Accelerated infarct development, cytogenesis and apoptosis following transient cerebral ischemia in aged rats

Abstract

Old age is associated with a deficient recovery from stroke, but the cellular mechanisms underlying such phenomena are poorly understood. To address this issue, focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. Aged rats showed a delayed and suboptimal functional recovery in the post-stroke period. Using BrdU-labeling, quantitative immunohistochemistry and 3-D reconstruction of confocal images, we found that aged rats are predisposed to rapidly develop an infarct within the first few days after ischemia. The emergence of the necrotic zone is associated with a high rate of cellular degeneration, premature accumulation of proliferating BrdU-positive cells that appear to emanate from capillaries in the infarcted area, and a large number of apoptotic cells. With double labeling techniques, we were able to identify, for the first time, over 60% of BrdU-positive cells either as reactive microglia (45%), oligodendrocyte progenitors (17%), astrocytes (23%), CD8+ lymphocytes (4%), or apoptotic cells (<1%). Paradoxically, despite a robust reactive phenotype of microglia and astrocytes in aged rats, at 1-week post-stroke, the number of proliferating microglia and astrocytes was lower in aged rats than in young rats. Our data indicate that aging is associated with rapid infarct development and a poor prognosis for full recovery from stroke that is correlated with premature cellular proliferation and increased cellular degeneration and apoptosis in the infarcted area.

Aging Neural Progenitor Cells Have Decreased Mitochondrial Content and Lower Oxidative Metabolism

“…Together, these results suggest that regulation of metabolic machinery, including mitochondrial quantity and proteomic content, contributes to age-specific metabolic strategies utilized by NPCs. These data provide a cellular mechanism underlying the increased proliferative response of aged NPCs to hypoxic conditions, which has been reported in vivo (30,31). It is possible that the more anaerobic metabolic strategy favored by aged cells may be due to a predisposition of individual cells toward an astrocytic, lactate-secreting phenotype.…”

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

“…To date, however, experimental studies of radiation-induced inflammation, brain injury and cognitive dysfunction have been conducted almost exclusively in animals a few weeks to a few months old, young ages that do not reflect important neurobiological changes that occur with normal aging, such as decreased proliferation and neurogenesis (15)(16)(17)(18), increased microglial activation (19,20) and expression of pro-inflammatory cytokines (20)(21)(22). Experimental studies of stroke, traumatic brain injury, exogenous cytokine administration, and axotomy support the hypothesis that aging impacts the intensity and duration of brain inflammation and glial activation following challenges (23)(24)(25)(26)(27)(28). Moreover, evidence that old age impacts the duration of some radiation-induced cognitive deficits in rodents (29,30) suggests greater radiation-induced injury in older rats.…”

Age-dependent modifications in vascular adhesion molecules and apoptosis after 48-h reperfusion in a rat global cerebral ischemia model

“…The similar amounts of the total number of neuronal nuclei for the different conditions and the general similar percentages of apoptotic cells led us to assume that differences in the pattern of caspase labelling mirror differences in the apoptotic time-course rather than the total amount of death due to apoptosis. Studies carried out using a middle cerebral artery occlusion (MCAO) model indicate that cell death in aged animals is higher after 3 days of the injury (Popa-Wagner et al 2007). However, the time-course of cell death in this model and the one studied here is difficult to compare.…”

“…However, the time-course of cell death in this model and the one studied here is difficult to compare. The areas studied in the MCAO model are close to the infarct core (Popa-Wagner et al 2007), while our model simulates only the penumbra area. The distance of a cell to the infarct core is crucial in deciding whether the cell survives or dies, and obviously, the onset of apoptosis can be radically different.…”

“…The results from the young animals confirm the ischemia-dependent decrease in GFAP expression that was previously described 48 h after reperfusion in a 4VO model of global ischemia in young Wistar rats (Zhang et al 2007). Several studies provide evidence that aging brain reacts stronger to I/R with an early inflammation response (Badan et al 2003;Popa-Wagner et al 2007;Buga et al 2013), and it has been reported that aged Sprague-Dawley rats present an early glial scar in an MCAO model (Popa-Wagner et al 2006). Also, GFAP reactivity in humans has been described to depend on the age of patient (Dziewulska 1997).…”