Research ReportCombined use of a cytoprotectant and rehabilitation therapy after severe intracerebral hemorrhage in rats
Introduction
Stroke, including ischemic and hemorrhagic events, is a leading cause of death and disability worldwide. Hemorrhagic stroke is one of the least treatable types of stroke and represents ∼15% of all stroke cases in Western populations [33]. Furthermore, up to 30% of ischemic strokes undergo hemorrhagic transformation [28]. An intracerebral hemorrhage (ICH) occurs when a vessel ruptures and blood infiltrates surrounding brain tissue. It causes high mortality (∼50% by 1 month) and poor neurological recovery in survivors [3]. Surgical removal of the hematoma and putative cytoprotectants aimed at treating the consequences of an ICH often fail to substantially improve outcome in humans ([23], [34], [47], but see [32]). Whereas these failures may be partly attributed to study limitations [8], [14], [11], [19], it is also likely that single cytoprotective agents will not sufficiently promote recovery after stroke [17]. Instead, the use of multiple cytoprotective drugs or the combination of a cytoprotectant and rehabilitation (e.g., to enhance recovery of rescued tissue) may be a more promising treatment strategy. Furthermore, severe insults will especially require a combination approach to achieve maximal recovery.
Delayed and prolonged hypothermia (HYPO) persistently reduces brain injury and improves neurological function following a moderate-sized striatal ICH in rats [30] as well as after global [6] and focal ischemia [7]. Furthermore, HYPO is a safe and feasible treatment for stroke in humans [41] and provides benefit after out-of-hospital cardiac arrest [43]. Experimentally, however, greater benefit is conferred after mild to moderate insults than after severe global [4], [5] or focal ischemia [39]. Thus, additional therapies (e.g., rehabilitation) may be needed in conjunction with HYPO to maximally promote recovery after extensive stroke damage. Constraint-induced movement therapy (CIMT) is a rehabilitation approach that involves restraining the less affected limb (ipsilateral to the lesion) to force the use of the impaired limb during daily activities and rehabilitation exercises. It has been repeatedly shown to improve recovery in ischemic stroke and trauma patients [36], [42], [45]. In rats, 7 days of CIMT coupled with daily exercises significantly improved motor performance when initiated 1 week after a moderate-sized ICH [12]. This regimen also reduced the volume of tissue lost, perhaps by reducing cell death and atrophy. CIMT is thought to promote functional improvement by overcoming learned nonuse of the affected limb, cortical reorganization [24], [27], [42] as well as other effects such as enhanced dendritic growth, and alterations in neurotrophins [21], [24].
Combinations of cytoprotective agents have been tested and are recommended [47], but the combination of a cytoprotective agent and subsequent rehabilitation therapy has not been assessed after hemorrhagic stroke. Whereas each treatment improves outcome following a moderate striatal ICH [12], [30], they may only benefit a larger ICH when combined. Therefore, we created a large ICH in rats and tested the efficacy of HYPO, CIMT, and the combination. We used a 60-day survival time with histopathology and multiple functional endpoints to gauge long-term efficacy, which is of greater clinical concern. Functional outcome was assessed with the staircase, cylinder, and ladder tests, which are all sensitive to striatal injury [12], [20], [31], [30]. We hypothesized that the most benefit would occur with the combination of treatments.
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Animals
Sixty-two male Sprague–Dawley rats were used in this study. Animals were obtained locally and weighed approximately 400 g (∼16 weeks old) at the time of ICH. All procedures were approved by the Biosciences Animal Policy and Welfare Committee at the University of Alberta and were in accordance with the guidelines of the Canadian Council on Animal Care.
Montoya staircase task
Prior to surgery, rats were trained in the staircase test, which measures forelimb reaching ability [37]. Starting 3 days before training, rats
Results
In total, 3 animals were excluded from this study. One HYPO + CIMT animal was excluded due to technical error during cooling; one CIMT animal was euthanized 7 days post-ICH because of excessive weight loss; one HYPO + CIMT animal was excluded due to surgical error.
Discussion
Our study examined the interaction of two putative therapies (HYPO, CIMT) currently undergoing clinical investigation for ischemic stroke and with potential to be used for ICH. Our results indicate that CIMT provides small but significant functional benefits after severe subcortical ICH in rats. Use of HYPO alone was neither beneficial nor harmful. These findings contrast with our earlier studies that show substantially improved recovery with HYPO [30] and CIMT [12] following a moderate-sized
Acknowledgments
The authors gratefully acknowledge technical assistance from L. Davies, M. Fingas, S. McGie, and A. Terapoki. Research support was provided to F. Colbourne by the Natural Sciences and Engineering Research Council of Canada (NSERC). F. Colbourne is supported by an Alberta Heritage Foundation for Medical Research Medical Scholar Award, and C. MacLellan is supported by an NSERC Doctoral Canada Graduate Scholarship.
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