Constraint-induced movement therapy and rehabilitation exercises lessen motor deficits and volume of brain injury after striatal hemorrhagic stroke in rats.

BACKGROUND AND PURPOSE: Constraint-induced movement therapy (CIMT) promotes motor recovery after occlusive stroke in humans, but its efficacy after intracerebral hemorrhage (ICH) has not been investigated clinically or in the laboratory. In this study we tested whether CIMT and a rehabilitation exercise program would lessen motor deficits after ICH in rats. METHODS: Rats were subjected to striatal ICH (via infusion of collagenase) or sham stroke. Seven days later, treatment began with CIMT (8 h/d of ipsilateral forelimb restraint), rehabilitation exercises (eg, reaching, walking; 1 h/d), or both for 7 days. Some rats were not treated. Motor deficits were assessed up to the 60-day survival time, after which the volume of tissue lost was determined. RESULTS: Untreated ICH rats made more limb slips traversing a horizontal ladder and showed an asymmetry toward less use of the contralateral paw in the cylinder test of limb use asymmetry (day 28). These rats were also significantly less successful in the Montoya staircase test (days 55 to 59) of skilled reaching. Neither therapy alone provided much benefit. However, the combination of daily exercises and CIMT substantially and persistently improved recovery. Unexpectedly, this group had a statistically smaller volume of tissue lost than untreated ICH rats. CONCLUSIONS: The combination of focused rehabilitation exercises and CIMT effectively promotes functional recovery after ICH, while either therapy alone is less effective. This therapy may work in part by reducing the volume of tissue lost, likely through reducing atrophy while promoting remodeling.

Incomplete assessment of experimental cytoprotectants in rodent ischemia studies.

BACKGROUND: Inadequate preclinical testing (e.g., rodent studies) has been partly blamed for the failure of many cytoprotectants to effectively treat stroke in humans. For example, some drugs went to clinical trial without rigorous functional and histological assessment over long survival times. In this study, we characterized recent experimental practices in rodent cytoprotection experiments to determine whether the limitations of early studies have been rectified. METHODS: We identified 138 rodent cytoprotection studies published in several leading journals (Journal of Neuroscience, Stroke, Journal of Cerebral Blood Flow and Metabolism and Experimental Neurology) for 2000-2002 and compared these to those published in 1990. From each study we determined the ischemia model, age and sex of the animal, the histological and functional endpoints used, and the methodology used to assess intra- and postischemic temperature. RESULTS: Ninety-eight percent of recent studies used young adult rodents and most used males. Most studies (60%) did not assess functional outcome and survival times were often < or = 48 hr (66%) for focal ischemia and < or = 7 days (80%) for global ischemia. Over 60% of the experiments relied solely upon rectal temperature during ischemia and only 32.6% of ischemia studies measured temperature after surgery. The 1990 data were similar. CONCLUSIONS: Many investigators ignore the need to assess long-term functional and histological outcome and do not accurately represent clinical conditions of ischemia (e.g., use of aged animals). In addition, intra- and postischemic temperature measurement and control is frequently neglected or inadequately performed. Further clinical failures are likely.

Immediate constraint-induced movement therapy causes local hyperthermia that exacerbates cerebral cortical injury in rats.

Constraint-induced movement therapy (CIMT), which involves restraint of the nonimpaired arm coupled with physiotherapy for the impaired arm, lessens impairment and disability in stroke patients. Surprisingly, immediate ipsilateral forelimb immobilization exacerbates brain injury in rats. We tested whether immediate ipsilateral restraint for 7 days aggravates injury after a devascularization lesion in rats. Furthermore, we hypothesized that ipsilateral restraint aggravates injury by causing hyperthermia. In experiment 1, each rat received two lesions, one in the motor cortex and one in the visual cortex. Ipsilateral restraint increased only the motor cortex lesion. In additional rats, no differences in core temperature occurred after ipsilateral or contralateral restraint. Thus, ipsilateral restraint does not aggravate injury by a systemic side effect. In experiment 2, we hypothesized that ipsilateral restraint causes hyperthermia in the region surrounding the initial cortical lesion. Brain temperature, measured via telemetry, was significantly higher (approximately 1 degrees C for 24 h) with ipsilateral restraint. A third experiment similarly found that ipsilateral restraint aggravates injury and causes local cortical hyperthermia and that contralateral restraint with externally induced mild hyperthermia aggravates injury. In conclusion, immediate ipsilateral restraint aggravates injury apparently by localized events that include hyperthermia. Caution must be exercised in applying early CIMT to humans, as hyperthermia is detrimental.

Stress-induced fever after postischemic rectal temperature measurements in the gerbil.

Postischemic temperature, which modulates brain injury, is commonly determined via a rectal temperature (Trec) probe. This procedure causes a stress-induced fever (SIF) in rodents that may aggravate injury or diminish the efficacy of a neuroprotectant. We continually measured core temperature (Tcore) via an implanted telemetry probe and made 16 Trec measurements over 4 days in sham and ischemic gerbils (5 min bilateral carotid artery occlusion). Controls did not have Trec sampled, but Tcore was measured. Rectal temperature measurements predicted Tcore in sham and ischemic gerbils. The Trec measurements caused a SIF (1 degrees C peak) in shams that did not habituate, whereas the SIF was initially absent and then increased over days in ischemic gerbils. Ischemic groups had similar CA1 injury (approximately 32% remaining), presumably because Trec measurements only resulted in a significant SIF starting on day 2 postischemia, when cell death is less sensitive to hyperthermia. Caution is warranted with Trec measurements, since the resultant SIF occurs to different extents in normal and ischemic rodents. Furthermore, the SIF could vary according to many other factors, such as the type and severity of insult, the time and frequency of measurement, and drug treatment. Accordingly, postischemic Trec measurements should be replaced with telemetry probes.