This study explores the role of mevalonate inhibitors in activation NF-kbeta and induction inducible nitric oxide synthase (iNOS) cytokines (TNF-alpha, IL-1beta, IL-6) rat primary astrocytes, microglia, macrophages. Lovastatin sodium phenylacetate (NaPA) were found to inhibit LPS- cytokine-mediated production NO expression iNOS astrocytes; this inhibition was not due depletion end products pathway (e.g., cholesterol ubiquinone). Reversal inhibitory effect lovastatin on LPS-induced by...

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Despite intense investigations, no effective therapy available to stop its onset or halt progression. The present study evaluates ability of peptide corresponding NF-kappaB essential modifier-binding domain (NBD) IkappaB kinase alpha (IKKalpha) IKKbeta prevent nigrostriatal degeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model PD and establish a role for human parkinsonism. First, we...

Increased expression of glial fibrillary acidic protein (GFAP) represents astroglial activation and gliosis during neurodegeneration. However, the molecular mechanism behind increased GFAP in astrocytes is poorly understood. The present study was undertaken to explore role nitric oxide (NO) GFAP. Bacterial lipopolysachharides (LPSs) induced production NO mouse primary astrocytes. Either a scavenger [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO)] or an inhibitor...

Abstract Microglial activation is an important pathological component in brains of patients with Alzheimer’s disease (AD), and fibrillar amyloid-β (Aβ) peptides play role microglial AD. However, mechanisms by which Aβ induce the microglia are poorly understood. The present study underlines importance TLR2 mediating peptide-induced microglia. Fibrillar Aβ1–42 induced expression inducible NO synthase, proinflammatory cytokines (TNF-α, IL-1β, IL-6), integrin markers (CD11b, CD11c, CD68) mouse...

Abstract Pathways to control the spreading of α-synuclein (α-syn) and associated neuropathology in Parkinson’s disease (PD), multiple system atrophy (MSA) dementia with Lewy bodies (DLB) are unclear. Here, we show that preformed α-syn fibrils (PFF) increase association between TLR2 MyD88, resulting microglial activation. The TLR2-interaction domain MyD88 (wtTIDM) peptide-mediated selective inhibition reduces PFF-induced inflammation vitro. In PFF-seeded A53T mice, nasal administration wtTIDM...

MAPK-p38 plays an important role in inflammation. Several studies have shown that blocking p38 activity attenuates the transcriptional of proinflammatory transcription factor NF-kappaB without altering its DNA-binding activity. We also observed human primary astrocytes suppresses but not and down-regulates expression NF-kappaB-dependent gene, inducible NO synthase. However, molecular mechanism p38-mediated regulation remains largely unknown. In this study, we delineate controls by regulating...

The present study underlines the importance of reactive oxygen species in cytokine-mediated degradation sphingomyelin (SM) to ceramide. Treatment rat primary astrocytes with tumor necrosis factor-α (TNF-α) or interleukin-1β led marked alteration cellular redox (decrease intracellular GSH) and rapid SM Interestingly, pretreatment N-acetylcysteine (NAC), an antioxidant efficient thiol source for glutathione, prevented cytokine-induced decrease GSH ceramide, whereas treatment diamide, a...

Increased expression of CD11b, the β-integrin marker microglia, represents microglial activation during neurodegenerative inflammation. However, molecular mechanism behind increased CD11b is poorly understood. The present study was undertaken to explore role nitric oxide (NO) in cells. Bacterial lipopolysaccharide (LPS) induced production NO and mouse BV-2 cells primary microglia. Either a scavenger (PTIO) or an inhibitor inducible nitric-oxide synthase (L-NIL) blocked this increase...

Parkinson's disease (PD) is second only to Alzheimer's as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy available for PD. We investigated whether simvastatin, a Food and Drug Administration-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication model PD in mice. First, MPP + induced activation of p21 ras nuclear factor-κB...

Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid catabolism. Here, we provide evidence PPARα constitutively expressed nuclei of hippocampal neurons and, surprisingly, controls calcium influx and the expression various plasticity-related via direct transcriptional regulation cyclic AMP response element binding (CREB). Accordingly, Pparα-null, but not Pparβ-null, mice are deficient CREB memory-associated proteins have...

Abstract Upon activation, microglia and astrocytes produce a number of proinflammatory molecules that participate in the pathophysiology several neurodegenerative disorders. This study explores anti-inflammatory property cinnamon metabolite sodium benzoate (NaB) astrocytes. NaB, but not formate, was found to inhibit LPS-induced expression inducible NO synthase (iNOS), cytokines (TNF-α IL-1β) surface markers (CD11b, CD11c, CD68) mouse microglia. Similarly, NaB also inhibited fibrillar amyloid...

Neuroinflammation and oxidative stress underlie the pathogenesis of various neurodegenerative disorders. Here we demonstrate that sodium phenylbutyrate (NaPB), an FDA-approved therapy for reducing plasma ammonia glutamine in urea cycle disorders, can suppress both proinflammatory molecules reactive oxygen species (ROS) activated glial cells. Interestingly, NaPB also decreased level cholesterol but involved only intermediates, not end product biosynthesis pathway these functions. While...

Glial activation plays an important role in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease. However, molecular mechanisms by which activated glia could kill neurons are poorly understood. The present study underlines importance neutral sphingomyelinase (N-SMase) mediating damaging effect fibrillar amyloid-β 1-42 (Aβ ) peptide-activated astroglia on neurons. In transwell experiments, soluble products released from primary human induced (N-SMase),...

Significance Although β-amyloid (Aβ) peptides participate in the pathogenesis of Alzheimer’s disease (AD), mechanisms that regulate Aβ production are poorly understood. Here, we demonstrate activation nuclear receptor peroxisome proliferator-activated α (PPARα) upregulates transcription “a disintegrin and metalloproteinase” 10 ( Adam10 ) gene shifts APP processing toward α-secretase pathway. These findings suggest PPARα could be a therapeutic target for reducing burden AD.

The response of the lysosomes, waste clearance machinery cell, to different environmental stimuli is coordinated by a gene network with master regulator Transcription factor EB (TFEB) at core. Disruption multiple facets lysosomal and autophagic has been linked various neurodegenerative storage disorders, making TFEB an attractive therapeutic target rescue or augment function under pathological scenario. In this study, we demonstrate that cinnamic acid, naturally occurring plant-based...