Enhancement of Post-Stroke Recovery via Delayed Pharmacological Intervention Using a Mouse Model of Stroke

Abstract

With an aging population there is increasing demand in the discovery of therapeutic interventions to enhance functional recovery in surviving stroke patients. Inflammation is an ongoing pathophysiological mechanism that may be modulated to enhance functional recovery post-stroke. Anecdotal evidence showed that medications used in management of post-stroke complications such as citalopram for depression and varenicline for smoking cessation may be beneficial for functional recovery via anti-inflammation. I conducted long-term pre-clinical studies to investigate whether delayed administration of the 7 nicotinic acetylcholine receptor agonist varenicline and selective serotonin reuptake inhibitor citalopram can reduce brain inflammation and whether this effect extends to structural changes in white matter (WM) structure, neuroplasticity, and functional performances poststroke. To optimize our C57Bl/6j and CSF-1R-EGFP mice models of stroke, I implemented clinically relevant endpoints, including diffusion tensor imaging, cytokine analysis, skilled motor function testing, sensorimotor function testing, and spontaneous motor function testing. Delayed administration of citalopram starting at 3 days post-stroke improved skilled motor function, suppressed chronic inflammation, and preserved WM structure integrity post-stroke in CSF-1R-EGFP mice. Further investigation on varenicline treatment starting at 3 days post-stroke showed worsened sensorimotor function, enhanced pro-inflammatory cytokines expression, and impaired the structural integrity of WM structures following stroke in C57Bl/6j mice. Quantitative analyses of DTI imaging in the mouse brain highlighted significant impairment in the structural integrity of corpus callosum and internal capsules in varenicline treated animals. Analytical evaluation of structural connectomes also identified varenicline treated induced changes in local efficiency and nodal degree at 2 weeks after washout. Implementation of ex vivo DTI in my experimental model of stroke successfully identified drug induced structural changes in the mouse neural network, which was associated with changes in sensorimotor function through the study. Designed to be administered in the sub-acute phase (days) after stroke, my results showed that an extended therapeutic window exists for the management of inflammation and neuroplasticity in the sub-acute and chronic phases of stroke and would be available to the large number of stroke patients who are unsuitable for thrombolytic therapy.