Phosphodiesterase 5 Inhibition Improves Synaptic Function, Memory, and Amyloid-  Load in an Alzheimer's Disease Mouse Model

Abstract

Memory loss, synaptic dysfunction, and accumulation of amyloid ␤-peptides (A␤) are major hallmarks of Alzheimer's disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after A␤ elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of A␤ levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated A␤ levels.

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…Puzzo et al [130] first demonstrated the preclinical efficacy of PDE5 inhibitors in AD mouse models and the findings were later confirmed by other groups [131][132][133]. Among reported PDE5 inhibitors, tadalafil and sildenafil can penetrate into the brain and ameliorate synaptic, learning, and memory deficits by modulating the cyclic guanosine monophosphate intracellular signaling pathway [130,134].…”

Phosphodiesterase‐5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury

“…PDE5 inhibitors, like sildenafil, extend the action of normally short‐lived cGMP and improve microvascular function when endothelial cells fail to produce sufficient NO. Furthermore, in studies on stroke animal models, sildenafil appears to have angiogenic properties in addition to its immediate vasodilatory effects 41, 42, 43, 44, 45. Sildenafil enters the brain readily and is a good candidate therapy for TCVI because of these vasodilatory and microvascular reparative properties.…”

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

“…Finally, the inhibition of HDAC6 may facilitate the degradation of misfolded proteins, such as Aβ and pTau (Sung et al, 2012;Yu et al, 2013;Zhang et al, 2014). Although different studies have demonstrated that HDACi or PDE5i improved cognitive deficits in animal models of AD, their role on amyloid pathology is controversial (Benito et al, 2015;Cuadrado-Tejedor et al, 2011b;Garcia-Barroso et al, 2013;Puzzo et al, 2009;Qing et al, 2008;Ricobaraza et al, 2009;Rumbaugh et al, 2015;Zhang and Schluesener, 2013). These differences may be because of the selectivity and potency of each compound and the different animal models and treatments employed.…”

“…PDE5 is upregulated in AD brains, often in conjunction with a decrease in cGMP in the cerebrospinal fluid (CSF) of AD patients , drawing attention to the possible therapeutic potential of PDE5 inhibitors in AD (Cuadrado-Tejedor et al, 2011a;Garcia-Barroso et al, 2013;Puzzo et al, 2009). It has been proposed that the activation of the cGMP/cAMP-responsive element-binding protein (CREB) pathway, which is crucial for memory formation, may contribute to the amelioration of AD symptoms observed with PDE5 inhibitors in animal models Puzzo et al, 2005).…”