Sildenafil treatment of vascular dementia in aged rats
Zacharek A, Venkat P, Chopp M, Landschoot-Ward J, and Chen J. Sildenafil treatment of vascular dementia in aged rats. Stroke 2019; 50(Suppl 1):TMP120.
Background and Purpose: Vascular Dementia (VaD) caused by silent or mini strokes, affects cognition and memory predominantly in the elderly. Sildenafil, a cGMP-specific phosphodiesterase type 5 inhibitor mediates vasodilation. In this study, we tested the therapeutic effects of Sildenafil on cognitive decline, white matter (WM) damage, autophagy and inflammatory response associated with a model of VaD in aged rats. Methods: Male, 16-18 month old Wistar rats were subjected to a multiple microinfarction (MMI) induced VaD model and were treated daily with or without Sildenafil (2mg/Kg, i.p) starting at 24 hours after MMI for 28 days (n=7/group). A battery of cognitive tests was performed and rats were sacrificed at 28 days after MMI for immunohistochemical evaluation, Western blot and PCR assays. Results: Compared to aged-control, aged-MMI rats exhibit significant (p<0.05): 1) short term memory loss, long term memory deficits and anxiety like behavior, respectively; 2) increased brain inflammatory factor expression such as IL-1β, MCP-1 and thrombin; 3) increased brain WM/axonal damage as well as increased autophagy in the brain. Compared to aged-MMI control rats, Sildenafil treatment in aged-MMI rats significantly (p<0.05): 1) improves short and long term memory as well as decreases anxiety like behavior; 2) improves spatial learning and memory; 3) increases axon and myelin density in the corpus callosum and white matter bundles in the striatum; 4) increases oligodendrocyte and oligodendrocyte progenitor cell number in the corpus callosum, cortex and striatum; 5), increases synaptic protein expression in the cortex and striatum as well as increases water channel protein Aquaporin-4 expression around cerebral blood vessels; 6) decreases inflammatory factors MCP-1, IL-1β and thrombin expression as well as decreases MMI induced autophagy indicated by LC3A and Beclin-1 expression. Conclusions: MMI in aged rats induces significant WM damage, autophagy, and inflammatory responses which lead to decline in cognition and memory. Sildenafil treatment increases white matter remodeling, synaptic plasticity, decreases autophagy and exerts anti-inflammatory effects which in concert may contribute to the improvement in cognition and memory.