Phosphodiesterase 5A inhibitors improve functional recovery after stroke in rats: optimized dosing regimen with implications for mechanism.
1. J Pharmacol Exp Ther. 2009 Dec;331(3):842-50. Epub 2009 Sep 3.
Phosphodiesterase 5A inhibitors improve functional recovery after stroke in rats:
optimized dosing regimen with implications for mechanism.
Menniti FS, Ren J, Coskran TM, Liu J, Morton D, Sietsma DK, Som A, Stephenson DT,
Tate BA, Finklestein SP.
Neuroscience Biology, Pfizer Global Research & Development, Groton, Connecticut,
Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery after middle
cerebral artery occlusion (MCA-o) in rats. We used the PDE5A inhibitor
pyrido[3,4-b]pyrazin-2(1H)-one hydrochloride (PF-5) to determine the timing,
duration, and degree of inhibition that yields maximum efficacy. We also
investigated the localization of PDE5A to determine the tissues and cells that
would be targets for PDE5 inhibition and that may mediate efficacy. Nearly
complete inhibition of PDE5A, starting 24 h after MCA-o and continued for 7 days,
resulted in nearly complete recovery of sensorimotor function that was sustained
for 3 months. Delaying administration until 72 h after MCA-o resulted in
equivalent efficacy, whereas delaying treatment for 14 days was ineffective.
Treatment for 7 days was equivalently efficacious to 28 or 84 days of treatment,
whereas treatment for 1 day was less effective. In the normal forebrain, PDE5A
immunoreactivity was prominent in smooth muscle of meningeal arteries and a few
smaller blood vessels, with weak staining in a few widely scattered cortical
neurons and glia. At 24 and 48 h after MCA-o, the number and intensity of blood
vessel staining increased in the infarcted cortex and striatum. PDE5A
immunoreactivity also was increased at 48 h in putative microglia in penumbra,
whereas there was no change in staining of the scattered cortical neurons. Given
the window for efficacy and the PDE5A distribution, we hypothesize that efficacy
results from an effect on vasculature, and perhaps modulation of microglial
function, both of which may facilitate recovery of neuronal function.
PMID: 19729580 [PubMed - indexed for MEDLINE]