myelin-basic-protein and Atrophy

Animal models of N-methyl-d-aspartate receptor (NMDAR) antagonism have been widely used for schizophrenia research. Less is known whether these models are associated with macroscopic brain structural changes that resemble those in clinical schizophrenia.. Magnetic resonance imaging (MRI) was used to measure brain structural changes in rats subjected to repeated administration of MK801 in a regimen (daily dose of 0.2mg/kg for 14 consecutive days) known to be able to induce schizophrenia-like cognitive impairments.. Voxel-based morphometry (VBM) revealed significant gray matter (GM) atrophy in the hippocampus, ventral striatum (vStr) and cortex. Diffusion tensor imaging (DTI) demonstrated microstructural impairments in the corpus callosum (cc). Histopathological results corroborated the MRI findings.. Treatment-induced behavioral abnormalities were not measured such that correlation between the brain structural changes observed and schizophrenia-like behaviors could not be established.. Chronic MK801 administration induces MRI-observable brain structural changes that are comparable to those observed in schizophrenia patients, supporting the notion that NMDAR hypofunction contributes to the pathology of schizophrenia. Imaging-derived brain structural changes in animal models of NMDAR antagonism may be useful measurements for studying the effects of treatments and interventions targeting schizophrenia.

Topics: Animals; Atrophy; Brain; Diffusion Tensor Imaging; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gray Matter; Image Processing, Computer-Assisted; Immunohistochemistry; Magnetic Resonance Imaging; Male; Myelin Basic Protein; Parvalbumins; Random Allocation; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Schizophrenia

After stroke, the blood-brain barrier is transiently disrupted, allowing leukocytes to enter the brain and brain antigens to enter the peripheral circulation. This encounter of normally sequestered brain antigens by the systemic immune system could therefore present an opportunity for an autoimmune response to brain to occur after stroke. In this study, we assessed the immune response to myelin basic protein (MBP) in animals subjected to middle cerebral artery occlusion (MCAO). Some animals received an intraperitoneal injection of lipopolysaccharide (LPS; 1 mg/kg) at reperfusion to stimulate a systemic inflammatory response. At 1 month after MCAO, animals exposed to LPS were more likely to be sensitized to MBP (66.7% versus 22.2%; P=0.007) and had more profound and persistent neurologic deficits than non-LPS-treated animals. Exposure to LPS was associated with increased expression of the costimulatory molecule B7.1 early after stroke onset (P=0.009) and increased brain atrophy 1 month after MCAO (P=0.03). These data suggest that animals subjected to a systemic inflammatory insult at the time of stroke are predisposed to develop an autoimmune response to brain, and that this response is associated with worse outcome. These data may partially explain why patients who become infected after stroke experience increased morbidity.

Topics: Animals; Atrophy; Autoantigens; Behavior, Animal; Blood-Brain Barrier; Brain; CD4-Positive T-Lymphocytes; Gram-Negative Bacteria; Infarction, Middle Cerebral Artery; Lipopolysaccharides; Male; Myelin Basic Protein; Rats; Rats, Inbred Lew

Neonatal hypoxic-ischemic (HI) white matter injury is a major contributor to chronic neurological dysfunction. Immature oligodendrocytes (OLGs) are highly vulnerable to HI injury. As little is known about in vivo OLG repair mechanisms in neonates, we studied whether new OLGs are generated after HI injury in P7 rats. Rats received daily BrdU injections at P12-14 or P21-22 and sacrificed at P14 to study the level of cell proliferation or at P35 to permit dividing OLG precursors to differentiate. In P14 HI-injured animals, the number of BrdU+ cells in the injured hemisphere is consistently greater than controls. At P35, sections were double-labeled for BrdU and markers for OLGs, astrocytes, and microglia. Double-labeled BrdU+/myelin basic protein+ and BrdU+/carbonic anhydrase+ OLGs are abundant in the injured striatum, corpus callosum, and the infarct core. Quantitative studies show four times as many OLGs are generated from P21-35 in HI corpora callosa than controls. Surprisingly, the infarct core contains many newly generated OLGs in addition to hypertrophied astrocytes and activated microglia. These glia and non-CNS cells may stimulate OLG progenitor proliferation or induce their migration. At P35, astrogliosis and microgliosis are dramatic ipsilaterally but only a few microglia and some astrocytes are BrdU+. This finding indicates microglial and astrocytic hyperplasia occurs shortly after HI but before the P21 BrdU injections. Although the neonatal brain undergoes massive cell death and atrophy the first week after injury, it retains the potential to generate new OLGs up to 4 weeks after injury within and surrounding the infarct.

Topics: Animals; Animals, Newborn; Astrocytes; Atrophy; Biomarkers; Bromodeoxyuridine; Carbonic Acid; Cell Count; Cell Death; Cell Differentiation; Cell Division; Cerebral Infarction; Disease Models, Animal; Gliosis; Hypoxia-Ischemia, Brain; Myelin Basic Protein; Nerve Fibers, Myelinated; Oligodendroglia; Rats; Rats, Sprague-Dawley; Stem Cells