective for improving symptoms such as pulmonary hypertension, heart failure, inflammatory response, and fibrin deposition [16][17][18]. In particular, sildenafil also has effect on the brain through neuroprotection, restoring neuronal development, improving brain injury, and 2 enhancing cognitive function [19][20][21]. However, the effects of sildenafil on delayed neuronal cell death and cognitive impairment following global ischemia, as well as its therapeutic mechanisms, remain unknown.…”

Synergistic effect of sildenafil combined with controlled hypothermia to alleviate microglial activation after neonatal hypoxia–ischemia in rats

“…The role of Sildenafil as a promising strategy to prevent or promote repair in adult and neonatal brain was recently reviewed, particularly in cerebral ischemia models [ 18 , 23 , 29 ]. In rodents, Sildenafil acts not only on the immediate deleterious effects induced by the reperfusion, but also on the secondary injuries with reduction of apoptotic cascade, oxidative stress, brain inflammation, and finally on neurorepair by the increase of angiogenesis, neurogenesis and oligodendrogenesis.…”

Chitosan Nanoparticles Alleviated the Adverse Effects of Sildenafil on the Oxidative Stress Markers and Antioxidant Enzyme Activities in Rats

“…PDE5 specifically breaks down the cyclic guanosine monophosphate (cGMP), responsible for nitric oxide-induced smooth muscle relaxation and vasodilatation [ 3 ]. As the PDE5 enzyme is also distributed in many cells throughout the body, PDE5 inhibitors have the potential for wider use in different clinical conditions such as neurodegenerative disorders and brain injuries [ 4 , 5 ], heart failure [ 6 ], and cancer [ 7 ].…”