Cornel Iridoid Glycoside Improves Locomotor Impairment and Decreases Spinal Cord Damage in Rats.

Purpose. This study was to investigate the effects of cornel iridoid glycoside (CIG) on spinal cord injury (SCI) in rats. Methods. The thoracic cord (at T9) of rats was injured by clip compression for 30 sec. Locomotor function was assessed using the Basso, Beattie, and Bresnahan (BBB) rating scale. Neuroanatomic stereological parameters as well as Nogo-A, p75 neurotrophin receptor (p75NTR), and ROCKII expression were measured by histological processing, immunohistochemistry, and stereological analyses. The axons passing through the lesion site were detected by BDA tracing. Results. Intragastric administration of CIG (60 and 180 mg/kg) improved the locomotor impairment at 10, 17, 24, and 31 days post-injury (dpi) compared with untreated SCI model rats. CIG treatment decreased the volume of the lesion epicenter (LEp) and increased the volume of spared tissue and the number of surviving neurons in the injured spinal cord at 31 dpi. CIG promoted the growth of BDA-positive axons and their passage through the lesion site and decreased the expression of Nogo-A, p75NTR, and ROCKII both in and around the LEp. Conclusion. CIG improved the locomotor impairment, decreased tissue damage, and downregulated the myelin-associated inhibition signaling pathway in SCI rats. The results suggest that CIG may be beneficial for SCI therapy.

Protective effect of tanreqing injection on axon myelin damage in the brain of mouse model for experimental autoimmune encephalomyelitis.

OBJECTIVE: To evaluate the effect of Tanreqing injection on axon myelin in the mouse brain of experimental autoimmune encephalomyelitis (EAE). METHODS: An EAE model was established by myelin oligodendrocyte glycoprotein (MOG)35-55 immunization in C57BL/6 mice. Mice were randomly divided into the following groups: normal, model, prednisone acetate (PA) (6 mg/kg), Tanreqing high dose (5.14 mL/kg), Tanreqing low dose (2.57 mL/kg). On the day of immunization, both Tanreqing groups were treated by intraperitoneal injection, with the PA group treated by intragastrical perfusion after T cell response, and the other groups treated with saline. Changes in body weight, neurological deficit score, incidence rate, mortality rate, and course of disease were observed for all mice. Brain tissue was isolated and stained with hematoxylin-eosin, and pathological investigations performed to evaluate axon myelin damage by transmission electron microscopy (TEM). Myelin basic protein and microtubule associated protein-2 were analyzed by immunohistochemistry. RESULTS: Tanreqing injection significantly prolonged EAE latency and decreased the neurological deficit score, alleviated infiltration of inflammatory cells in the focus area, up-regulated hippocampal MBP expression at the acute stage and the remission stage, and increased microtubule associated protein-2 expression in the EAE brain to varying degrees in the acute stage. TEM analysis indicated that Tanreqing injection alleviates myelin damage in the EAE mouse and maintains the integrity of circular layer structures and alleviates axon mitochondrial swelling. CONCLUSION: Tanreqing injection alleviates EAE symptoms.

Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse.

Niemann-Pick type C 1 (NPC1) disease is an autosomal recessive cholesterol transport defect resulting in a neurodegenerative process in patients mainly at an early age, although some patients may start with manifestation in adult. Since loss of myelin is considered as a main pathogenetic factor, the precise mechanism inducing dysmylination in NPC1 disease is still unclear. In the present study, a quantitative evaluation on the myelin protein and its regulatory factors of oligodendrocytes, such as SRY-related HMG-box 10 (Sox10), Yin Yang 1 factor (YY1) and myelin gene regulatory factor (MRF), in different parts of the brain and spinal cord was performed in NPC1-mutant mice. The results showed that NPC1 protein was expressed in oligodendrocytes and the amount of myelin protein was generally decreased in all parts of the brain and spinal cord in NPC1-mutant mice. Compared to wild type, the amount of Sox10 and YY1 was not different in NPC1-mutant mice, but MRF was significantly decreased, suggesting a possible mechanism perturbing differentiation of oligodendrocytes and the myelination process in the NPC1-mutant mouse.

Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments.

Psychotropic treatments such as second generation or atypical antipsychotics are efficacious in a wide spectrum of psychiatric disorders ranging from schizophrenia to depression, bipolar disorder, and autism. These treatments are associated with peripheral metabolic derangements that are often also present in drug-naive patients. Furthermore, altering lipid composition/levels (with omega 3 fatty acids) and ameliorating oxidative toxicities may treat/prevent disease. The above observations are reexamined from the perspective of a myelin-centered model of the human brain. The model proposes that the human brain's extensive myelination required higher metabolic resources that caused evolutionary adaptations resulting in our quadratic (inverted U) myelination trajectory that peaks in the sixth decade of life. It further proposes that optimal brain function depends on exquisite action potential synchronization that myelin makes possible and that myelin's exceptional vulnerability to subtle metabolic/oxidative abnormalities may promote both developmental and degenerative diseases. Available data are integrated herein to suggest that widely used psychotropic treatments have under-appreciated CNS metabolic and neurotransmitter effects on myelination, its plasticity, and repair that may substantially contribute to their mechanisms of action.

The Yin and Yang of cell cycle progression and differentiation in the oligodendroglial lineage.

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor cells involves errors in the sequence of events that normally occur during development when progenitors proliferate, migrate through the white matter, contact the axon, and differentiate into myelin-forming oligodendrocytes. Multiple mechanisms underlie the eventual progressive deterioration that typifies the natural history of developmental demyelination in LD and PVL and of adult-onset demyelination in MS. Over the past few years, pathophysiological studies have mostly focused on seeking abnormalities that impede oligodendroglial maturation at the level of migration, myelination, and survival. In contrast, there has been a strikingly lower interest for early proliferative and differentiation events that are likely to be equally critical for white matter development and myelin repair. This review highlights the Yin and Yang principles of interactions between intrinsic factors that coordinately regulate progenitor cell division and the onset of differentiation, i.e. the initial steps of oligodendrocyte lineage progression that are obviously crucial in health and diseases.

Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare genetic defect of GABA degradation recently modelled in mice (SSADH(-/-) mice), manifests early absence seizures that evolve into generalized convulsive seizures and lethal status epilepticus in gene-ablated mice. Disrupted GABA homeostasis, in conjunction with the epileptic phenotype and increased gamma-hydroxybutyric acid (GHB), suggested that expression profiling with the U74Av2 Affymetrix system would reveal dysregulation of receptor genes associated with GABAergic and glutamatergic neurotransmission. Unexpectedly, we found significant downregulation for genes associated with myelin biogenesis and compaction, predominantly in hippocampus and cortex. These results were confirmed by: (1) myelin basic protein (MBP) immunohistochemistry; (2) western blotting of myelin-associated glycoprotein (MAG) and MBP; (3) qRT-PCR analyses of myelin-associated oligodendrocytic basic protein (MOBP), MAG, MBP and proteolipid protein (PLP) in hippocampus, cortex and spinal cord; (4) quantitation of ethanolamine and choline plasmalogens, all core myelin components; (5) evaluation of myelin content in brain sections employing toluidine blue staining; and (6) ultrastructural evaluation of myelin sheath thickness via electron microscopy. We speculate that increased GABA/GHB, acting through GABAergic systems, results in decreased levels of the neurosteroids progesterone and allopregnanolone [Gupta et al (2003) Ann Neurol 54(Supplement 6): S81-S90] and phosphorylation of mitogen-activated protein (MAP) kinase, with resulting myelin protein abnormalities primarily in the cortex of SSADH(-/-) mice.

Plasticity of gene expression in injured human dorsal root ganglia revealed by GeneChip oligonucleotide microarrays.

Root avulsion from the spinal cord occurs in brachial plexus lesions. It is the practice to repair such injuries by transferring an intact neighbouring nerve to the distal stump of the damaged nerve; avulsed dorsal root ganglia (DRG) are removed to enable nerve transfer. Such avulsed adult human cervical DRG ( [Formula: see text] ) obtained at surgery were compared to controls, for the first time, using GeneChip oligonucleotide arrays. We report 91 genes whose expression levels are clearly altered by the injury. This first study provides a global assessment of the molecular events or "gene switches" as a consequence of DRG injuries, as the tissues represent a wide range of surgical delay, from 1 to 100 days. A number of these genes are novel with respect to sensory ganglia, while others are known to be involved in neurotransmission, trophism, cytokine functions, signal transduction, myelination, transcription regulation, and apoptosis. Cluster analysis showed that genes involved in the same functional groups are largely positioned close to each other. This study represents an important step in identifying new genes and molecular mechanisms in human DRG, with potential therapeutic relevance for nerve repair and relief of chronic neuropathic pain.

Activation of myelin genes during transdifferentiation from melanoma to glial cell phenotype.

Induction of myelin genes occurs around birth in the last stage of Schwann cells differentiation and is reactivated in case of nerve injury. Previous studies showed that activation of the gp130 receptor system, using as ligand interleukin-6 fused to its soluble receptor (IL6RIL6), causes induction of myelin genes such as myelin basic protein (MBP) and myelin protein zero (Po) in embryonic dorsal root ganglia Schwann cells. We also reported that in murine melanoma B16/F10.9 cells, IL6RIL6 causes a shut-off of melanogenesis mediated by a down-regulation of the paired-homeodomain factor Pax3. The present work demonstrates that these IL6RIL6-treated F10.9 cells undergo transdifferentiation to a myelinating glial phenotype characterized by induction of the transcriptional activities of both Po and MBP promoters and accumulation of myelin gene products. For both Po and MBP promoters, a repression by Pax3 and stimulation by Sox10 can be demonstrated. Because after IL6RIL6-treatment, Pax3 disappears from the F10.9 cells (as it does in mature myelinating Schwann cells) whereas the level of Sox10 rather increases, we modulated the relative level of these factors and show their involvement in the induction of myelin gene expression by IL6RIL6. In addition, however, we show that a C/G-rich CACC box in the Po promoter is required for activation by IL6RIL6, as well as by ectopic Sox10, and identify a Kruppel-type zinc finger factor acting through this CACC box, which stimulates Po promoter activity.

Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics.

Alcoholism is a major health problem in Western countries, yet relatively little is known about the mechanisms by which chronic alcohol abuse causes the pathologic changes associated with the disease. It is likely that chronic alcoholism affects a number of signaling cascades and transcription factors, which in turn result in distinct gene expression patterns. These patterns are difficult to detect by traditional experiments measuring a few mRNAs at a time, but are well suited to microarray analyses. We used cDNA microarrays to analyze expression of approximately 10 000 genes in the frontal and motor cortices of three groups of chronic alcoholic and matched control cases. A functional hierarchy was devised for classification of brain genes and the resulting groups were compared based on differential expression. Comparison of gene expression patterns in these brain regions revealed a selective reprogramming of gene expression in distinct functional groups. The most pronounced differences were found in myelin-related genes and genes involved in protein trafficking. Significant changes in the expression of known alcohol-responsive genes, and genes involved in calcium, cAMP, and thyroid signaling pathways were also identified. These results suggest that multiple pathways may be important for neuropathology and altered neuronal function observed in alcoholism.

Diet, lipids and brain development.

Brain development is a sequential anatomical process characterised by specific well-defined stages of growth and maturation. One of the fundamental and necessary events in the normal development of the central nervous system in vertebrates is the formation of a myelin sheath. It is becoming more evident that this process is influenced by dietary lipids. A number of findings have indicated that the administration of a diet deficient in essential fatty acids during development causes hypomyelination in the rat brain. Our studies have shown that lipids can also play a role in accelerating myelinogenesis in the brain of rats whose mothers had been fed, during pregnancy and lactation, a lipid fraction extracted from yeast grown on n-alkanes. Further studies have shown that accelerated myelinogenesis is connected to a precocious appearance of behavioural reflexes. Thus, the use of particular lipids in human nutrition must be carefully screened for possible effects on brain development.

Messenger RNAs located in myelin sheath assembly sites.

The targeting of mRNAs to specific subcellular locations is believed to facilitate the rapid and selective incorporation of their protein products into complexes that may include membrane organelles. In oligodendrocytes, mRNAs that encode myelin basic protein (MBP) and select myelin-associated oligodendrocytic basic proteins (MOBPs) locate in myelin sheath assembly sites (MSAS). To identify additional mRNAs located in MSAS, we used a combination of subcellular fractionation and suppression subtractive hybridization. More than 50% of the 1,080 cDNAs that were analyzed were derived from MBP or MOBP mRNAs, confirming that the method selected mRNAs enriched in MSAS. Of 90 other cDNAs identified, most represent one or more mRNAs enriched in rat brain myelin. Five cDNAs, which encode known proteins, were characterized for mRNA size(s), enrichment in myelin, and tissue and developmental expression patterns. Two of these, peptidylarginine deiminase and ferritin heavy chain, have recognized roles in myelination. The corresponding mRNAs were of different sizes than the previously identified mRNA, and they had tissue and development expression patterns that were indistinguishable from those of MBP mRNA. Three other cDNAs recognize mRNAs whose proteins (SH3p13, KIF1A, and dynein light intermediate chain) are involved in membrane biogenesis. Although enriched in myelin, the tissue and developmental distribution patterns of these mRNAs differed from those of MBP mRNA. Six other cDNAs, which did not share significant sequence homology to known mRNAs, were also examined. The corresponding mRNAs were highly enriched in myelin, and four had tissue and developmental distribution patterns indistinguishable from those of MBP mRNA. These studies demonstrate that MSAS contain a diverse population of mRNAs, whose locally synthesized proteins are placed to contribute to myelin sheath assembly and maintenance. Characterization of these mRNAs and proteins will help provide a comprehensive picture of myelin sheath assembly.