Strategies to improve post-stroke behavioral recovery in aged subjects

Abstract

Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury. Therefore, find therapeutic strategies aimed at improving functional recovery after brain ischemia in aged subjects is of considerable clinical interest. While environmental enrichment has been shown to improve the behavioral outcome of stroke in young animals, the effect of an enriched environment, hypothermia and Granulocyte-Colony Stimulating Factor (G-CSF) on behavioral and neuropathological recovery in aged animals is not known. Focal cerebral ischemia was produced by occlusion of the right middle cerebral artery in 3-month- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests conducted over a period of 14-28 days following surgery. Brain tissue then was immunostained for proliferating astrocytes and the infarct and scar tissue volumes were measured. Aged rats showed more severe behavioral impairments and diminished functional recovery compared to young rats. Most infarcted animals had disturbances of sensorimotor function, with recovery beginning later, progressing more slowly, and reaching a lower functional endpoint in aged animals. However, the enriched environment significantly improved the rate and extent of recovery in aged animals. Correlation analysis revealed that the beneficial effect of the enriched environment on recovery, both in young and aged rats, correlated highly with a reduction in infarct size, in the number of proliferating astrocytes, and in the volume of the glial scar. These results suggest that temporally modulating astrocytic proliferation and the ensuing scar formation might be a fruitful approach to improving functional recovery after stroke in aged rats. In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. A viable alternative to conventional drug-based neuroprotective therapies is brain/body cooling, or hypothermia. In animal studies of focal ischemia, short-term hypothermia consistently reduces infarct size. Nevertheless, efficient neuroprotection requires long-term, regulated lowering of whole body temperature. In this study, we show that two days post-stroke exposure of aged rats to a mixture of air and a mild inhibitor of oxidative phosphorylation, H2S, causes deep hypothermia (27.8+/-0.3 degrees C) and a 50% reduction in infarct size without obvious neurological deficits or physiological side effects. G-CSF treatment after stroke exerted a robust and sustained beneficial effect on survival rate and running function. Transient improvement after G-CSF treatment could be observed for coordinative motor function on the inclined plane test and for working memory in the radial maze test. At cellular level, G-CSF treatment increased the number of proliferating cells in the SVZ and the dentate gyrus and increased the number of newborn neurons in the SVZ, ipsilateral to the lesion. These results suggests that the G-CSF treatment in aged rats has a survival enhancing capacity and a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis.

Conclusions: These findings are important for the further clinical development of the drug in elderly stroke patients. Future studies should focus on an optimization of treatment schedule to achieve a maximum of post-stroke recovery enhancement in aged subjects.