The Emerging Role of Phosphodiesterase 5 Inhibition in Neurological Disorders: The State of the Art

Abstract

Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.

Keywords: PDE5i; cGMP; neurodegeneration; neuroinflammation; sildenafil.

Figure 1

PDE inhibition contributes to cell survival and memory improvement via the modulation of NO signaling. NO, produced by NOS, leads to the activation of sGC and production of cGMP, which in turn activates PKG [63,64]. (A). Retrograde signaling of NO can promote the release of vesicles containing neurotransmitters in presynaptic neurons. (B). PKG also promotes cell survival via the AKT pathway. (C). PKG activation leads to CREB phosphorylation and the expression of memory-related genes. CaMKII: Ca2+/calmodulin-dependent protein kinase II; cGMP: cyclic guanosine monophosphate; CREB: cAMP response element-binding element; NMDAR: N-methyl-D-aspartate receptor; NO: nitric oxide; NOS: nitric oxide synthase; PI3k: phosphatidylinositol 3-kinase; PDE: phosphodiesterase; PKG: protein kinase G; sGC: soluble guanylate cyclase.