Current Trends in Biomarkers for Traumatic Brain Injury.

Neurotrauma, especially Traumatic Brain Injury (TBI) is a major health concern not only for the civilian population but also for the military personnel. Currently there are no precision and regenerative therapies available for the successful treatment of TBI patients. Hence, early detection and treatment options may prevent the severity and untoward harmful effects of TBI. However, currently there are no effective biomarkers available for the rapid and robust diagnosis as well as prognosis of TBI. Several biomarkers in blood, cerebrospinal fluid (CSF), saliva and urine have been explored to assess the onset, progression, severity and prognosis of TBI recently. Present knowledge on the blood biomarkers including cytokines and chemokines and in vivo imaging modalities are useful to some extent to detect and treat TBI patients. Here, we review S100B, Glial Fibrillary Acidic Protein (GFAP), Neuron Specific Enolase (NSE), Myelin Basic Protein (MBP), Ubiquitin C-terminal Hydrolase L1 (UCHL1), tau protein, and alpha spectrin II break down products regarding their usefulness as a set of reliable biomarkers for the robust diagnosis of TBI. We suggest that these biomarkers may prove very useful for the diagnosis and prognosis of TBI.

Mast Cell Proteases Activate Astrocytes and Glia-Neurons and Release Interleukin-33 by Activating p38 and ERK1/2 MAPKs and NF-κB.

Inflammatory mediators released from activated microglia, astrocytes, neurons, and mast cells mediate neuroinflammation. Parkinson's disease (PD) is characterized by inflammation-dependent dopaminergic neurodegeneration in substantia nigra. 1-Methyl-4-phenylpyridinium (MPP+), a metabolite of parkinsonian neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), induces inflammatory mediators' release from brain cells and mast cells. Brain cells' interaction with mast cells is implicated in neuroinflammation. However, the exact mechanisms involved are not yet clearly understood. Mouse fetal brain-derived cultured primary astrocytes and glia-neurons were incubated with mouse mast cell protease-6 (MMCP-6) and MMCP-7, and mouse bone marrow-derived mast cells (BMMCs) were incubated with MPP+ and brain protein glia maturation factor (GMF). Interleukin-33 (IL-33) released from these cells was quantitated by enzyme-linked immunosorbent assay. Both MMCP-6 and MMCP-7 induced IL-33 release from astrocytes and glia-neurons. MPP+ and GMF were used as a positive control-induced IL-33 and reactive oxygen species expression in mast cells. Mast cell proteases and MPP+ activate p38 and extracellular signal-regulated kinases 1/2 (ERK1/2), mitogen-activated protein kinases (MAPKs), and transcription factor nuclear factor-kappa B (NF-κB) in astrocytes, glia-neurons, or mast cells. Addition of BMMCs from wt mice and transduction with adeno-GMF show higher chemokine (C-C motif) ligand 2 (CCL2) release. MPP+ activated glial cells and reduced microtubule-associated protein 2 (MAP-2) expression indicating neurodegeneration. IL-33 expression increased in the midbrain and striatum of PD brains as compared with age- and sex-matched control subjects. Glial cells and neurons interact with mast cells and accelerate neuroinflammation and these interactions can be explored as a new therapeutic target to treat PD.

Glia Maturation Factor in the Pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative and neuroinflammatory disease characterized by the presence of extracellular amyloid plaques (APs) and intracellular neurofibrillary tangles (NFTs) in the brain. There is no disease modifying therapeutic options currently available for this disease. Hippocampus, entorhinal cortex (Broadmann area 28), perirhinal cortex (Broadmann area 35) and insular cortices are areas within the brain that are first ones to be severely affected in AD. Neuroinflammation is an important factor that induces neurodegeneration in AD. Glia maturation factor (GMF), a proinflammatory factor plays a crucial role in AD through activation of microglia and astrocytes to release proinflammatory mediators in the brain. Through immunohistochemical studies, we have previously shown that GMF is highly expressed in the vicinity of APs and NFTs in AD brains. Glial fibrillary acidic protein (GFAP), reactive astrocytes, ionized calcium binding adaptor molecule-1 (Iba-1) labelled activated microglia and GMF immunoreactive glial cells are increased in the entorhinal cortical layers especially at the sites of APs and Tau containing NFTs indicating a role for GMF. Overexpression of GMF in glial cells leads to neuroinflammation and neurodegeneration. Inhibition of GMF expression reduces neurodegeneration. Therefore, we suggest that GMF is a novel therapeutic target not only for AD but also for various other neurodegenerative diseases.