Abstract
Introduction: GDF11 is a pleiotropic circulating blood factor and member of the transforming growth factor β (TGFβ) superfamily. In animal models of stroke, GDF11 is linked to regeneration and recovery through neovascularization, neurogenesis, and anti-inflammatory effects, among other potential mechanisms. Methods: Focal cerebral infarcts were made by permanent occlusion of the proximal right middle cerebral artery (MCA) by microbipolar coagulation, following a modification of the method of Tamura et al. rGDF11 or vehicle was delivered via multiple routes of administration to male Sprague Dawley Rats at single and multiple doses ranging from 0.1 - 4 mg/kg per dose. Dosing started ~24 hours following injury. Behavioral assessments (e.g., limb placement and body swing) were captured at days 3, 5, 7, 14, 21, and 28 post-injury. Results: Dose-dependent improvements in all behavioral assessments were seen at all animals receiving any dose level or frequency of rGDF11. Vehicle vs. rGDF11 comparisons yielded statistically significant improvements (p < 0.05) in all 3 behavioral assessments at several post-injury timepoints, including follow-up days 14 & 28. No major tolerability events were observed, and no animals were lost during the study. Histologic and serum markers indicated rGDF11’s beneficial effects on neovascularization, neurogenesis, and inflammation. Conclusions: Treatment of pMCAO rats with rGDF11 ~24hrs post-injury resulted in dose-dependent, durable improvements in motor function-focused behavioral assessments. These data support continued development of the potential clinical therapeutic application of rGDF11 in stroke and related disorders.
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