Introduction: Drugs and mechanical devices for retrieving blood clot are effective; however, they must be used within few hours of stroke onset. No pharmacological therapy has been shown to be effective in the recovery phase of stroke, which occurs days after the initial insult. Growth differentiation factor (GDF) 11, a member of transforming growth factor beta superfamily, has been effective in ameliorating age associated cardiac hypertrophy, skeletal muscle dysfunction and decreased neurogenesis in older mice. Therefore, we hypothesized; exogenous GDF11 will improve tissue loss and functional outcomes in old mice.
Methods: Middle cerebral artery occlusion (MCAo) (n=32) or sham surgery (n=12) was induced in old male mice (19-20 months). Five days after MCAo, GDF11 (0.1mg/kg) and BrdU (75 mg/kg) was administered for 5 days. Y maze, Barnes maze was performed on day 14, 21 and 28-post ischemia. Tail suspension and open field was performed on day 29 and day 30 respectively. The mice were euthanized on day 30-post stroke for assessment of tissue loss, gliosis and neurogenesis.
Results: Cerebral atrophy was significantly lower in the MCAo GDF11 (13.1 ± 1.62) vs MCAo vehicle treated group (22 ± 2.06) (p<0.05). Additionally, a reduced mortality was observed in MCAo GDF11 group (p=0.09). Exogenous GDF11 resulted in reduced GFAP+ cells (p<0.05) and Iba-1+ cells (p=0.17) in the peri-infarct cortex of MCAo GDF11 group. Moreover, an increase in CD31+ cells was seen in the MCAo GDF11 group, though this did not reach significance (p=0.12). On behavior task, there was no difference in spontaneous alterations and escape latency between MCAo GDF11 vs MCAo vehicle treated groups as assessed on Y and Barnes maze respectively. Additionally, no effect of GDF11 was seen on motor function or immobility when assessed on open field and tail suspension test respectively. Five days of exogenous GDF11 did not increase neurogenesis in the MCAo GDF11 group.
Conclusion: Exogenous GDF11 reduced tissue damage, decreased gliosis and enhanced angiogenesis in old mice. However, no benefit of GDF11 treatment was observed on long-term functional outcomes.