Cellular and molecular mechanisms underlying neurorehabilitation after stroke in aged subjects.

Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are uncertain. Therefore studying the basic mechanism underlying functional recovery after brain ischemia in aged subjected it is of considerable clinical interest. Potential mechanisms include neuroinflammation, changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Available data indicate that behaviorally, aged rats were more severely impaired by ischemia than were young rats, and they also showed diminished functional recovery. Further, as compared to young rats, aged rats develop a larger infarct area, as well as a necrotic zone characterized by a higher rate of cellular degeneration, and a larger number of apoptotic cells. In both old and young rats, the early intense proliferative activity following stroke leads to a precipitous formation of growth-inhibiting scar tissue, a phenomenon amplified by the persistent expression of neurotoxic factors. Reduced transcriptional activity in the healthy, contralateral hemisphere in conjunction with an early upregulation of DNA damage related genes and the early induction of proapoptotic genes in the periinfarct area of aged rats are likely to account for poor neurorehabilitation after stroke in aged rats. Finally, the regenerative potential of the rat brain is largely preserved up to 20 months of age but gene expression is temporally displaced, has lower amplitude, and is sometimes of relatively short duration. Most interestingly, it has recently been shown that the human brain can respond to stroke with increased progenitor proliferation in aged patients opening the possibilities to utilize this intrinsic attempt for neuroregeneration of the human brain as a potential therapy for stroke. Given the heterogeneity of stroke, a universal anti-inflammatory solution may be a distant prospect, but probably neuroprotective drug cocktails targeting inflammatory pathways in combination with thrombolysis may be a possibility for acute stroke treatment in the future.

Modified variant of the Rieske iron-sulfur protein in the hippocampus of kindled rats and human epileptic patients.

Kindled seizures are widely used to model epileptogenesis, but the molecular mechanisms underlying the attainment of kindling status are largely unknown. Recently we showed that achievement of kindling status in the Sprague-Dawley rat is associated with a critical developmental interval of 25 +/- 1 days; the identification of this long, well-defined developmental interval for inducing kindling status makes possible a dissection of the cellular and genetic events underlying this phenomenon and its relationship to normal and pathological brain function. Now we report the identification, by proteomics, of a modified variant of the Rieske iron-sulfur protein, a component of the mitochondrial cytochrome bc1 complex, whose isoelectric point is shifted toward more alkaline values in the hippocampus of kindled rats. By immunohistochemistry the Rieske protein is well-expressed in the hippocampus except in the CA1 subfield, a region of selective vulnerability to seizures in humans and animal models. We also noted an asymmetric, selective expression of the Rieske protein in the subgranular neurons of the dorsal dentate gyrus, a region implicated in neurogenesis. Abnormal changes in Rieske protein immunoreactivity also were found in sections obtained from human epileptic patients. These results suggest that the Rieske protein may play a role in the response of neurons to seizure activity and could give important new insights into the molecular pathogenesis of epilepsy.