Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats.
OBJECTIVE
We tested the hypothesis that sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, promotes functional recovery and neurogenesis after stroke.


METHODS
Male Wistar rats were subjected to embolic middle cerebral artery occlusion. Sildenafil (Viagra) was administered orally for 7 consecutive days starting 2 or 24 hours after stroke onset at doses of 2 or 5 mg/kg per day. Ischemic rats administered the same volume of tap water were used as a control group. Functional outcome tests (foot-fault, adhesive removal) were performed. Rats were killed 28 days after stroke for analysis of infarct volume and newly generated cells within the subventricular zone and the dentate gyrus. Brain cGMP levels, expression of PDE5, and localized cerebral blood flow were measured in additional rats.


RESULTS
Treatment with sildenafil significantly (P<0.05) enhanced neurological recovery in all tests performed. There was no significant difference of infarct volume among the experimental groups. Treatment with sildenafil significantly (P<0.05) increased numbers of bromodeoxyuridine-immunoreactive cells in the subventricular zone and the dentate gyrus and numbers of immature neurons, as indicated by betaIII-tubulin (TuJ1) immunoreactivity in the ipsilateral subventricular zone and striatum. The cortical levels of cGMP significantly increased after administration of sildenafil, and PDE5 mRNA was present in both nonischemic and ischemic brain.


CONCLUSIONS
Sildenafil increases brain levels of cGMP, evokes neurogenesis, and reduces neurological deficits when given to rats 2 or 24 hours after stroke. These data suggest that this drug that is presently in the clinic for sexual dysfunction may have a role in promoting recovery from stroke.
Zhang
Ruilan
R
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Mich, USA.
Wang
Ying
Y
Zhang
Li
L
Zhang
Zhenggang
Z
Tsang
Wayne
W
Lu
Mei
M
Zhang
Lijie
L
Chopp
Michael
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001973:Bromodeoxyuridine; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D018891:Dentate Gyrus / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D020547:Lateral Ventricles / Q000187:drug effects / Q000473:pathology; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D000068677:Sildenafil Citrate; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013450:Sulfones; D016896:Treatment Outcome
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D012333:RNA, Messenger; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D001973:Bromodeoxyuridine; D006152:Cyclic GMP