Longitudinal magnetic resonance imaging of sildenafil treatment of embolic stroke in aged rats

Abstract

Background and purpose: Sildenafil provides restorative therapeutic benefits in the treatment of experimental stroke. The majority of experimental studies on treatment of stroke have been performed in young animals; however, stroke is primarily a disease of the aged. Thus, using MRI, we evaluated the effects of sildenafil treatment of embolic stroke in aged animals.

Methods: Aged male Wistar rats (18 months) were subjected to embolic stroke and treated daily with saline (n=10) or with sildenafil (n=10) initiated at 24 hours and subsequently for 7 days after onset of ischemia. MRI measurements were performed at 24 hours and weekly to 6 weeks after embolization.

Results: MRI and histological measurements demonstrated that sildenafil treatment of aged rats significantly enhanced angiogenesis and axonal remodeling after stroke compared to saline-treated aged rats. Local cerebral blood flow in the angiogenic area was elevated and expansion of the ipsilateral ventricle and, consequently, brain atrophy was significantly reduced in the sildenafil-treated rats.

Conclusions: Treatment of embolic stroke in aged rats with sildenafil significantly augments angiogenesis and axonal remodeling, which increased local blood flow and reduced expansion of the ipsilateral ventricle 6 weeks after stroke compared to control aged rats. MRI can be used to investigate brain repair after stroke in aged rats.

Figure 1

T₂ map acquired 24h after stroke (a) shows lesion volume. T₂ map acquired 6w after MCAo (b) identifies the final infarction and expansion of the ipsilateral ventricle. The ischemic boundary zone (green) and core (red) are shown on the H&E slice (c) warped to the 6w T₂ map.

Figure 2

For a representative aged rat with sildenafil treatment after ischemia, the hypointensity regions in T₂* map (a) were obtained 4w after stroke. The elevated CBF was observed 1 week later (b). Six weeks after stroke, an increase of DA values was apparent (c).

Figure 3

T₂* ratios (a) of cerebral tissue in the sildenafil treated group had lower values during 6 weeks after stroke than in the control group; the differences were significant at 4w and 5w after stroke (p<0.04). Higher CBF ratios were observed in sildenafil treated aged animals compared to control rats (b). At 6w after stroke, CBF was significantly higher in treated group than in the control group (p<0.05). DA values monotonically increased after stroke in aged rats (c). Starting from 4w after stroke, the DA ratios were significantly different between the two groups (p<0.03). Ventricular volume ratios monotonically increased after stroke for all aged rats (d). However, the increasing rate was slower in the treated group, and was significant at 6 weeks after stroke.

Figure 4

the EBA-stained section of the microvascular density from a representative treated aged rat (a) was increased compared with a control aged rat (b). And the axonal length and density at the same location were longer and higher in the treated aged rat (c) than in the control aged one (d) on B&LFB-stained sections. Bars in b & d are 50μm.