Molecular and cellular neurosciences
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Mol. Cell. Neurosci. · Dec 2017
CHI3L1 and CHI3L2 overexpression in motor cortex and spinal cord of sALS patients.
Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the degeneration and death of upper (UMN) and lower (LMN) motor neurons. In the last decade, it has been shown that Chitinases are an important prognostic indicator of neuro-inflammatory damage induced by microglia and astrocytes. ⋯ This study suggests that CHI3L1 and CHI3L2 are associated with the progression of neurodegeneration in motor cortex and spinal cord of sALS patients.
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Mol. Cell. Neurosci. · Jul 2017
Effects of repeated cocaine exposure and withdrawal on voluntary ethanol drinking, and the expression of glial glutamate transporters in mesocorticolimbic system of P rats.
Glutamatergic neurotransmission within the brain's reward circuits plays a major role in the reinforcing properties of both ethanol and cocaine. Glutamate homeostasis is regulated by several glutamate transporters, including glutamate transporter type 1 (GLT-1), cystine/glutamate transporter (xCT), and glutamate aspartate transporter (GLAST). Cocaine exposure has been shown to induce a dysregulation in glutamate homeostasis and a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc). ⋯ Co-exposure of cocaine and ethanol decreased the relative mRNA expression and the expression of GLT-1 in the NAc but not in the medial prefrontal cortex (mPFC). Importantly, co-exposure of cocaine and ethanol decreased relative expression of xCT in the NAc but not in the mPFC. Our findings demonstrated that chronic cocaine exposure affects ethanol intake; and ethanol and cocaine co-abuse alters the expression of glial glutamate transporters.
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Mol. Cell. Neurosci. · Jul 2017
Activation of adenosine A2A receptor signaling regulates the expression of cytokines associated with immunologic dysfunction in BTBR T+ Itpr3tf/J mice.
Autism spectrum disorder (ASD) is neurodevelopmental disorders characterized by stereotypical repetitive behavior, impaired social interaction, and deficits in communication. The BTBR T+ Itpr3tf/J (BTBR) mice have been extensively used as an animal model of the ASD-like phenotype. Adenosine A2A receptors (A2ARs) are considered potential targets in the treatment of neurodegenerative diseases. ⋯ Our results showed that the levels of IL-2+, IL-6+, IL-9+, IFN-γ+, and TNF-α+ were significantly lower, whereas the levels of TGF-β+ in the spleen and in splenic CD4+ T cells were significantly higher in the CGS-treated mice than in the BTBR control and SCH-treated mice. In addition, reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis showed a decrease in the mRNA and protein expression levels of IL-2, IL-6, IL-9, IFN-γ+, and TNF-α+ and an increase in the mRNA and protein expression levels of TGF-β in the CGS-treated mice, while treatment with BTBR alone and SCH resulted in increased Th1 levels and decreased Th2 levels in the brain tissue. Our results suggest that treatment the A2AR agonist CGS may be a promising therapeutic option for neuroimmune dysfunction.
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Mol. Cell. Neurosci. · Apr 2017
Identification of a fatty acid binding protein4-UCP2 axis regulating microglial mediated neuroinflammation.
Hypothalamic inflammation contributes to metabolic dysregulation and the onset of obesity. Dietary saturated fats activate microglia via a nuclear factor-kappa B (NFκB) mediated pathway to release pro-inflammatory cytokines resulting in dysfunction or death of surrounding neurons. Fatty acid binding proteins (FABPs) are lipid chaperones regulating metabolic and inflammatory pathways in response to fatty acids. ⋯ Hypothalamic tissue from mice lacking FABP4 exhibit increased UCP2 expression and reduced iNOS, tumor necrosis factor-alpha (TNF-α), and ionized calcium-binding adapter molecule 1 (Iba1; microglial activation marker) expression compared to wild type mice. Further, this effect is negated in microglia lacking UCP2, indicating the FABP4-UCP2 axis is pivotal in obesity induced neuroinflammation. To our knowledge, this is the first report demonstrating a FABP4-UCP2 axis with the potential to modulate the microglial inflammatory response.
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Global brain ischemia/reperfusion induces neuronal damage in vulnerable brain regions, leading to mitochondrial dysfunction and subsequent neuronal death. Induction of neuronal death is mediated by release of cytochrome c (cyt c) from the mitochondria though a well-characterized increase in outer mitochondrial membrane permeability. However, for cyt c to be released it is first necessary for cyt c to be liberated from the cristae junctions which are gated by Opa1 oligomers. ⋯ Mitochondrial fragmentation aligned temporally with specific apoptotic events, including cyt c release, caspase 3/7 activation, and interestingly, release of the fusion protein Opa1. Moreover, we uncovered evidence of loss of Opa1 complexes during the progression of reperfusion, and electron microscopy micrographs revealed a loss of cristae architecture following global brain ischemia. These data provide novel evidence implicating a temporal connection between Opa1 alterations and dysfunctional mitochondrial dynamics following global brain ischemia.