Abstract
The aim of this study was to evaluate the potential of pharmacological modulation of adrenergic and serotoninergic systems in post-stroke motor recovery in mice. For this purpose, the effects of selective norepinephrine reuptake inhibitor atomoxetine (1 mg/kg, once a day, i.p.) and selective serotonin reuptake inhibitor fluoxetine (10 mg/kg, once a day, i.p.) were studied on recovery of motor function in adult male mice after photothrombotic stroke. Vehicle or drug treatments were initiated on day 5 after photothrombosis and lasted until post-stroke day 16. In addition to pharmacological therapy, mice were allowed to voluntarily run on a wheel in their home cage starting from day 9 after stroke. Motor function was assessed in grid walking and cylinder tests 3 days before and 3, 7, 14, 28 and 42 days after stroke. On post-stroke day 42, mouse brains were fixed by cardiac perfusion and collected for sectioning and evaluation of infarct volume (cresyl violet staining) and molecular markers (immunofluorescence). The results of both sensorimotor tests indicated that all groups had substantial and comparable motor impairment on post-stroke day 3 (p < 0.01 compared to respective baselines), and that voluntary running started 9 days post-stroke did not significantly facilitate motor recovery after stroke (p > 0.05, vehicle-treated vs. stroke alone). However, treatment of mice with atomoxetine or fluoxetine significantly potentiated motor recovery by day 42 after stroke (p < 0.05 compared to vehicle-treated and stroke alone groups). The average total distance run by mice receiving vehicle or either of the drugs was comparable (1653 ± 110 meters). Infarct volumes measured at day 42 post-stroke were also comparable in experimental groups (1.7 ± 0.2 mm
3
). Our data indicate that moderate voluntary running starting 9 days after stroke does not facilitate motor recovery after stroke in mice. However, pharmacological modulation of adrenergic or serotoninergic systems, in addition to moderate voluntary running, enhances motor recovery in mice. Our ongoing studies focus on evaluation of the dose-dependence of atomoxetine and fluoxetine effects, and elucidation of molecular signaling pathways responsible for the observed effects of these drugs.