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ABSTRACT: Aging is associated with a temporally dysregulated cellular response to ischemia as well as poor functional recovery. While environmental enrichment has been shown to improve the behavioral outcome of stroke in young animals, the effect of an enriched environment on behavioral and neuropathological recovery in aged animals is not known.
Focal cerebral ischemia was produced by electrocoagulation 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 28 days following surgery. Brain tissue was then 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.
Restorative neurology and neuroscience 02/2007; 25(5-6):467-84. · 2.51 Impact Factor
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ABSTRACT: Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular mechanisms underlying such phenomena are not known. Using BrdU-labeling, quantitative immunohistochemistry and 3D-reconstruction of confocal images in a rat model of mild cerebral ischemia, we found that aged rats are highly susceptible to develop an early infarct that is associated with premature cellular proliferation originating from the vascular tree. In aged rats we also found a rapid delimitation of the infarct area by capillary-derived neuroepithelial cells and an early incorporation of these cells into the glial scar. Since most proliferating cells at the infarct site are microglia or nestin-positive cells derived from the vascular wall, we conclude that the vasculature plays a hitherto unrecognized role as a source of proliferating neuroepithelial cells after stroke. Age-associated alterations in the timing and origin of the cytogenic response to cerebral ischemia may underlie the poor functional recovery from stroke. Clarifying the molecular basis of these phenomena could yield novel approaches to enhancing neurorestoration in the elderly. Studies of stroke in experimental animals have demonstrated the neuroprotective efficacy of a variety of interventions, but most of the strategies that have been clinically tested failed to show benefit in aged humans. One possible explanation for this discrepancy between laboratory and clinical investigations is the role that age plays in the recovery of the brain from insult. Although it is well known that aging is a risk factor for stroke (Barnett HJ, 2002), the majority of experimental studies of stroke have been performed on young animals, and therefore may not fully replicate the effects of ischemia on neural tissue in aged subjects (Wang LC et al., 1995; Davies M et al., 1995; Sutherland GR et al., 1996; Popa-Wagner A et al., 1998, 1999a). Hence, the aged post-acute animal model is clinically most relevant to stroke rehabilitation and cellular studies (Lindner MD et al., 2003; Brown AW et al., 2003; Badan I et al., 2003).
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie 02/2006; 47(3):215-28. · 0.52 Impact Factor
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ABSTRACT: The age-related decline in plasticity of the brain may be one factor underlying poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity in old age could be the result of an altered temporal relationship between factors promoting brain plasticity [microtubule-associated protein 1B (MAP1B)] and neurotoxic factors such as C-terminal betaAPP. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14 and 28 days after surgery. At the indicated timepoints, brains were removed and immunostained for C- and N-terminal betaAPP and MAP1B. At 2 weeks poststroke, we found an age-related increase in the amount of the C-terminal fragment of betaAPP in the peri-infarcted area and the infarct core as well as an early, vigorous incorporation of N-terminal betaAPP into the developing astroglial scar. The recovery of the plasticity-associated protein MAP1B following stroke was delayed in both age groups and became prominent between days 14 and 28. As aged rats showed diminished functional recovery compared with young rats, these results suggest that the accumulation of C-terminal betaAPP, together with the early incorporation of N-terminal betaAPP into the glial scar, may over-ride the beneficial role of plasticity factors such as MAP1B.
European Journal of Neuroscience 05/2004; 19(8):2270-80. · 3.63 Impact Factor
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ABSTRACT: The age-related decline in plasticity of the brain may be one factor underlying poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity in old age could be the result of an altered temporal relationship between factors promoting brain plasticity [microtubule-associated protein 1B (MAP1B)] and neurotoxic factors such as C-terminal βAPP. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests at 3, 7, 14 and 28 days after surgery. At the indicated timepoints, brains were removed and immunostained for C- and N-terminal βAPP and MAP1B. At 2 weeks poststroke, we found an age-related increase in the amount of the C-terminal fragment of βAPP in the peri-infarcted area and the infarct core as well as an early, vigorous incorporation of N-terminal βAPP into the developing astroglial scar. The recovery of the plasticity-associated protein MAP1B following stroke was delayed in both age groups and became prominent between days 14 and 28. As aged rats showed diminished functional recovery compared with young rats, these results suggest that the accumulation of C-terminal βAPP, together with the early incorporation of N-terminal βAPP into the glial scar, may over-ride the beneficial role of plasticity factors such as MAP1B.
European Journal of Neuroscience 03/2004; 19(8):2270 - 2280. · 3.63 Impact Factor
