The genomic response of the ipsilateral and contralateral cortex to stroke in aged rats

Abstract

Aged rats recover poorly after unilateral stroke, whereas young rats recover readily possibly with the help from the contralateral, healthy hemisphere. In this study we asked whether anomalous, age-related changes in the transcriptional activity in the brains of aged rats could be one underlying factor contributing to reduced functional recovery. We analysed gene expression in the periinfarct and contralateral areas of 3-month- and 18-month-old Sprague Dawley rats. Our experimental end-points were cDNA arrays containing genes related to hypoxia signalling, DNA damage and apoptosis, cellular response to injury, axonal damage and re-growth, cell lineage differentiation, dendritogenesis and neurogenesis. The major transcriptional events observed were: (i) Early up-regulation of DNA damage and down-regulation of anti-apoptosis-related genes in the periinfarct region of aged rats after stroke; (ii) Impaired neurogenesis in the periinfarct area, especially in aged rats; (iii) Impaired neurogenesis in the contralateral (unlesioned) hemisphere of both young and aged rats at all times after stroke and (iv) Marked up-regulation, in aged rats, of genes associated with inflammation and scar formation. These results were confirmed with quantitative real-time PCR. We conclude that reduced transcriptional activity in the healthy, contralateral hemisphere of aged rats in conjunction with an early up-regulation of DNA damage-related genes and pro-apoptotic genes and down-regulation of axono- and neurogenesis in the periinfarct area are likely to account for poor neurorehabilitation after stroke in old rats.

Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia

“…Probably early post-ischemic Alzheimer-related gene dysregulation triggers delayed gene dysfunction in post-stroke patients and old ischemic rats [57][58][59]. Buga et al [57][58][59] have identified an age-related gene expression pattern following brain ischemia.…”

“…Buga et al [57][58][59] have identified an age-related gene expression pattern following brain ischemia. These studies indicated that genes specific for anxiety, depression, stress, and neuropathic syndrome had harmful response to ischemia in aged rats.…”

“…The considerable majority of genes associated with angiogenesis, formation of a new basal lamina and involved in maturation had a delayed overexpression in these rats. Buga et al [57][58][59] have suggested that the angiogenesis response, in above circumstances, was diminished by the continual overexpression of neuroinflammatory and scar formation genes. The ischemia-induced remodeling of brain tissue presented above seems an important event for the final development of neurodegenerative changes.…”

Role of neural precursor cells in promoting repair following stroke

“…Furthermore, the response of NPCs to activation factors such as G-CSF and VEGF have been shown to be attenuated in aged mice [80,138] , or absent with FGF-2 [139] . Gene expression analysis in the ischemic young and aged brains have shown that the aged brain upregulates the expression of genes related to DNA damage, cell cycle arrest, apoptosis, and inflammation, while genes related to axon and dentrite growth are downregulated [140] . These global changes in gene expression may explain the differential response of the aged brain to ischemia.…”

Potential and pitfalls of stem cell therapy in old age

“…In fact, several studies have revealed an impairment in regeneration after brain injury in the aged brain (Popa-Wagner et al, 2009). Young rats recover more quickly than aged rats and undergo complete functional recovery following ischemic cortical injury, whereas aged animals only recover approximately 70% of their pre-stroke motor function (Rosen et al, 2005;Buga et al, 2008). Further highlighting the need to perform studies in appropriate age cohorts is the recent finding that apocynin (a NOX2 inhibitor) administration, a therapy that promotes recovery by reducing oxidative stress following stroke injury in young rats, leads to reduced functional recovery in aged rats (Kelly et al, 2009).…”