Functional Recovery in Aged and Young Rats After Embolic Stroke: Treatment With a Phosphodiesterase Type 5 Inhibitor
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 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. 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.
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In aged rats with ischaemia, treatment with anti-NogoA antibodies, pharmacological compounds, or bone-marrow-derived stromal cells improved neurological recovery and was linked to preservation of ipsilateral pyramidal tract axons and enhanced contralateral pyramidal tract sprouting.
“Improved neurological recovery associated with preservation of pyramidal tract axons ipsilateral to the stroke and enhanced pyramidal tract sprouting contralateral to the stroke was identified in 25-month-old or 12-month-old rats with ischaemia treated with neutralising anti-NogoA antibodies,17 pharmacological compounds, 76 or bone-marrow-derived stromal cells.26”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [76]
Aged rats can respond to plasticity-promoting treatments, though age may influence some processes that neurorestorative interventions target.
“Aged rats respond to plasticity-promoting therapies, but age might have an effect on some of the processes targeted by neurorestorative interventions.”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [76]
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- Authors
- Zhang, L., Zhang, R. L., Wang, Y., Zhang, C., Zhang, Z. G., Meng, H., & Chopp, M.
- Affiliations
- Henry Ford Health (US)
- Venue
- Stroke
- Published
- 2005-04
- Volume
- 36
- Issue
- 4
- Pages
- 847-852
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- OpenAlex
- W2002956393
- Cited by
- 198
- References
- 25
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 7 · 2016: 4 · 2015: 12 · 2014: 16 · 2013: 16 · 2012: 24
- FWCI
- 15.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL064766, R01HL64766)
- National Institute of Neurological Disorders and Stroke (P01NS23393, P01NS023393, P01NS42345, R01 NS 38292, P01NS042345, R01NS038292)
- Topics
- Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- embolic stroke, sildenafil, aging, functional recovery, neuroplasticity, angiogenesis, endothelial cell proliferation, synaptogenesis, cyclic GMP, vessel density, phosphodiesterase-5 inhibitors
- MeSH terms
- Sildenafil Citrate, Aging, Animals, Bromodeoxyuridine, Disease Models, Animal, Endothelium, Vascular, Cyclic GMP, Immunohistochemistry, Male, Neovascularization, Pathologic, Neuronal Plasticity, Phosphodiesterase Inhibitors, Phosphoric Diester Hydrolases, Piperazines, Purines, Sodium Chloride, Sulfones, Synapses, Time Factors, 3',5'-Cyclic-GMP Phosphodiesterases, Synaptophysin, Treatment Outcome, Rats, Wistar, Stroke, Cell Proliferation, Rats, Cyclic Nucleotide Phosphodiesterases, Type 5
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