Functional Recovery in Aged and Young Rats After Embolic Stroke

Abstract

Background and Purpose-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 3Ј,5Ј-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. Conclusion-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.

A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

“…30,45,62,68,83 Lastly, when cerebral blood flow to an area decreases to ischemic levels, sildenafil has demonstrated the ability to decrease the size of the infarct and improve outcomes by promoting angiogenesis in hypoxic areas. 14,66,[87][88][89] Each of these pathways represents future areas of study in determining sildenafil's role in treating DCI.…”

“…In studies of SAH in animals, sildenafil has shown to reduce plasma levels of endothelin-1, 9,25,26,44,47,55,60,64,65 limit platelet induced microthrombosis, 30,45,62,68,83 and promote cerebral angiogenesis in hypoxic areas. 14,66,[87][88][89] Sildenafil has been extensively studied and proven safe in both healthy and cardiovascularly ill patients. 1,5,18,24,35,41,67,80,81,90,91 However, to date there have been no studies in humans providing rigorous data on the safety of sildenafil in the setting of SAH.…”

Neurorestorative treatment of stroke: Cell and pharmacological approaches

“…88 Treatment of stroke with sildenafil starting at 24 hours after stroke significantly increased brain levels of cGMP, evoked neurogenesis, and reduced neurological deficits after stroke in both young adult and aged rats. 86,89 Increasing age decreases the number of new neurons in the dentate gyrus and the SVZ. 90 Sildenafil not only enhances angiogenesis and neurogenesis in young adults, but also augments angiogenesis and neurogenesis in aged ischemic rats.…”

Angiogenesis Detected After Embolic Stroke in Rat Brain Using Magnetic Resonance T2*WI

“…9 -10 Administration of sildenafil, therefore, by inhibiting cGMP breakdown, causes intracellular accumulation and increased brain levels of cGMP. [11][12][13] Previous studies showed that treatment of rats with sildenafil significantly increased the cortical levels of cGMP in both hemispheres for nonischemic rats, 12 and in the ipsilateral hemisphere at 7 days after stroke compared with levels in control animals. 13 Elevated cGMP levels in cerebral tissues may be involved in promoting angiogenesis during recovery up to 4 weeks after embolic stroke in rats.…”