Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer's disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.
Humans ; Biomarkers/cerebrospinal fluid* ; Nervous System Diseases/diagnosis* ; Brain Injuries/metabolism* ; Phosphopyruvate Hydratase/cerebrospinal fluid* ; Glial Fibrillary Acidic Protein/blood* ; S100 Calcium Binding Protein beta Subunit/blood* ; tau Proteins/cerebrospinal fluid* ; Ubiquitin Thiolesterase/blood* ; Myelin Basic Protein/cerebrospinal fluid* ; Neurofilament Proteins/blood* ; MicroRNAs/blood* ; Brain Injuries, Traumatic/metabolism*

OBJECTIVES: To investigate whether mesenchymal stem cell-derived exosomes (MSC-Exo) alleviate white matter damage (WMD) in neonatal rats by targeting the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3). METHODS: Three-day-old Sprague-Dawley rats were randomly assigned to four groups: Sham, hypoxia-ischemia (HI), MSC-Exo, and MCC950 (NLRP3 inhibitor) (n=24 per group). The WMD model was established by unilateral common carotid artery ligation combined with hypoxia. Exosomes (1×10⁸ particles/μL) were transplanted into the lateral ventricle using stereotaxic guidance. Fourteen days after modeling, hematoxylin-eosin staining was used to observe pathological changes in brain tissue, and transmission electron microscopy was used to assess myelinated axons. Western blotting was performed to detect the expression of myelin basic protein (MBP), NLRP3, caspase-1, and interleukin-1β (IL-1β). Immunohistochemistry was used to measure NLRP3, caspase-1, and IL-1β expression. Twenty-eight days post-modeling, behavioral changes were evaluated using the Morris water maze. RESULTS: In the HI group, marked inflammatory cell infiltration, extensive vacuolation, and decreased numbers of myelinated axons were observed compared to the Sham group. The MSC-Exo group showed reduced inflammatory infiltration, fewer vacuoles, and increased myelinated axons compared to the HI group, while the MCC950 group showed nearly normal cell morphology. Compared to the Sham group, the HI group exhibited decreased MBP expression, fewer platform crossings, shorter time in the target quadrant, increased expression of NLRP3, caspase-1, and IL-1β, and longer escape latency (all P<0.05). Compared to the HI group, the MSC-Exo and MCC950 groups showed increased MBP expression, more platform crossings, longer target quadrant stay, and reduced NLRP3, caspase-1, and IL-1β expression, as well as shorter escape latency (all P<0.05). CONCLUSIONS MSC-Exo may attenuate white matter damage in neonatal rats by targeting the NLRP3 inflammasome and promoting oligodendrocyte maturation.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors* ; Rats, Sprague-Dawley ; White Matter/pathology* ; Inflammasomes/physiology* ; Rats ; Animals, Newborn ; Mesenchymal Stem Cells ; Interleukin-1beta/analysis* ; Male ; Caspase 1/analysis* ; Hypoxia-Ischemia, Brain/therapy* ; Myelin Basic Protein/analysis*

Oligodendrocyte lineage cells, including oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs), are essential in establishing and maintaining brain circuits. Autophagy is a conserved process that keeps the quality of organelles and proteostasis. The role of autophagy in oligodendrocyte lineage cells remains unclear. The present study shows that autophagy is required to maintain the number of OPCs/OLs and myelin integrity during brain aging. Inactivation of autophagy in oligodendrocyte lineage cells increases the number of OPCs/OLs in the developing brain while exaggerating the loss of OPCs/OLs with brain aging. Inactivation of autophagy in oligodendrocyte lineage cells impairs the turnover of myelin basic protein (MBP). It causes MBP to accumulate in the cytoplasm as multimeric aggregates and fails to be incorporated into integral myelin, which is associated with attenuated endocytic recycling. Inactivation of autophagy in oligodendrocyte lineage cells impairs myelin integrity and causes demyelination. Thus, this study shows autophagy is required to maintain myelin quality during aging by controlling the turnover of myelin components.
Animals ; Autophagy/physiology* ; Oligodendroglia/metabolism* ; Myelin Sheath/physiology* ; Aging/pathology* ; Myelin Basic Protein/metabolism* ; Cell Lineage/physiology* ; Mice ; Oligodendrocyte Precursor Cells ; Mice, Inbred C57BL ; Brain/cytology* ; Cells, Cultured ; Cell Count

OBJECTIVE: To investigate the effects of different doses of propofol on myelin basic protein (MBP) synthesis and myelination of oligodendrocytes in neonatal SD rats. METHODS: A total of 57 neonatal SD rats (7 days old) were randomly divided into control group (=13), vehicle (fat emulsion) group (=5), and 25, 50 and 100 mg/kg propofol groups (=13 in each group). Eight hours after a single intraperitoneal injection of propofol or the vehicle, the rats were examined for expressions of mRNA, caspase-3 mRNA, cleaved caspase-3 and MBP in the brain tissues using qPCR and Western blotting. Immunofluorescence assay was used to detect the apoptosis of the oligodendrocytes at 8 h after the injection and the myelination of the corpus callosum and internal capsule at 24 h. RESULTS: Compared with the control group, the neonatal rats with propofol injections showed significantly down-regulated expressions of mRNA and MBP protein in the brain tissue ( < 0.05). Propofol dose-dependently increased the transcription level of caspase-3 and the protein levels of cleaved caspase-3 at 8 h after the injection ( < 0.05). Propofol injection significantly increased the apoptosis of the oligodendrocytes, and the effect was significantly stronger in 50 and 100 mg/kg groups than in 25 mg/kg group ( < 0.05). At 24 h after propofol injection, myelin formation was significantly decreased in the corpus callosum of the neonatal rats in 100 mg/kg propofol group and in the internal capsule in 50 and 100 mg/kg groups ( < 0.05). CONCLUSIONS In neonatal SD rats, propofol can dose-dependently promote oligodendrocyte apoptosis, decrease MBP expressions in the brain, and suppress myelin formation in the corpus callosum and the internal capsule.
Animals ; Myelin Basic Protein ; Oligodendroglia ; Propofol ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley

The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells (OPCs) to differentiate, since OPCs and oligodendrocyte-lineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid (SA) is mainly derived from star anise, and is reported to have anti-influenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis (EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination. Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated mTOR. Taken together, our results demonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.
Animals ; Apoptosis ; drug effects ; Cell Differentiation ; drug effects ; Cell Proliferation ; drug effects ; Cells, Cultured ; Demyelinating Diseases ; prevention & control ; Encephalitis ; prevention & control ; Encephalomyelitis, Autoimmune, Experimental ; prevention & control ; Female ; Mice, Inbred C57BL ; Myelin Basic Protein ; metabolism ; Neuroprotective Agents ; administration & dosage ; Oligodendrocyte Precursor Cells ; drug effects ; metabolism ; Rats ; Remyelination ; drug effects ; Shikimic Acid ; administration & dosage ; TOR Serine-Threonine Kinases ; metabolism

In this study, we observed chronological changes in the immunoreactivity and expression level of myelin basic protein (MBP), one of the most abundant proteins in the central nervous system, in the hippocampus of Zucker diabetic fatty (ZDF) rats and their control littermates (Zucker lean control; ZLC). In the ZLC group, body weight steadily increased with age; the body weight of the ZDF group, however, peaked at 30 weeks of age, and subsequently decreased. Based on the changes of body weight, animals were divided into the following six groups: early (12-week), middle (30-week), and chronic (52-week) diabetic groups and their controls. MBP immunoreactivity was found in the alveus, strata pyramidale, and lacunosum-moleculare of the CA1 region, strata pyramidale and radiatum of the CA3 region, and subgranular zone, polymorphic layer, and molecular layer of the dentate gyrus. MBP immunoreactivity was lowest in the hippocampus of 12-week-old rats in the ZLC group, and highest in 12-week-old rats in the ZDF group. Diabetes increased MBP levels in the 12-week-old group, while MBP immunoreactivity decreased in the 30-week-old group. In the 52-week-old ZLC and ZDF groups, MBP immunoreactivity was detected in the hippocampus, similar to the 30-week-old ZDF group. Western blot results corroborated with immunohistochemical results. These results suggested that changes in the immunoreactivity and expression of MBP in the hippocampus might be a compensatory response to aging, while the sustained levels of MBP in diabetic animals could be attributed to a loss of compensatory responses in oligodendrocytes.
Aging ; Animals* ; Blotting, Western ; Body Weight ; Central Nervous System ; Dentate Gyrus ; Hippocampus* ; Models, Animal* ; Myelin Basic Protein* ; Myelin Sheath* ; Oligodendroglia ; Rats

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated autoimmune central nervous system disease characterized by inflammation with oxidative stress. The aim of this study was to evaluate an anti-inflammatory effect of Ishige okamurae on EAE-induced paralysis in rats. An ethanolic extract of I. okamurae significantly delayed the first onset and reduced the duration and severity of hind-limb paralysis. The neuropathological and immunohistochemical findings in the spinal cord were in agreement with these clinical results. T-cell proliferation assay revealed that the ethyl-acetate fraction of I. okamurae suppressed the proliferation of myelin basic protein reactive T cells from EAE affected rats. Flow cytometric analysis showed TCRαβ+ T cells was significantly reduced in the spleen of EAE rats with I. okamurae treatment with concurrent decrease of inflammatory mediators including tumor necrosis factor-α and cyclooxygenase-2. Collectively, it is postulated that I. okamurae ameliorates EAE paralysis with suppression of T-cell proliferation as well as decrease of pro-inflammatory mediators as far as rat EAE is concerned.
Animals ; Central Nervous System ; Cyclooxygenase 2 ; Encephalomyelitis, Autoimmune, Experimental* ; Ethanol ; Inflammation ; Myelin Basic Protein ; Necrosis ; Oxidative Stress ; Paralysis ; Rats ; Spinal Cord ; Spleen ; T-Lymphocytes

Oligodendrocytes (OLs) are myelinating glial cells that form myelin sheaths around axons to ensure rapid and focal conduction of action potentials. Here, we found that an axonal outgrowth regulatory molecule, AATYK (apoptosis-associated tyrosine kinase), was up-regulated with OL differentiation and remyelination. We therefore studied its role in OL differentiation. The results showed that AATYK knockdown inhibited OL differentiation and the expression of myelin genes in vitro. Moreover, AATYK-deficiency maintained the proliferation status of OLs but did not affect their survival. Thus, AATYK is essential for the differentiation of OLs.
Animals ; Animals, Newborn ; Apoptosis Regulatory Proteins ; genetics ; metabolism ; Cell Differentiation ; drug effects ; physiology ; Cell Proliferation ; drug effects ; genetics ; Cells, Cultured ; Cuprizone ; toxicity ; Demyelinating Diseases ; chemically induced ; metabolism ; pathology ; Embryo, Mammalian ; Gene Expression Regulation, Developmental ; genetics ; Ki-67 Antigen ; metabolism ; Mice ; Mice, Inbred C57BL ; Myelin Basic Protein ; metabolism ; Myelin Proteolipid Protein ; metabolism ; Myelin Sheath ; drug effects ; metabolism ; Oligodendroglia ; drug effects ; metabolism ; Protein-Tyrosine Kinases ; genetics ; metabolism ; RNA, Small Interfering ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley

Influenza virus infection is a zoonosis that has great socioeconomic effects worldwide. Influenza infection induces respiratory symptoms, while the influenza virus can infect brain and leave central nervous system sequelae. As children are more vulnerable to infection, they are at risk of long-term neurological effects once their brains are infected. We previously demonstrated that functional changes in hippocampal neurons were observed in mice recovered from neonatal influenza infection. In this study, we investigated changes in myelination properties that could affect neural dysfunction. Mice were infected with the influenza virus on postnatal day 5. Tissues were harvested from recovered mice 21-days post-infection. The expression levels for myelin basic protein (MBP) were determined, and immunohistochemical staining and transmission electron microscopy were performed. Real-time polymerase chain reaction and Western blot analyses showed that mRNA and protein expressions increased in the hippocampus and cerebellum of recovered mice. Increased MBP-staining signal was observed in the recovered mouse brain. By calculating the relative thickness of myelin sheath in relation to nerve fiber diameter (G-ratio) from electron photomicrographs, an increased G-ratio was observed in both the hippocampus and cerebellum of recovered mice. Influenza infection in oligodendrocyte-enriched primary brain cell cultures showed that proinflammatory cytokines may induce MBP upregulation. These results suggested that increased MBP expression could be a compensatory change related to hypomyelination, which may underlie neural dysfunction in recovered mice. In summary, the present results demonstrate that influenza infection during the neonatal period affects myelination and further induces functional changes in influenza-recovered mouse brain.
Animals ; Blotting, Western ; Brain ; Cell Culture Techniques ; Central Nervous System ; Cerebellum ; Child ; Cytokines ; Hippocampus ; Humans ; Influenza, Human ; Mice ; Microscopy, Electron, Transmission ; Myelin Basic Protein ; Myelin Sheath ; Nerve Fibers ; Neurons ; Oligodendroglia ; Orthomyxoviridae ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; Up-Regulation

Myelin degeneration is one of the characteristics of aging and degenerative diseases. This study investigated age-related alterations in expression of myelin basic protein (MBP) in the hippocampal subregions (dentate gyrus, CA2/3 and CA1 areas) of gerbils of various ages; young (1 month), adult (6 months) and aged (24 months), using western blot and immunohistochemistry. Western blot results showed tendencies of age-related reductions of MBP levels. MBP immunoreactivity was significantly decreased with age in synaptic sites of trisynaptic loops, perforant paths, mossy fibers, and Schaffer collaterals. In particular, MBP immunoreactive fibers in the dentate molecular cell layer (perforant path) was significantly reduced in adult and aged subjects. In addition, MBP immunoreactive mossy fibers in the dentate polymorphic layer and in the CA3 striatum radiatum was significantly decreased in the aged group. Furthermore, we observed similar age-related alterations in the CA1 stratum radiatum (Schaffer collaterals). However, the density of MBP immunoreactive fibers in the dentate granular cell layer and CA stratum pyramidale was decreased with aging. These findings indicate that expression of MBP is age-dependent and tissue specific according to hippocampal layers.
Adult* ; Aging ; Blotting, Western ; CA1 Region, Hippocampal ; Gerbillinae* ; Hippocampus* ; Humans ; Immunohistochemistry ; Myelin Basic Protein* ; Myelin Sheath* ; Perforant Pathway