Differential effect of the PDE5 inhibitors, sildenafil and zaprinast, in aging‐ and lipopolysaccharide‐induced cognitive dysfunction in mice

Abstract

In the present study, we have investigated the effects of exogenously administered cyclic GMP-specific PDE5 inhibitors, sildenafil and zaprinast, on cognitive performance in aged-and lipopolysaccharide (LPS)-treated mice using passive avoidance and plus-maze tasks. Aged and LPStreated mice showed poor retention of memory in step-through passive avoidance and plus-maze task. Administration of PDE5 inhibitors reversed the age-induced retention deficits in both of the test paradigms. Also, PDE5 inhibitors on acute administration in young mice showed improvement in memory retention when tested in both of the paradigms. However, the effect of two PDE5 inhibitors was more pronounced in aged animals than that in young mice. PDE5 inhibitors enhanced the retention deficits in LPS-treated animals, which might be due to elevation of cGMP levels caused by sildenafil and zaprinast. In conclusion, these results indicated that differential effects of PDE5 inhibitors in aging and LPS-treated mice, but its prudential effect in aged mice may suggest new therapeutic use of these compounds. Drug Dev.

From Age-Related Cognitive Decline to Alzheimer’s Disease: A Translational Overview of the Potential Role for Phosphodiesterases

“…Next to PDE5, zaprinast also weakly inhibits PDE1, PDE9, PDE10 and PDE11, though, in low concentrations like in this study, it should only inhibit PDE5 (Domek-Lopacinska and Strosznajder 2008). In contrast to the restricted effects on young animals, Patil et al showed improvement in memory function in age-impaired mice in an adapted version of elevated plus maze and the passive avoidance task after zaprinast treatment as well as after sildenafil treatment (Patil et al 2004). In fact, the improvement in memory functioning was more pronounced in the aged animals compared the young animals.…”

“…Indeed, sildenafil (~1 mg/kg) has been found to dilate the middle meningeal artery (Kruuse et al 2012) and to increase local cerebral blood flow in anesthetized rats (Zhang et al 2002). However, tadalafil and vardenafil, both considered to be the most potent PDE5-Is (Patil et al 2004;Yuan et al 2013), have not shown any effects on blood flow (Rutten et al 2009;Kruuse et al 2012). These findings argue against a cerebrovascular mechanism of action underlying the cognition-enhancing effects of PDE5-Is.…”