Annexin A3 expression after stroke in the aged rat brain.

In an effort to identify new proteins involved in functional recovery after cerebral ischemia, young (3 months) and aged (18 months) male rats were subjected to middle cerebral artery (MCA) occlusion. Brains were harvested at 3- and 14-days post ischemia and proteins from the peri-infarcted and the corresponding contralateral area and total proteins were analyzed by two-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry analysis. Annexin A3 (ANXA3) was identified as one upregulated protein in the post-ischemic rat brain. Using western blotting, real-time PCR and immunohistochemistry, we confirmed that at 3-14 days post-stroke, ANXA3 expression in the peri-infarct area was consistently increased over the corresponding area of control rats. Double staining revealed that ANXA3 is produced by activated microglial cells. We found that aged rats also had more newly proliferating cells expressing ANXA3 than young rats do. Occasionally, ANXA3-immunopositive cells wraped around neurons, suggesting that annexin A3 may be involved in the removal of dying neurons after stroke.

Environmental enrichment improves functional and neuropathological indices following stroke in young and aged rats.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Stroke: epidemiology, risk factors, and genetics]. / Schlaganfall: Epidemiologie, Risikofaktoren und Genetik.

Stroke constitutes a major global challenge for health policy and healthcare economics. Reducing stroke burden requires extensive knowledge of risk factors and, if applicable, preventive control. Risk factors may be categorized in non-modifiable biological factors, such as age, gender, race/ethnicity; proatherosclerotic/prothrombotic factors (hypertension, diabetes, dyslipidaemia, other serologic and haemostasis factors); cardiac comorbidity (CAD, CHF, atrial fibrillation); lifestyle factors, which play an increasing role, e.g. smoking, physical inactivity, alcohol consumption. These traditional risk factors are extended by rapidly growing efforts in elucidating genetic backgrounds for stroke. Genetic polymorphisms of functionally or pathophysiologically important proteins are investigated in the setting of case-control-studies for their role as candidate genes. Meta-analyses have corroborated the association of the factor V-Leiden arg506gln, MTHFR-C677T, and ACE-insertion-deletion polymorphisms with stroke. Current population-based, genome-wide linkage analyses face high expectations for identifying new genetic risk factors.

Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery.

Following cerebral ischemia, perilesional astrocytes and activated microglia form a glial scar that hinders the genesis of new axons and blood vessels in the infarcted region. Since glial reactivity is chronically augmented in the normal aging brain, the authors hypothesized that postischemic gliosis would be temporally abnormal in aged rats compared to young rats. 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. Brain tissue was immunostained for microglia, astrocytes, oligodendrocytes, and endothelial cells. Behaviorally, aged rats were more severely impaired by stroke and showed diminished functional recovery compared with young rats. Histologically, a gradual activation of both microglia and astrocytes that peaked by days 14 to 28 with the formation of a glial scar was observed in young rats, whereas aged rats showed an accelerated astrocytic and microglial reaction that peaked during the first week after stroke. Oligodendrocytes were strongly activated at early stages of infarct development in all rats, but this activation persisted in aged rats. Therefore, the development of the glial scar was abnormally accelerated in aged rats and coincided with the stagnation of recovery in these animals. These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats leads to the premature formation of scar tissue that impedes functional recovery after stroke.

Age influences the expression of GAP-43 in the rat hippocampus following seizure.

BACKGROUND: Normal aging is associated with impairments in learning and memory and motor function. One viable hypothesis is that these changes reflect an age-related decrease in brain plasticity. OBJECTIVE: The aim of the present study was to identify age-related changes in the time course of expression of the axonal growth associated protein 43 (GAP-43) in a rat model of brain plasticity. METHODS: We examined by Northern blotting, in situ hybridization, and immunohistochemistry the effects of age on the time course of the expression GAP-43 following pentylenetetrazole-induced seizure in the hippocampus of 3-, 18-, and 28-month-old rats. RESULTS: In this model of brain plasticity, young rats displayed a decrease in GAP-43 mRNA levels in CA1, CA3, and polymorphic regions, lasting from 10 h to 3 days after seizure. This was followed by recovery, with peak expression between days 10 and 20. The baseline levels of GAP-43 mRNA decreased with age, especially in the CA3 region. Despite lower baseline levels, middle-aged rats showed the same pattern of upregulation of GAP-43 mRNA expression as the young animals. Old rats showed only minimal upregulation, however, and this occurred only in the polymorphic layer. The level GAP-43 protein itself was higher in old control rats than in the other two control groups, a condition that was transiently reversed by seizure activity. CONCLUSIONS: Middle-aged rats are still capable of a sustained, though diminished, response to seizure activity, while old rats lose this ability. Disruption of the temporal and anatomical coordination of expression of GAP-43 may contribute to the general decline in brain plasticity with age.