Phosphodiesterase type 5 (PDE5) inhibition improves object recognition memory: Indications for central and peripheral mechanisms

Tadalafil crosses the blood–brain barrier and reverses cognitive dysfunction in a mouse model of AD

“…Although tadalafil exerts in vivo central effects (Ko et al, 2009;Baek et al, 2011) this may be due to altered BBB permeability occurring in pathological conditions such as ischemia (Mark et al, 2004) and in neonates (Arya et al, 2006). Moreover, very recent studies report that PDE5 inhibitors may have central effects (anxiolytic or memory enhancers) in rats by mechanisms involving the cerebrovasculature (Liebenberg et al, 2012;Reneerkens et al, 2012). Therefore, since it is not formally demonstrated whether tadalafil does indeed cross the BBB, here we show that tadalafil penetrates into the CNS and that the concentrations reached may lead to a marked inhibition of PDE5 in the brain.…”

“…2). Most of the studies reporting an acute effect of PDE5 inhibitors using for instance, passive avoidance or novel object recognition tests, are carried out in non-transgenic animals, that show no amyloid or pTau pathologies Reneerkens et al, 2012). Therefore it was somehow expected that an acute increase of cGMP would not be sufficient to reverse the severe cognitive deficit of the J20 mice that exhibits marked amyloid burden, hyperphosphorylation of Tau and synaptic loss (Mucke et al, 2000).…”

Chronic phosphodiesterase type 2 inhibition improves memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease

“…However, our chronic BAY60-7550 treatment was given at a relatively low dose (0.3 mg/kg) and perhaps a higher dose might have been more effective on biochemical and morphological levels (Boess et al, 2004). In addition, PDEs are also well-known for their vasodilatory effects, and it cannot be ruled out that an enhanced cerebral blood flow and nutrient transport to the brain underlies the cognition-enhancing effects (Reneerkens et al, 2012).…”

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

“…We administered three selective PDE inhibitors: PDE2 inhibitor BAY 60-7550 (IC 50 : 4.7 nM; kindly donated by BAYER AG, Wuppertal, Germany), PDE4 inhibitor rolipram (IC 50 : 1.5 nM; Sigma Aldrich, Zwijndrecht, the Netherlands) and PDE5 inhibitor vardenafil (IC 50 : 0.7 nM; kindly donated by BAYER AG). All three PDE inhibitors have been shown to cross the blood-brain barrier (Krause and Kuhne, 1988;Reneerkens et al, 2012;Reneerkens et al, 2013). The PKA inhibitor Rp-8-Br-cAMPS and PKG inhibitor Rp-8-Br-cGMPS were obtained from Biolog (Bremen, Germany).…”