title: Tadalafil, a long-acting type 5 phosphodiesterase isoenzyme inhibitor, improves neurological functional recovery in a rat model of embolic stroke.
abstract: Sildenafil, a type 5 phosphodiesterase isoenzyme (PDE5) inhibitor with a short half-life, increases brain cyclic guanosine monophosphate (cGMP) levels and improves neurological functional recovery when administered after stroke. In the present study, we investigated the effects of tadalafil (Cialis), a long acting PDE5 inhibitor, on brain cGMP levels, neurogenesis, angiogenesis, and neurological function during stroke recovery in a rat model of embolic stroke. Male Wistar rats (n=28) were subjected to embolic middle cerebral artery (MCA) occlusion. Tadalafil was orally administered every 48 h at a dose of 2 mg/kg or 10 mg/kg for 6 consecutive days starting 24 h after stroke onset. Control animals received the equivalent volume of saline at the same time points. For mitotic labeling, bromodeoxyuridine (BrdU, 100 mg/kg) was administered twice a day at 5, 6, and 7 days after stroke. ELISA assays were performed to evaluate the specificity of the effect of tadalafil on cGMP. Treatment with tadalafil at a dose of 2 or 10 mg/kg significantly improved neurological functional recovery compared with saline-treated rats. In addition, tadalafil treatment increased cerebral vascular density and the percentage of BrdU-positive endothelial cells around the ischemic boundary compared with saline-treated rats. Moreover, tadalafil-treated rats showed greater ipsilateral SVZ cell proliferation than saline-treated rats. However, treatment with tadalafil did not reduce infarct volume when compared to the saline group. Tadalafil selectively increased cGMP but not cyclic adenosine monophosphate (cAMP) in brain. Our data demonstrate that treatment of ischemic stroke with tadalafil improved functional recovery, which was associated with increases of brain cGMP levels and enhancement of angiogenesis and neurogenesis.
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Rui Lan
authors.initials: RL
authors.lastname: Zhang
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Cui
authors.forename: Margot C
authors.initials: MC
authors.lastname: LaPointe
authors.forename: Brian
authors.initials: B
authors.lastname: Silver
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002536:Cerebral Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020766:Intracranial Embolism / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D000068581:Tadalafil; D016896:Treatment Outcome
chemical_list: D002243:Carbolines; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D000068581:Tadalafil; D000242:Cyclic AMP; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP