Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor.
OBJECTIVE
Advanced age is associated with a decrease in brain plasticity compared with the young adult. Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor promotes brain plasticity and improves functional outcome after stroke in the young animal. Here, we test the hypothesis that sildenafil provides restorative therapeutic benefit to the aged animal.


METHODS
Male Wistar rats (aged, 18-month old; young, 3-month old) were subjected to embolic stroke. Saline or sildenafil was administered daily at a dose of 2 mg/kg orally or 10 mg/kg subcutaneously for 7 consecutive days starting 24 hour after stroke onset.


RESULTS
Aged rats exhibited significant impairment of functional recovery and reductions of vascular density, and endothelial cell proliferation compared with young rats. Aged rats treated with sildenafil at a dose of 10 mg/kg but not 2 mg/kg, showed significant improvements of functional recovery and concomitant increases in cortical cyclic guanosine 3',5'-cyclic monophosphate (cGMP) level, vascular density, endothelial cell proliferation, and synaptogenesis compared with aged rats treated with saline. In young rats, treatment with sildenafil at a dose of 2 or 10 mg/kg significantly enhanced functional recovery and amplified brain plasticity compared with young rats treated with saline.


CONCLUSIONS
Age is associated with reduction of angiogenesis, and poor neurological functional recovery after stroke. However, treatment of aged stroke rats with sildenafil improves functional recovery that is likely fostered by enhancement of angiogenesis and synaptogenesis.
Zhang
Li
L
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Mich, USA.
Zhang
Rui Lan
RL
Wang
Ying
Y
Zhang
Chunling
C
Zhang
Zheng Gang
ZG
Meng
He
H
Chopp
Michael
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000375:Aging; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D049109:Cell Proliferation; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D009389:Neovascularization, Pathologic; D009473:Neuronal Plasticity; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use; D011687:Purines; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D012965:Sodium Chloride / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy* / Q000401:mortality; D013450:Sulfones; D013569:Synapses / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D016708:Synaptophysin; D012965:Sodium Chloride; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D001973:Bromodeoxyuridine; D006152:Cyclic GMP