The alterations of oligodendrocyte, myelin in corpus callosum, and cognitive dysfunction following chronic cerebral ischemia in rats (original) (raw)
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International Journal of Molecular Sciences, 2022
Stroke is one of the leading causes of death and long-term disabilities worldwide, resulting in a debilitating condition occasioned by disturbances in the cerebral vasculature. Primary damage due to metabolic collapse is a quick outcome following stroke, but a multitude of secondary events, including excitotoxicity, inflammatory response, and oxidative stress cause further cell death and functional impairment. In the present work, we investigated whether a primary ischemic damage into the dorsal striatum may cause secondary damage in the circumjacent corpus callosum (CC). Animals were injected with endothelin-1 and perfused at 3, 7, 14, and 30 post-lesion days (PLD). Sections were stained with Cresyl violet for basic histopathology and immunolabeled by antibodies against astrocytes (anti-GFAP), macrophages/microglia (anti-IBA1/anti MHC-II), oligodendrocytes (anti-TAU) and myelin (anti-MBP), and Anti-Nogo. There were conspicuous microgliosis and astrocytosis in the CC, followed by la...
Molecular Medicine Reports, 2019
The differentiation and maturation of oligodendrocyte precursor cells (oPcs) is important for remyelination in the central nervous system. nevertheless, this process is often limited and incomplete in ischemic injury. oligodendrocyte transcription factor 1 (olig1) is important for the maturation of oPcs and the repair of demyelinated lesions. However, how olig1 modulates the development of oPcs or the remyelination associated with ischemic injury remains unclear. The present study aimed to examine alterations in oPcs, and the expression of myelin and olig1, at different time-points after focal cerebral ischemia using immunohistochemistry and western blot techniques to elucidate the role of olig1 in the maturation of oPcs and remyelination. The present results showed that the expression of Olig1 significantly decreased at 1 day after middle cerebral artery occlusion (Mcao) and returned to normal levels from day 3 to 28. additionally, olig1 was found to translocate into the nucleus following ischemia in the brain. The number of OPCs in the ischemic striatum significantly declined at days 1 and 3 following Mcao, and increased at days 7, 14 and 28 compared with the control. The expression of myelin basic protein, a marker of mature oligodendrocytes and myelin, gradually decreased from day 1 to 7 after ischemia and recovered at day 14 and 28; however, the levels were lower than those in the control group. The present results indicated that the restored normal level of olig1 following ischemia may play an important role in the maturation of oPcs through its translocation into the nucleus, where it may promote the growth and development of myelin under pathological conditions. However, this endogenous recovery mechanism fails to fully repair the demyelinated lesion. The data of the present study may help clinicians understand the expression pattern of olig1 and its potential role in endogenous remyelination after ischemia, which may have implications for the treatment of diseases that lead to demyelination.
Neurodegeneration, Myelin Loss and Glial Response in the Three-Vessel Global Ischemia Model in Rat
International Journal of Molecular Sciences, 2020
(1) Background: Although myelin disruption is an integral part of ischemic brain injury, it is rarely the subject of research, particularly in animal models. This study assessed for the first time, myelin and oligodendrocyte loss in a three-vessel model of global cerebral ischemia (GCI), which causes hippocampal damage. In addition, we investigated the relationships between demyelination and changes in microglia and astrocytes, as well as oligodendrogenesis in the hippocampus; (2) Methods: Adult male Wistar rats (n = 15) underwent complete interruption of cerebral blood flow for 7 min by ligation of the major arteries supplying the brain or sham-operation. At 10 and 30 days after the surgery, brain slices were stained for neurodegeneration with Fluoro-Jade C and immunohistochemically to assess myelin content (MBP+ percentage of total area), oligodendrocyte (CNP+ cells) and neuronal (NeuN+ cells) loss, neuroinflammation (Iba1+ cells), astrogliosis (GFAP+ cells) and oligodendrogenesis (NG2+ cells); (3) Results: 10 days after GCI significant myelin and oligodendrocyte loss was found only in the stratum oriens and stratum pyramidale. By the 30th day, demyelination in these hippocampal layers intensified and affected the substratum radiatum. In addition to myelin damage, activation and an increase in the number of microglia and astrocytes in the corresponding layers, a loss of the CA1 pyramidal neurons, and neurodegeneration in the neocortex and thalamus was observed. At a 10-day time point, we observed rod-shaped microglia in the substratum radiatum. Parallel with ongoing myelin loss on the 30th day after ischemia, we found significant oligodendrogenesis in demyelinated hippocampal layers; (4) Conclusions: Our study showed that GCI-simulating cardiac arrest in humans-causes not only the loss of pyramidal neurons in the CA1 field, but also the myelin loss of adjacent layers of the hippocampus.
Oligodendrocyte Pathophysiology and Treatment Strategies in Cerebral Ischemia
CNS Neuroscience & Therapeutics, 2014
Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system, form a functional unit with axons and play a crucial role in axonal integrity. An episode of hypoxia-ischemia causes rapid and severe damage to these particularly vulnerable cells via multiple pathways such as overactivation of glutamate and ATP receptors, oxidative stress, and disruption of mitochondrial function. The cardinal effect of OL pathology is demyelination and dysmyelination, and this has profound effects on axonal function, transport, structure, metabolism, and survival. The OL is a primary target of ischemia in adult-onset stroke and especially in periventricular leukomalacia and should be considered as a primary therapeutic target in these conditions. More emphasis is needed on therapeutic strategies that target OLs, myelin, and their receptors, as these have the potential to significantly attenuate white matter injury and to establish functional recovery of white matter after stroke. In this review, we will summarize recent progress on the role of OLs in white matter ischemic injury and the current and emerging principles that form the basis for protective strategies against OL death.
Brain Research, 2005
The effects of oligemia (moderate ischemia) on the brain need to be explored because of the potential role of subtle microvascular changes in vascular cognitive impairment and dementia. Chronic bilateral common carotid artery occlusion (BCCAO) in adult rats has been used to study effects of oligemia (hypoperfusion) using neuropathological and neurochemical analysis as well as behavioral tests. In this study, BCCAO was induced for 1 week, or 2, 4, and 6 months. Sensitive immunohistochemistry with marker proteins was used to study reactions of astrocytes (GFAP, nestin), and lectin binding to study microglial cells during BCCAO. Overt neuronal loss was visualized with NeuN antibodies. Astrocytes reacted to changes in the optic tract at all time points, and strong glial reactions also occurred in the target areas of retinal fibers, indicating damage to the retina and optic nerve. Astrocytes indicated a change in the corpus callosum from early to late time points. Diffuse increases in GFAP labeling occurred in parts of the neocortex after 1 week of BCCAO, in the absence of focal changes of neuronal marker proteins. No significant differences emerged in the cortex at longer time points. Nestin labeling was elevated in the optic tract. Reactions of microglia cells were seen in the cortex after 1 week. Measurements of the basilar artery indicated a considerable hypertrophy, indicative of macrovascular compensation in the chronic occlusion model. These results indicate that chronic BCCAO and, by inference, oligemia have a transient effect on the neocortex and a long-lasting effect on white matter structures. D
Oxidative medicine and cellular longevity, 2016
Stroke is a leading cause of death and neurological disability worldwide and striatal ischemic stroke is frequent in humans due to obstruction of middle cerebral artery. Several pathological events underlie damage progression and a comprehensive description of the pathological features following experimental stroke in both acute and chronic survival times is a necessary step for further functional studies. Here, we explored the patterns of microglial activation, astrocytosis, oligodendrocyte damage, myelin impairment, and Nogo-A immunoreactivity between 3 and 30 postlesion days (PLDs) after experimental striatal stroke in adult rats induced by microinjections of endothelin-1 (ET-1). The focal ischemia induced tissue loss concomitant with intense microglia activation between 3 and 14 PLDs (maximum at 7 PLDs), decreasing afterward. Astrocytosis was maximum around 7 PLDs. Oligodendrocyte damage and Nogo-A upregulation were higher at 3 PLDs. Myelin impairment was maximum between 7 and 1...
Journal of Cerebral Blood Flow & Metabolism, 2010
Vascular dementia is caused by blockage of blood supply to the brain, which causes ischemia and subsequent lesions primarily in the white matter, a key characteristic of the disease. In this study, we used a chronic cerebral hypoperfusion rat model to show that the regeneration of white matter damaged by hypoperfusion is enhanced by inhibiting phosphodiesterase III. A rat model of chronic cerebral hypoperfusion was prepared by bilateral common carotid artery ligation. Performance at the Morris water-maze task, immunohistochemistry for bromodeoxyuridine, as well as serial neuronal and glial markers were analyzed until 28 days after hypoperfusion. There was a significant increase in the number of oligodendrocyte progenitor cells in the brains of patients with vascular dementia as well as in rats with cerebral hypoperfusion. The oligodendrocyte progenitor cells subsequently underwent cell death and the number of oligodendrocytes decreased. In the rat model, treatment with a phosphodiesterase III inhibitor prevented cell death, markedly increased the mature oligodendrocytes, and promoted restoration of white matter and recovery of cognitive decline. These effects were cancelled by using protein kinase A/C inhibitor in the phosphodiesterase III inhibitor group. The results of our study indicate that the mammalian brain white matter tissue has the capacity to regenerate after ischemic injury.
Cell and Tissue Biology, 2016
⎯It is known that the mechanisms of brain damage after a stroke are regulated by interaction within several cell types, primarily neurons, astrocytes, the endothelium, and microglia. Ischemic exposure disrupts the balance in the brain cellular content; thus, in the lesion, cells die by necrosis, while delayed induction of apoptosis occurs in the tissue surrounding the ischemic zone. Named cells die in the lesion and their ratio determines the clinical outcome of the disease. Thus, the detection of deaths within various cell types of the neurovascular unit is an important part of fundamental studies of the mechanisms of brain damage and preclinical studies of potential neuroprotective drugs. For this reason, we conducted a comparative study of the two most often used methods: immunohistochemical staining of brain sections, which allows to determine the number and localization of specific cells in the tissue among other types of cells, and immunoblotting, which detects specific proteins in the tissue homogenate. We found that, depending on the cell type, changes in their number and composition after a stroke can be localized in a limited part of the tissue or cover the entire hemisphere, which imposes restrictions on the use of any method of determining the number of cells in brain tissue. In general, the most preferable is the use of immunohistochemistry; however, with certain limitations, immunoblotting can be used to determine the proportion of astroglia and microglia.