Accelerated infarct development, cytogenesis and apoptosis following cerebral ischemia in aged rats (original) (raw)
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Acta Neuropathologica, 2007
Old age is associated with a deWcient 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 Wrst 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 Wrst 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 and disease, 2018
Stroke occurs mostly in patients with advanced age. Elderly patients have a less favorable prognosis compared with young adult patients. To understand the underlying mechanisms, we tested our hypothesis that an increased inflammatory response to acute ischemic injury in old stroke mice leads to more severe brain damage and behavioral dysfunction. An ischemic stroke model was created in 2-and 12-month-old C57BL/6 mice through permanent occlusion of the left distal middle cerebral artery (dMCAO). Infarct/atrophy volumes were quantified by staining the brain sections with Cresyl Violet. Sensorimotor function was assessed using the corner test and adhesive removal test. Quantification of CD68 + cells in the peri-infarct region was performed at 1, 3 and 14 days after dMCAO. Interleukin-6 (IL-6), interleukin-1 β (IL-1β) and vascular endothelial growth factor (VEGF) levels in the ischemic brain tissue were measured using ELISA. Western blot was used to determine the expression levels of tight junction proteins, claudin-5 and zonula occludens (ZO)-1. Blood-brain barrier permeability was measured by Evans blue (EB) extravasation. Gelatinase B (MMP-9, type IV collagenase) was measured by gel zymography. Compared to 2-month-old mice, 12-month-old mice had more severe behavioral deficits at both the acute and chronic stages of stroke. Compared with the 2-month-old mice, 12-month-old mice had larger infarct/atrophy volumes at 1 and 14 days after dMCAO, higher levels of IL-6 and IL-1β, higher MMP9 activity, and lower levels of claudin-5 and ZO-1 at 1 and 3 days after dMCAO. 12-month-old mice also had more CD68 + cells in the peri-infarct region at 1, 3 and 14 days after dMCAO and more EB leakage at 3 days after dMCAO. A higher inflammatory response at the acute stage of ischemic stroke in old mice is associated with more severe neuronal injury and long-term behavioral dysfunction.
Gerontology, 2008
Background: Age-related brain injuries, including stroke, are a major cause of physical and mental disabilities. Objective: Therefore, studying the basic mechanism underlying functional recovery after brain stroke in aged subjects is of considerable clinical interest. Methods: This review summarizes the effects of age on recovery after stroke in an animal model, with emphasis on the underlying cellular mechanisms. Results: Data from our laboratory and elsewhere indicate that, behaviorally, aged rats were more severely impaired by stroke than young rats, and they also showed diminished functional recovery. Infarct volume did not differ significantly between young and aged animals, but critical differences were apparent in the cytological response to stroke, most notably an age-related acceleration in the development of the glial scar. Early infarct in older rats is associated with premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocy...
Attenuated Inflammatory Response in Aged Mice Brains following Stroke
2011
Background: Increased age is a major risk factor for stroke incidence, post-ischemic mortality, and severe and long-term disability. Stroke outcome is considerably influenced by post-ischemic mechanisms. We hypothesized that the inflammatory response following an ischemic injury is altered in aged organisms.
Neuroscience, 2010
Neuroinflammation is associated with glial activation following a variety of brain injuries, including stroke. While activation of perilesional astrocytes and microglia following ischemic brain injury is well documented, the influence of age on these cellular responses after stroke is unclear. This study investigated the influence of advanced age on neuronal degeneration, neuroinflammation, and glial activation in female Sprague-Dawley rats after reversible embolic occlusion of the middle cerebral artery (MCAO). Results indicate that in comparison to young adult rats (3 months), aged rats (18 months) showed enhanced neuronal degeneration, altered microglial response, and a markedly increased expression of proinflammatory cytokines/ chemokines following MCAO. In addition, the time-course for activation of STAT3, the signaling mechanism that regulates astrocyte reactivity, was truncated in the aged rats after MCAO. Moreover, the expression of SOCS3, which is associated with termination of astrogliosis, was enhanced as a function of age after MCAO. These findings are suggestive of an enhanced proinflammatory response and a truncated astroglial response as a function of advanced age following MCAO. These data provide further evidence of the prominent role played by age in the molecular and cellular responses to ischemic stroke and suggest that astrocytes may represent targets for future therapies aimed at improving stroke outcome.
Journal of Neuroinflammation, 2015
Background: Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. Methods: We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young-(2 to 3 months) and middle-aged mice (13 to 14 months). Results: Aging increased both microglial proliferation, as shown by a higher number of BrdU + cells and BrdU/ Iba1 + cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1 + /epidermal growth factor receptor (EGFR) + /nestin + /glial fibrillary acidic protein (GFAP) + cells) and type-C cells (prominin-1 + /EGFR + /nestin − /Mash1 + cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX + cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN + /BrdU + and GAD67 + cells) in the peri-infarct cortical area 14 days after stroke. Conclusions: Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in the cortical peri-infarct area. Thus, our results highlight the importance of using aged animals for translation to clinical studies.
The response of the aged brain to stroke: Too much, too soon?
2007
Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are only recently coming to light. Potential mechanisms include 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. Behaviorally, aged rats are more severely impaired by stroke than are young rats, and they also show diminished functional recovery. Infarct volume does not differ significantly in young and aged animals, but critical differences are apparent in the cytological response to stroke, most notably an age-related acceleration of the establishment of the glial scar. The early infarct in older rats is associated with a premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocytes, a high incidence of neuronal degeneration, and accelerated apoptosis. Regeneration-associated mechanisms in the rat brain are active thoughout life, albeit at lower levels in the aged animals. However; after stroke in aged rats, neuroepithelial marker-positive cells emanating largely from capillaries did not make a significant contribution to neurogenesis in the infarcted cortex of aged animals. Furthermore, the expression of plasticity-associated proteins, such as MAP1B, was delayed in aged rats. Tissue recovery was further delayed by the upregulation of Nogo, ephrin-A5 and MAG, which exert a powerful negative effect on axonal sprouting in the aged peri-infarct cortex, and by an age-related increase in the amount of the neurotoxic C-terminal fragment of the -amyloid precursor protein ( APP) at 2 wks post-stroke. Our findings indicate that the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic response to cerebral insult is dysregulated in aged animals, thereby further compromising functional recovery. Elucidating the molecular basis of this phenomenon in the aging brain could yield novel approaches to neurorestoration following stroke or head injury in the elderly.
Mechanisms of Ageing and Development, 2020
Age is the only one non-modifiable risk of cerebral ischemia. Advances in stroke medicine and behavioral adaptation to stroke risk factors and comorbidities was successful in decreasing stroke incidence and increasing the number of stroke survivors in western societies. Comorbidities aggravates the outcome after cerebral ischemia. However, due to the increased in number of elderly, the incidence of stroke has increased again paralleled by an increase in the number of stroke survivors, many with severe disabilities, that has led to an increased economic and social burden in society. Animal models of stroke often ignore age and comorbidities frequently associated with senescence. This might explain why drugs working nicely in animal models fail to show efficacy in stroke survivors. Since stroke afflicts mostly the elderly comorbid patients, it is highly desirable to test the efficacy of stroke therapies in an appropriate animal stroke model. Therefore, in this review, we make parallels between animal models of stroke und clinical data and summarize the impact of ageing and age-related comorbidities on stroke outcome. 2. The risk of cerebral ischemia increases with age Age is the only one non-modifiable risk of cerebral ischemia. Advances in emergency medicine and primary, secondary and tertiary medical care has led to a 12 % decrease in first stroke incidence in
Stem cell therapies in preclinical models of stroke associated with aging
Frontiers in Cellular Neuroscience, 2014
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.
AGE, 2014
Stroke is one of the leading causes of death and permanent disability in the elderly. However, most of the experimental studies on stroke are based on young animals, and we hypothesised that age can substantially affect the stroke response. The two-vessel occlusion model of global ischemia by occluding the common carotid arteries for 15 min at 40 mmHg of blood pressure was carried out in 3-and 18-month-old male Sprague-Dawley rats. The adhesion molecules E-and P-selectin, cell adhesion molecules (CAMs), both intercellular (ICAM-1) and vascular (VCAM-1), as well as glial fibrillary acidic protein (GFAP), and cleaved caspase-3 were measured at 48 h after ischemia in the cerebral cortex and hippocampus using Western blot, qPCR and immunofluorescence techniques. Diametric expression of GFAP and a different morphological pattern of caspase-3 labelling, although no changes in the cell number, were observed in the neurons of young and old animals. Expression of E-selectin and CAMs was also modified in an age-and ischemia/reperfusiondependent manner. The hippocampus and cerebral cortex had similar response patterns for most of the markers studied. Our data suggest that old and young animals present different time-courses of neuroinflammation and apoptosis after ischemic damage. On the other hand, these results suggest that neuroinflammation is dependent on age rather than on the different vulnerability described for the hippocampus and cerebral cortex. These differences should be taken into account in searching for therapeutic targets.