Aerobic Physical Training Attenuates Oxidative Stress in the Spinal Cord of Adult Rats Induced by Binge-like Ethanol Intake.

Binge drinking is the most frequent consumption pattern among young adults and remarkably changes the central nervous system; thus, research on strategies to protect it is relevant. This study aimed to investigate the detrimental effects of binge-like EtOH intake on the spinal cord of male rats and the potential neuroprotective effects provided by moderate-intensity aerobic physical training. Male Wistar rats were distributed into the 'control group', 'training group', 'EtOH group', and 'training + EtOH'. The physical training protocol consisted of daily 30-min exercise on a treadmill for 5 consecutive days followed by 2 days off during 4 weeks. After the fifth day of each week, distilled water ('control group' and 'training group') or 3 g/kg of EtOH diluted at 20% w/v ('EtOH group' and 'training + EtOH group') was administered for 3 consecutive days through intragastric gavage to simulate compulsive consumption. Spinal cord samples were collected for oxidative biochemistry and morphometric analyses. The binge-like EtOH intake induced oxidative and tissue damage by decreasing reduced glutathione (GSH) levels, increasing lipid peroxidation (LPO), and reducing motor neurons (MN) density in the cervical segment. Even under EtOH exposure, physical training maintained GSH levels, reduced LPO, and prevented MN reduction at the cervical segment. Physical training is a non-pharmacological strategy to neuroprotect the spinal cord against oxidative damage induced by binge-like EtOH intake.

Astrocytosis, Inflammation, Axonal Damage and Myelin Impairment in the Internal Capsule following Striatal Ischemic Injury.

Secondary degeneration is defined as a set of destructive events that damage cells and structures that were initially spared or only peripherally affected by the primary insult, constituting a key factor for functional impairment after traumatic brain injury or stroke. In the present study, we evaluated the patterns of astrocytosis, inflammatory response, axonal damage and oligodendrocytes/myelin impairment in the internal capsule following a focal injection of endothelin-1 (ET-1) into the dorsal striatum. Animals were perfused at 1, 3 and 7 post-lesion days (PLD), and tissue was processed to immunohistochemistry for neutrophils (MBS1), macrophages/microglia (ED1), astrocytes (GFAP), axonal lesion (ßAPP), oligodendrocytes (Tau) and myelin (MBP). A significant number of neutrophils was observed at 1PLD, followed by intense recruitment/activation of macrophages/microglia at 3PLD and astrocytic reaction with a peak at 7PLD. Oligodendrocyte damage was pronounced at 3PLD, remaining at 7PLD. Progressive myelin impairment was observed, with reduction of immunoreactivity at 7PLD. Axonal lesion was also identified, mainly at 7PLD. Our results indicate that acute inflammatory response elicited by the ischemic insult in the striatum can be associated with the axonal impairment and damage of both oligodendrocytes and myelin sheath identified in the internal capsule, which may be related to loss of tissue functionality observed in secondary degeneration.

Methylmercury Causes Neurodegeneration and Downregulation of Myelin Basic Protein in the Spinal Cord of Offspring Rats after Maternal Exposure.

Methylmercury (MeHg) is one of the most dangerous toxic pollutants spread throughout the earth. Chronic MeHg intoxication by contaminated food ingestion is the most common threat to human health, including impairment to the developing fetus. The present study aims at investigating the effects of maternal exposure to MeHg during gestation and lactation on the spinal cord of offspring. Pregnant rats received oral doses of MeHg (40 µg/kg/day) over a period of 42 days (21 gestation and 21 lactation). Control animals received the vehicle only. Total mercury concentration was measured in blood samples from offspring collected at the 41st postnatal day. Counting of motor neurons and immunoreactivity for myelin basic protein (MBP) were assessed in the spinal cords in both control and MeHg-intoxicated animals. Our results showed that MeHg promoted an increase in blood Hg levels. In addition, it caused a reduction in the number of spinal cord motor neurons as well as decreased MBP immunoreactivity in the cervical, thoracic and lumbar segments. Our present findings suggest that MeHg intoxication during rat pregnancy and lactation is associated with a pattern of motor neuron degeneration and downregulation of myelin basic protein in different segments of a developing spinal cord. Further studies are needed to establish the effect of MeHg intoxication in both young and adult rats.

Inflammatory Response and Secondary White Matter Damage to the Corpus Callosum after Focal Striatal Stroke in Rats.

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 later oligodendrocyte death and myelin impairment. Our results suggest that secondary white matter damage in the CC follows a primary focal striatal ischemia in adult rats.

Compensatory Hippocampal Neurogenesis in the Absence of Cognitive Impairment Following Experimental Hippocampectomy in Adult Rats.

Temporal lobe epilepsy (TLE) is the commonest type of focal epilepsy in adult humans, and hippocampal sclerosis (HS) is the main pathological finding in this type of epilepsy. In refractory TLE, patients are indicated for unilateral resection of the affected hippocampus by a surgical procedure called hippocampectomy which generally does not cause any cognitive impairment. Once adult hippocampus is a region of endogenous neurogenesis, even in elderly people, we have hypothesized that a compensatory increase in hippocampal neurogenesis might occur in the remaining hippocampus after unilateral hippocampectomy. To test this hypothesis, we performed unilateral hippocampectomy in adult Wistar rats, which were perfused at 15 (G15) and 30 (G30) days post-surgery. Eighteen Wistar rats were randomly distributed in the following experimental groups: control (no surgery, N = 6), G15 (N = 6), and G30 (N = 6). Adjacent cortex and hippocampus of the left hemisphere were completely removed. Behavioral procedures were performed to address possible cognitive impairments. Brains were collected and fixed from animals belonging to all experimental groups. Gross histopathology was performed using thionine staining. Neuroblasts and mature neurons were immunolabeled using anti-doublecortin (DCX) and anti-NeuN antibodies, respectively. Numbers of DCX and NeuN positive cells were quantified for all experimental groups. Animals submitted to hippocampectomy did not present any cognitive impairment as evaluated by eight-arm radial maze behavioral test. The remaining hippocampus presented a higher number of DCX positive cells compared to control (p < 0.001, ANOVA-Tukey) at both G15 and G30. A higher number of NeuN positive cells were present in the granular layer of dentate gyrus at G30 compared to control and G15 (p < 0.001, ANOVA-Tukey). The data suggest that unilateral hippocampectomy induces compensatory neurogenic effect in the contralateral hippocampus. This may underlie the reported absence of significant cognitive impairment and parallels the findings in human patients submitted to unilateral hippocampectomy to treat refractory TLE.

Adult Hippocampal Neurogenesis and Affective Disorders: New Neurons for Psychic Well-Being.

A paradigm shift in neuroscience was the discovery that new neurons are constantly produced in the adult mammalian brain of several species, including Homo sapiens. These new-born cells are formed in some main neurogenic niches, including the subventricular zone (SVZ) at the margin of the lateral ventricle and subgranular zone (SGZ) in the hippocampal dentate gyrus (DG). In the DG, neuroblasts derive from SGZ progenitors and migrate to the hippocampal granular layer becoming adult granule cells, which are integrated into functional adult circuits. It has been confirmed that adult hippocampal neurogenesis (AHN) is a long-lasting phenomenon in the human brain. The functions of hippocampal new-born cells are not fully established. Experimental studies suggest that they have unique electrophysiological properties, including hyperexcitability, which enable them to regulate adult granule cells. Their specific function depends on the anatomical hippocampal location along the hippocampal dorsal-ventral axis. Dorsal hippocampus plays a more defined role on spatial learning and contextual information, while the ventral hippocampus is more related to emotional behavior, stress resilience and social interaction. Several reports suggest a role for AHN in pattern separation, cognitive flexibility, forgetting and reversal learning. It has been proposed that deficits in AHN might impair normal DG function, including pattern separation and cognitive flexibility, which could play a role on the etiology of affective disorders, such as depression, anxiety and post-traumatic stress disorder (PTSD). In this paper, we review recent scientific evidence suggesting that impairment of AHN may underlie the pathophysiology of affective disorders even in humans and that neurogenesis-inspired therapies may be a promising approach to reduce symptoms of affective disorders in humans.

Microglial activation and adult neurogenesis after brain stroke.

The discovery that new neurons are produced in some regions of the adult mammalian brain is a paradigm-shift in neuroscience research. These new-born cells are produced from neuroprogenitors mainly in the subventricular zone at the margin of the lateral ventricle, subgranular zone in the hippocampal dentate gyrus and in the striatum, a component of the basal ganglia, even in humans. In the human hippocampus, neuroblasts are produced even in elderlies. The regulation of adult neurogenesis is a complex phenomenon involving a multitude of molecules, neurotransmitters and soluble factors released by different sources including glial cells. Microglia, the resident macrophages of the central nervous system, are considered to play an important role on the regulation of adult neurogenesis both in physiological and pathological conditions. Following stroke and other acute neural disorders, there is an increase in the numbers of neuroblast production in the neurogenic niches. Microglial activation is believed to display both beneficial and detrimental role on adult neurogenesis after stroke, depending on the activation level and brain location. In this article, we review the scientific evidence addressing the role of microglial activation on adult neurogenesis after ischemia. A comprehensive understanding of the microglial role after stroke and other neural disorders it is an important step for development of future therapies based on manipulation of adult neurogenesis.

Effects of methylmercury on the pattern of NADPH diaphorase expression and astrocytic activation in the rat.

Mercury (Hg) is an environmental contaminant that poses great risk to human health. However, it is still widely used in artisanal gold-mining enterprises around the world, especially in developing countries. Methylmercury (MeHg) is produced environmentally by biomethylation of inorganic Hg present in water sediments, leading to its subsequent accumulation in the aquatic food chain. Due to its high metabolic rate, the Central Nervous System (CNS) is one of the main targets of MeHg. In the present study, we investigate the impact of chronic MeHg intoxication on NADPH diaphorase (NADPH-d) activity and astrocyte mobilization in the visual cortex of the rat. After 60 days of MeHg administration by oral gavage (0.04 mg/kg/day), tissue samples containing the visual cortex were submitted to measurements of Hg levels, NADPH-d activity, and GFAP immunohistochemistry for identification of astrocytes. MeHg intoxication was associated with increased Hg deposits and with reduced NADPH-d neuropil reactivity in the visual cortex. A morphometric analysis suggested that NADPH-d-positive neurons were mostly spared from MeHg harmful action and intoxicated animals had astrocytic activation similar to the control group. The decrease in NADPH-d neuropil reactivity may be due to the negative effect of chronic MeHg poisoning on both the synthesis and transport of this enzyme in afferent pathways to the visual cortex. The relative resistance of NADPH-d-reactive neurons to chronic MeHg intoxication may be associated with peculiarities in cell metabolism or to a protective role of nitric oxide, safeguarding those neurons from Hg deleterious effects.

Spinal cord neurodegeneration after inorganic mercury long-term exposure in adult rats: Ultrastructural, proteomic and biochemical damages associated with reduced neuronal density.

Mercury chloride (HgCl2) is a chemical pollutant widely found in the environment. This form of mercury is able to promote several damages to the Central Nervous System (CNS), however the effects of HgCl2 on the spinal cord, an important pathway for the communication between the CNS and the periphery, are still poorly understood. The aim of this work was to investigate the effects of HgCl2 exposure on spinal cord of adult rats. For this, animals were exposed to a dose of 0.375 mg/kg/day, for 45 days. Then, they were euthanized, the spinal cord collected and we investigated the mercury concentrations in medullary parenchyma and the effects on oxidative biochemistry, proteomic profile and tissue structures. Our results showed that exposure to this metal promoted increased levels of Hg in the spinal cord, impaired oxidative biochemistry by triggering oxidative stress, mudulated antioxidant system proteins, energy metabolism and myelin structure; as well as caused disruption in the myelin sheath and reduction in neuronal density. Despite the low dose, we conclude that prolonged exposure to HgCl2 triggers biochemical changes and modulates the expression of several proteins, resulting in damage to the myelin sheath and reduced neuronal density in the spinal cord.

Origins of Neural Progenitor Cell-Derived Axons Projecting Caudally after Spinal Cord Injury.

Neural progenitor cells (NPCs) transplanted into sites of spinal cord injury (SCI) extend large numbers of axons into the caudal host spinal cord. We determined the precise locations of neurons in the graft that extend axons into the caudal host spinal cord using AAV9-Cre-initiated retrograde tracing into floxed-TdTomato-expressing NPC grafts. 7,640 ± 630 grafted neurons extended axons to a single caudal host spinal cord site located 2 mm beyond the lesion, 5 weeks post injury. While caudally projecting axons arose from neurons located in all regions of the graft, the majority of caudally projecting graft neurons (53%) were located within the caudal one-third of the graft. Numerous host corticospinal axons formed monosynaptic projections onto caudally projecting graft neurons; however, we find that the majority of host axonal neuronal projections formed by neural progenitor cell interneuronal "relays" across sites of SCI are likely polysynaptic in nature.

Why microglia kill neurons after neural disorders? The friendly fire hypothesis.

Neuroinflammation plays a fundamental role on the pathophysiology of acute and chronic neural disorders. Microglia activation is a major event following central nervous system inflammation displaying different phenotypes with beneficial and detrimental actions (a Janus face). The reason for this apparent duality is unknown. We have previously shown that following experimental middle cerebral artery occlusion in the rat brain, microglia seem to support and impair adult neurogenesis in the same ischemic striatum. Based on these results, we raised the hypothesis that in the same pathologic environment, gradients of different ligands distributed over different anatomical niches might contribute to both detrimental and beneficial microglial phenotypes. These ligands ("danger signals") are released by dying cells and bind to microglial receptors in their membranes. Activation of different microglial receptors induces downstream biochemical pathways culminating in a spectrum of microglial phenotypes like M1 and M2 and others. In this paper, we first review the immune functions of microglia and the role of toll-like receptors on the fight against infections. We then briefly revise the dual role of microglia after neural disorders. We then propose a novel hypothesis to explain the Janus face of microglia during the pathophysiology of central nervous system diseases: the "friendly fire hypothesis". According to this idea "danger signals" or danger associated molecular patterns released by stressed, damaged and/or dying cells during stroke, trauma and other diseases might activate microglial pattern-recognition receptors (i.e., toll like receptors) or other unidentified receptors normally activated by pathogens. This could activate the same genetic and biochemical machinery used by microglia to fight against pathogens even in the absence of infection. According to this notion, microglia may cause bystander neuronal damage with a kind of blind "friendly fire", fighting against a non-existing infection during non-infectious disorders, like stroke and trauma. The "friendly fire hypothesis" is a novel proposal to explain why microglia may be detrimental and beneficial after acute and chronic neural disorders and may direct future investigations for developing of neuroprotective agents.

Methylmercury intoxication and cortical ischemia: Pre-clinical study of their comorbidity.

Stroke is one of the main causes of human disability worldwide. Ischemic stroke is mostly characterized by metabolic collapse and fast tissue damage, followed by secondary damage in adjacent regions not previously affected. Heavy metals intoxication can be associated with stroke incidence, because of their damaging action in the vascular system. Mercury, in particular, possesses a high tropism by metabolically active regions, such as the brain. In the present study we sought to evaluate whether methylmercury (MeHg) intoxication can aggravate the tissue damage caused by an ischemic stroke induced by microinjections of endothelin-1 (ET-1) into the motor cortex of adult rats. Following MeHg intoxication by gavage (0.04 mg/kg/day) during 60 days, the animals were injected with ET-1 (1 µl, 40 pmol/µl) or vehicle (1 µl). After 7 days, all animals were submitted to behavioral tests and then their brains were processed to biochemical and immunohistochemical analyses. We observed that long-term MeHg intoxication promoted a significant Hg deposits in the motor cortex, with concomitant increase of microglial response, followed by reduction of the neuronal population following ischemia and MeHg intoxication, as well as disturbance in the antioxidant defense mechanisms by misbalance of oxidative biochemistry with increase of both lipid peroxidation and nitrite levels, associated to behavioral deficits. MeHg exposure and cortical ischemia demonstrated that both injuries are able of causing significant neurobehavioural impairments in motor coordination and learning accompanied of an exacerbated microglial activation, oxidative stress and neuronal loss in the motor cortex, indicating that MeHg as a source of metabolic disturbance can act as an important increasing factor of ischemic events in the brain.

Cunaniol-elicited seizures: Behavior characterization and electroencephalographic analyses.

This study aimed at describing the characteristics and properties of seizures induced by cunaniol, a polyacetylenic alcohol isolated from the Clibadium genus, which is ubiquitous in the Amazon biodiversity and its potential use as a convulsant model. Wistar rat behavior was assessed upon cunaniol administration and animals were evaluated for neural activity through electroencephalographic records whereby epidural electrodes were positioned over the motor cortex under cunaniol-elicited seizures and seizure's control using three anticonvulsant agents, namely phenytoin, phenobarbital and diazepam. Cunaniol-induced seizures displayed a cyclic development of electrocorticographic seizures, presenting interictal-like spike and ictal period, which correlates to the behavioral observations and is in line with acute seizures induced by pentylenetetrazole. Cunaniol-elicited seizures were intractable by phenytoin treatment and controlled under the GABAergic activities of phenobarbital and diazepam. The results indicate that the cunaniol-induced changes show characteristics of seizure activity, making this plant compound a suitable animal convulsant model for seizure-related studies that could be used to assist in the development of novel anticonvulsant agents.

Interlimb Dynamic after Unilateral Focal Lesion of the Cervical Dorsal Corticospinal Tract with Endothelin-1.

Handedness is one of the most recognized lateralized behavior in humans. Usually, it is associated with manual superiority regarding performance proficiency. For instance, more than 90% of the human population is considered more skilled with the right hand, which is controlled by the left hemisphere, than with the left. However, during the performance of bimanual tasks, the two hands usually assume asymmetric roles, with one hand acting on objects while the other provides support, stabilizing the object. Traditionally, the role of the two hands is viewed as fixed. However, several studies support an alternate view with flexible assignments for the two hands depending on the task. The supporting role of the hand depends on a closed loop pathway based on proprioceptive inputs from the periphery. The circuit's efferent arm courses through the dorsal corticospinal tract (dCST) in rodents and terminate on spinal cord interneurons which modulate the excitability of motoneurons in the ventral horn. In the present work, we developed an experimental model of unilateral lesion targeting the cervical dCST with microinjections of the vasoconstrictor endothelin-1 (ET-1) to evaluate the degree of flexibility of forelimb assignment during a food manipulation task. Our results show that just 3 days after unilateral corticospinal tract (CST) injury in the cervical region, rats display severe motor impairment of the ipsilateral forepaw together with a remarkable reversal of motor assignment between the forelimbs.

Comparative Therapeutic Effects of Minocycline Treatment and Bone Marrow Mononuclear Cell Transplantation following Striatal Stroke.

We explored the comparative effects of minocycline treatment and intrastriatal BMMC transplantation after experimental striatal stroke in adult rats. Male Wistar adult rats were divided as follows: saline-treated (N = 5), minocycline-treated (N = 5), and BMMC-transplanted (N = 5) animals. Animals received intrastriatal microinjections of 80 pmol of endothelin-1 (ET-1). Behavioral tests were performed at 1, 3, and 7 days postischemia. Animals were treated with minocycline (50 mg/kg, i.p.) or intrastriatal transplants of 106 BMMCs at 24 h postischemia. Animals were perfused at 7 days after ischemic induction. Coronal sections were stained with cresyl violet for gross histopathological analysis and immunolabeled for the identification of neuronal bodies (NeuN), activated microglia/macrophages (ED1), and apoptotic cells (active caspase-3). BMMC transplantation and minocycline reduced the number of ED1+ cells (p < 0.05, ANOVA-Tukey), but BMMC afforded better results. Both treatments afforded comparable levels of neuronal preservation compared to control (p > 0.05). BMMC transplantation induced a higher decrease in the number of apoptotic cells compared to control and minocycline treatment. Both therapeutic approaches improved functional recovery in ischemic animals. The results suggest that BMMC transplantation is more effective in modulating microglial activation and reducing apoptotic cell death than minocycline, although both treatments are equally efficacious on improving neuronal preservation.

Indomethacin treatment reduces microglia activation and increases numbers of neuroblasts in the subventricular zone and ischaemic striatum after focal ischaemia.

Neuroblasts from the subventricular zone (SVZ) migrate to striatum following stroke, but most of them die in the ischaemic milieu and this can be related to exacerbated microglial activation. Here, we explored the effects of the non-steroidal anti-inflammatory indomethacin on microglial activation, neuronal preservation and neuroblast migration following experimental striatal stroke in adult rats. Animals were submitted to endothelin-1 (ET-1)-induced focal striatal ischaemia and were treated with indomethacin or sterile saline (i.p.) for 7 days, being perfused after 8 or 14 days. Immunohistochemistry was performed to assess neuronal loss (anti-NeuN), microglial activation (anti-Iba1, ED1) and migrating neuroblasts (anti-DCX) by counting NeuN, ED1 and DCX-positive cells in the ischaemic striatum or SVZ. Indomethacin treatment reduced microglia activation and the number of ED1+ cells in both 8 and 14 days post injury as compared with controls. There was an increase in the number of DCX+ cells in both SVZ and striatum at the same survival times. Moreover, there was a decrease in the number of NeuN+ cells in indomethacin-treated animals as compared with the control group at 8 days but not after 14 days post injury. Our results suggest that indomethacin treatment modulates microglia activation, contributing to increased neuroblast proliferation in the SVZ and migration to the ischaemic striatum following stroke.

Chronic Alcohol Intoxication and Cortical Ischemia: Study of Their Comorbidity and the Protective Effects of Minocycline.

Chronic alcohol intoxication (CAI) increases both morbidity and mortality of stroke patients. Despite the high prevalence of CAI and ischemic stroke, studies addressing their comorbidity and/or protective alternatives remain scarce. Thus, the influence of CAI on both stroke outcome and minocycline treatment (recognized for its neuroprotective effect) was investigated. Female Wistar rats (35 days old) were treated with water or ethanol (6.5 g/kg/day, 22.5% w/v) for 55 days. Then, focal ischemia was induced by endothelin-1 in the motor cortex. Two hours later, four doses of 50 mg/kg of minocycline every 12 hours followed by five doses of 25 mg/kg every 24 hours were administered. Behavioral performance (open field and rotarod tests) and immunohistochemical (cellular density, neuronal death, and astrocytic activation) and biochemical (lipid peroxidation and nitrite levels) analyses were performed. CAI increased motor disruption, nitrite and lipid peroxidation levels, and neuronal loss caused by ischemia, whereas it reduced the astrogliosis. Minocycline was effective in preventing the motor and tissue damage caused by stroke. However, these effects were attenuated when CAI preceded stroke. Our data suggest that CAI beginning in adolescence contributes to a worse outcome in ischemic stroke survivors and reduces the benefits of minocycline, possibly requiring adjustments in therapy.

Morphometric analysis of NADPH diaphorase reactive neurons in a rat model of focal excitotoxic striatal injury.

Excitotoxicity is the major component in neuropathological conditions, related to harmful action of imbalanced concentrations of glutamate and its agonists in the nervous tissue, ultimately resulting in cell death. In the present study, we evaluated the effects of an acute striatal lesion induced by a focal N-methyl-D-aspartate (NMDA) microinjection on the morphometry of NADPH diaphorase-reactive neurons (NADPH-d+ ), a subset of cells which release nitric oxide (NO) in the brain and are known by its resistance in pathological conditions. Two hundred and forty NADPH-d neurons from NMDA-lesioned striatum and contralateral counterpart were tridimensionally reconstructed at 1, 3 and 7 post-lesion days (PLDs). Cell body and dendritic field areas, length of dendrites by order and fractal dimension were analyzed. There were no significant morphometric differences when NADPH-d+ neurons from lesioned and control striatal regions were compared among PLDs evaluated. Conversely, a conspicuous pallor in striatal neuropil reactivity was evidenced, especially in latter survival time. In addition, we observed a noticeable inflammatory response induced by NMDA. Our results suggest that NADPH-d+ neurons were spared from deleterious effects of acute NMDA excitotoxic damage in the striatum, reinforcing the notion that this cell group is selectively resistant to injury in the nervous system.

Neurodegeneration and Glial Response after Acute Striatal Stroke: Histological Basis for Neuroprotective Studies.

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 14 PLDs. Nogo-A expression was higher in the first week in comparison to control. The results add important histopathological features of ET-1 induced stroke in subacute and chronic survival times. In addition, the establishment of the temporal evolution of these neuropathological events is an important step for future studies seeking suitable neuroprotective drugs targeting neuroinflammation and white matter damage.