Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation

Abstract

Cerebral stroke, traumatic brain injury, and hypoxic ischemic encephalopathy are among the most frequently occurring brain injuries. A complex pathogenesis, characterized by a synergistic interaction between alterations of the cerebrovascular system, cell death, and inflammation, is at the basis of the brain damage that leads to behavioral and neurodevelopmental disabilities in affected subjects. Sildenafil is a selective inhibitor of the enzyme phosphodiesterase 5 (PDE5) that is able to cross the blood-brain barrier. Preclinical data suggest that sildenafil may be a good candidate for the prevention or repair of brain injury in both adults and neonates. The aim of this review is to summarize the evidence supporting the neuroprotective action of sildenafil and discuss the possible benefits of the association of sildenafil with current therapeutic strategies.

Keywords: brain injury; neuroprotection; sildenafil.

Figure 1

Sildenafil and the modulation of cerebral blood flow (CBF): the binding of NO to sGC, the main NO physiological receptor, stimulated the synthesis of cGMP, which binds to and activates cGMP-dependent protein kinase I (PKG1). Activated PKG1 then phosphorylates the alpha subunit of the vascular smooth cell K⁺ channel, resulting in a K⁺ efflux, cell hyperpolarization, vascular smooth cell relaxation and in an increase of CBF. Sildenafil modulate cGMP stability via inhibition of the enzyme PDE5 that catalyzes the conversion of cGMP into the 5′ GMP inactive form.

Figure 2

Cellular mechanism associated with the neuroprotective effect of sildenafil.