Abstract Body: Background and Purpose: Our previous studies in a rat model of ischemic stroke identified that intraperitoneal (IP), but not intracerebroventricular (ICV) administration of IGF-1 reduced stroke-induced gut leakiness and peripheral inflammation in the acute phase and attenuated stroke-induced impairment in acyclic middle-aged female rats. These data suggest that the gut may be implicated in IGF-1-mediated effects on stroke-induced cognitive impairment. To directly assess whether the effect of IGF-1 on behavioral improvement is mediated by the gut, study utilized a novel tet-inducible rAAV construct to block IGF1R specifically in the gut.

Methods: Female Sprague Dawley rats (9-11 mo) were intragastrically gavaged with either recombinant rAAV construct containing IGFR-shRNA (IGFR-sh) downstream of the IESC promoter Lgr5 in a Tet-inducible system or rAAV-empty vector (Scr-sh) 4 weeks prior to experimental ischemia. Animals were subjected to endothelin-1 induced MCAo. Doxycycline was administered 4h later and IGF-1 was given ip at 4 and 24 h post-stroke. Sensorimotor function as well as peripheral inflammation (in serum samples) was assessed at 5d post-stroke and long-term cognitive impairment was evaluated after 60 days.

Results: The mCherry reporter in the rAAV construct was observed in the intestinal crypt, indicating appropriate delivery of the construct. Sensorimotor function evaluated by vibrissae evoked forelimb placement task was significantly impaired in the ipsilateral paw after stroke in IGFR-Sh+IGF-1 compared to Scr-sh+IGF-1(p<0.005). IL-17 levels in serum were significantly elevated in the animals with IGFR-Sh+IGF1 compared to Scr_sh+IGF1 (p<0.004). Cognitive impairment assessed by Barnes maze showed no differences in spatial learning but revealed significant impairment in spatial recall in IGFR-sh+IGF1 group compared to SCR-sh+IGF1 animals (p<0.02).

Conclusions: The present findings indicate that the beneficial effects of IGF-1 on long-term stroke recovery may be partially mediated by its effects on the gut and implicate the inflammatory cytokine IL-17a as a modifier of stroke-induced cognitive impairment.

Supported by RF1NS119872 to FS and SB