myelin-basic-protein and Carotid-Artery-Diseases

This study investigated the neuronal protective effect of monosialotetrahexosylganglioside (GM1) on the hypoxia-ischemia white matter damage (WMD) in neonatal rats. Brain hypoxia-ischemia was induced by bilateral carotid artery occlusion in 4-day-old neonatal rats. Bilateral carotid artery occlusion (BCAO) was performed in rats in WMD and GM1 groups, while in sham group; the rat bilateral carotid arteries were merely exposed without occlusion. Immunohistochemical staining was used to determine the expression of myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and beta-amyloid precursor protein (beta-APP). In addition, suspension test, slope test, and open-field test were carried out on day 26 after BCAO to determine the neurobehavioral function. The percentage of MBP-positive cells was decreased while beta-APP-and GFAPpositive cells were increased in WMD group. After treated with GM1, the percentage of MBP-positive cells increased significantly than WMD rats at post-operation 72 h and day 7. GFAP-positive cells and beta-APP-positive cells decreased significantly in WMD group at post-operation 72 h, day 7 and 26. The suspension test, slope test, and open-field test showed that neurobehavioral function was improved in ganglioside GM1 group compared with WMD group. Taken together, our findings suggested that ganglioside GM1 treatment reduces hypoxia-ischemia induced impairment of the neurobehavioral function in WMD in neonatal rats.

Topics: Amyloid beta-Protein Precursor; Animals; Animals, Newborn; Carotid Artery Diseases; Disease Models, Animal; Female; G(M1) Ganglioside; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Leukoencephalopathies; Male; Myelin Basic Protein; Neurons; Rats; Rats, Sprague-Dawley; Time Factors

The biology of cerebral white matter injury has been woefully understudied, in part because of the difficulty of reliably modeling this type of injury in rodents. Periventricular leukomalacia (PVL) is the predominant form of brain injury and the most common cause of cerebral palsy in premature infants. PVL is characterized by predominant white matter injury. No specific therapy for PVL is presently available, because the pathogenesis is not well understood. Here we report that two types of mouse PVL models have been created by hypoxia-ischemia with or without systemic coadministration of lipopolysaccharide (LPS). LPS coadministration exacerbated hypoxic-ischemic white matter injury and led to enhanced microglial activation and astrogliosis. Drug trials with the antiinflammatory agent minocycline, the antiexcitotoxic agent NBQX, and the antioxidant agent edaravone showed various degrees of protection in the two models, indicating that excitotoxic, oxidative, and inflammatory forms of injury are involved in the pathogenesis of injury to immature white matter. We then applied immunoelectron microscopy to reveal fine structural changes in the injured white matter and found that synapses between axons and oligodendroglial precursor cells (OPCs) are quickly and profoundly damaged. Hypoxia-ischemia caused a drastic decrease in the number of postsynaptic densities associated with the glutamatergic axon-OPC synapses defined by the expression of vesicular glutamate transporters, vGluT1 and vGluT2, on axon terminals that formed contacts with OPCs in the periventricular white matter, resulted in selective shrinkage of the postsynaptic OPCs contacted by vGluT2 labeled synapses, and led to excitotoxicity mediated by GluR2-lacking, Ca(2+) -permeable AMPA receptors. Overall, the present study provides novel mechanistic insights into the pathogenesis of PVL and reveals that axon-glia synapses are highly vulnerable to white matter injury in the developing brain. More broadly, the study of white matter development and injury has general implications for a variety of neurological diseases, including PVL, stroke, spinal cord injury, and multiple sclerosis.

Topics: Animals; Animals, Newborn; Antigens; Brain Injuries; Carotid Artery Diseases; Disease Models, Animal; Excitatory Amino Acid Antagonists; Functional Laterality; Glial Fibrillary Acidic Protein; Hypoxia-Ischemia, Brain; Leukoencephalopathies; Luminescent Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron, Transmission; Minocycline; Myelin Basic Protein; Nerve Fibers, Myelinated; Neuroglia; Polysaccharides; Proteoglycans; Quinoxalines; Receptors, AMPA; Synapses; Vesicular Glutamate Transport Protein 1; Vesicular Glutamate Transport Protein 2

White matter impairment is a feature of vascular depression. The anti-psychotic quetiapine has been shown to enhance the therapeutic effects of anti-depressants on vascular depression, but the mechanism remains unknown. In this study, we found that 2 weeks of treatment with quetiapine prior to bilateral carotid artery occlusion and reperfusion, in an animal model of vascular depression, resulted in reduced myelin breakdown and oligodendrocyte loss compared to placebo-treated mice on post-operative day (POD) 7. For late stage of recovery (POD40), quetiapine treatment resulted in enhanced oligodendrocyte maturation relative to placebo. The results suggest that quetiapine is a potential intervention for oligodendrocyte damage and this may contribute to its anti-depressant effects through white matter protection in vascular depression.

Topics: Analysis of Variance; Animals; Antigens; Antipsychotic Agents; Brain Ischemia; Bromodeoxyuridine; Carotid Artery Diseases; Cell Differentiation; Dibenzothiazepines; Disease Models, Animal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hippocampus; Male; Mice; Myelin Basic Protein; Myelin Sheath; Oligodendroglia; Proteoglycans; Quetiapine Fumarate; Time Factors

The neurotrophin nerve growth factor (NGF) is produced by different cell types in the anterior and posterior eye, exerting a neuroprotective role in the adult life. The visual system is highly sensitive to NGF and the retina and optic nerve provides suitable subjects for the study of central nervous system degeneration. The model of bilateral carotid occlusion (two-vessel occlusion, 2VO) is a well-established model for chronic brain hypoperfusion leading to brain capillary pathology, to retina and optic nerve degeneration. In order to study if a single intravitreal injection of NGF protects the retina and the optic nerve from degeneration during systemic circulatory diseases, we investigated morphological and molecular changes occurring in the retina and optic nerve of adult rats at different time-points (8, 30 and 75 days) after bilateral carotid occlusion.. We demonstrated that a single intravitreal injection of NGF (5 microg/3 microl performed 24 hours after 2VO ligation) has a long-lasting protective effect on retina and optic nerve degeneration. NGF counteracts retinal ganglion cells degeneration by early affecting Bax/Bcl-2 balance- and c-jun- expression (at 8 days after 2VO). A single intravitreal NGF injection regulates the demyelination/remyelination balance after ischemic injury in the optic nerve toward remyelination (at 75 days after 2VO), as indicated by the MBP expression regulation, thus preventing optic nerve atrophy and ganglion cells degeneration. At 8 days, NGF does not modify 2VO-induced alteration in VEFG and related receptors mRNA expression.. The protective effect of exogenous NGF during this systemic circulatory disease seems to occur also by strengthening the effect of endogenous NGF, the synthesis of which is increased by vascular defect and also by the mechanical lesion associated with NGF or even vehicle intraocular delivery.

Topics: Analysis of Variance; Animals; bcl-2-Associated X Protein; Carotid Artery Diseases; Disease Models, Animal; Gene Expression Regulation; Injections, Intraventricular; Male; Myelin Basic Protein; Nerve Growth Factor; Optic Nerve Diseases; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-jun; Rats; Rats, Sprague-Dawley; Receptor, Nerve Growth Factor; Receptor, trkA; Reflex, Pupillary; Retinal Degeneration; RNA, Messenger; Tubulin

Though cerebral white matter injury is a frequently described phenomenon in aging and dementia, the cause of white matter lesions has not been conclusively determined. Since the lesions are often associated with cerebrovascular risk factors, ischemia emerges as a potential condition for the development of white matter injury. In the present study, we induced experimental cerebral hypoperfusion by permanent, bilateral occlusion of the common carotid arteries of rats (n=6). A sham-operated group served as control (n=6). Thirteen weeks after the onset of occlusion, markers for astrocytes, microglia, and myelin were found to be labeled by means of immunocytochemistry in the corpus callosum, the internal capsule, and the optic tract. The ultrastructural integrity and oligodendrocyte density in the optic tract were investigated by electron microscopy. Quantitative analysis revealed that chronic cerebral hypoperfusion caused mild astrogliosis in the corpus callosum and the internal capsule, while astrocytic disintegration in the optic tract increased by 50%. Further, a ten-fold increase in microglial activation and a nearly doubled oligodendrocyte density were measured in the optic tract of the hypoperfused rats as compared with the controls. Finally, vacuolization and irregular myelin sheaths were observed at the ultrastructural level in the optic tract. In summary, the rat optic tract appears to be particularly vulnerable to ischemia, probably because of the rat brain's angioarchitecture. Since the detected glial changes correspond with those reported in vascular and Alzheimer dementia, this model of cerebral hypoperfusion may serve to characterize the causal relationship between ischemia and white matter damage.

Topics: Analysis of Variance; Animals; Brain; Carotid Artery Diseases; Carotid Artery, Common; CD11b Antigen; Cell Count; Constriction; Disease Models, Animal; Glial Fibrillary Acidic Protein; Hypoxia-Ischemia, Brain; Immunohistochemistry; Male; Microscopy, Electron; Myelin Basic Protein; Nerve Fibers, Myelinated; Neuroglia; Rats; Rats, Wistar