Physical therapy exerts sub-additive and suppressive effects on intracerebral neural stem cell implantation in a rat model of stroke

Intracerebral cell therapy (CT) is emerging as a new therapeutic paradigm for stroke. However, the impact of physical therapy (PT) on implanted cells and their ability to promote recovery remains poorly understood. To address this translational issue, a clinical-grade neural stem cell (NSC) line was implanted into peri-infarct tissue using MRI-defined injection sites, two weeks after stroke. PT in the form of aerobic exercise (AE) was administered 5 × per week post-implantation using a paradigm commonly applied in patients with stroke. A combined AE and CT exerted sub-additive therapeutic effects on sensory neglect, whereas AE suppressed CT effects on motor integration and grip strength. Behavioral testing emerged as a potentially major component for task integration. It is expected that this study will guide and inform the incorporation of PT in the design of clinical trials evaluating intraparenchymal NSCs implantation for stroke.

Abstract T P68: Delayed Progesterone Treatment Improves Long-Term Recovery of Function Following Permanent Stroke in Older Rats

BACKGROUND: Less is known about the long-term sustained effects of PROG on recovery of function following stroke. Two objectives were evaluated, First, whether functional deficits caused by pMCAO persist and if repeated testing in itself reduce the extent of injury over long periods (8 weeks). Second, determine PROG's effects on a panel of behavioral tests performed several weeks post-pMCAO Methods: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham surgery. For the first study, repeated long term group with pMCAO began a battery of tests at repeated intervals (during the 3rd, 6th, and 8th weeks post-pMCAO), while long term with pMCAO group testing began during the 8 th week post-pMCAO. For the second study, beginning 3 h post-occlusion, rats were given IP injections of 8 mg/kg of PROG or vehicle, followed by SC injections at 8 h and then every 24 h for 9 days with tapering of final 2 treatments. All animals received: motor, sensory and cognitive tests; grip strength, rotarod, sensory neglect tests and spatial navigation learning and memory test; and computerized analysis of gait impairment. Results: Functional deficits caused by pMCAO showed modest improvement over time but were still persistent in older rats. Repeated testing (3 times over 8 weeks) did not reduce the effects of injury. Despite modest recovery in vehicle treated rats at eight weeks post-pMCAO, PROG treatment given 3 h after stroke and compared with vehicle group, showed improvement in grip strength by 59.28%, rotarod stability by 46.36 %, reduced sensory neglect by 28.69% and memory deficits by 38.56%. Automated gait assessment showed that PROG treatments significantly improved motor deficits in the affected limb on parameters like stride length, strand, paw print, and swing cycle. Conclusions: 1. The above tested behavioral assays over long-term assessment period, can be used for evaluating therapeutic agents in models of ischemic stroke in older rats. 2 . PROG was found to have sustained effect up to 8 weeks post stroke. PROG shows pre-clinical promise and should be examined for safety and efficacy in a clinical trial for ischemic stroke.

Abstract WP95: Delayed Progesterone Treatment Attenuates Infarct and Behavioral Deficits Induced by Permanent Middle Cerebral Artery Occlusion (pMCAO) in Middle-Aged Rats: Therapeutic Time Window Study

BACKGROUND: Previously we carried out a dose response study and reported 8 mg/kg PROG to be the optimal therapeutic dose following in pMCAO. A systematic preclinical progesterone (PROG) therapeutic time window study is lacking. In the present study we used a clinically relevant middle-aged rat and long-term sensory, motor, and cognitive outcome measures to determine the effects of delayed PROG treatment. METHODS: Male Sprague-Dawley rats (12 months old) underwent pMCAO by electrocoagulation or sham operation. Beginning 3, 6, or 24 h post-occlusion, rats were given IP injections of 8 mg/kg of PROG or vehicle, followed by SC injections at 5 h after the first IP injection and then every 24 h for 7 days. The dose was tapered over the final 2 treatments. Behavioral recovery was evaluated at repeated intervals on sensory, motor, and cognitive tasks. Rats were killed at 22 days post-stroke and brains perfused for infarct evaluation. RESULTS: Three weeks post-pMCAO, PROG treatment delayed by 3 h improved grip strength by 64.48%, rotarod stability by 94.29%, sensory neglect by 94.48%, and long-term memory deficits by 60.56%. PROG treatment delayed by 6 h improved grip strength by 82.62%, rotarod stability by 75.89%, sensory neglect by 60.14%, and long-term memory deficits by 60.16%. Automated, computer-assisted gait assessment showed that PROG treatments significantly improved motor deficits in the affected limb on parameters like stride length, paw print and swing speed. When PROG treatment was compared to non-treated group, a significant reduction of 49.59 and 58.06% in infarct size was observed with 3- ( F (1,14) = 8.25, p <0.01) and 6-h delay of treatment ( F (1,13) = 4.44, p <0.05), respectively. CONCLUSION: The therapeutic dose of 8 mg/kg PROG was found to be effective within a large therapeutic time window. After both 3- and 6-h delays, PROG was effective in improving motor, sensory and memory function deficit. A 24-h treatment delay did not produce significant improvement in most of the outcome measures. PROG shows pre-clinical promise and should be examined for safety and efficacy in a clinical trial for ischemic stroke.

Infarction in the territory of the anterior cerebral artery

Infarction in the anterior cerebral artery (ACA) territory is an uncommon cause of stroke. The clinical findings of ACA infarctions are not fully characterized but include contralateral hemiparesis, urinary incontinence, transcortical aphasia, agraphia, apraxia, and executive dysfunction. We report a patient with a large right ACA infarction, who in addition to previously reported findings also had a complete hemiplegia, profound sensory neglect, and micrographia.