Abstract
Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson’s disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 μM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson’s disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.
Highlights
Lacking an effective treatment, increased environmental exposure of chemicals, and predisposing genetic factors, neurodegenerative diseases, have always been of prime interest to researchers
In the present study we investigated the inhibitory effects of hydroxy-4-methylbenzoic anhydride (HMA) on neuroinflammation and explored the underlying mechanisms using in vitro lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and an in vivo model of Parkinson’s disease (PD) based on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neuroinflammation in mice
To determine whether HMA possessed any effect on overall cell viability, we analyzed the viability in BV-2 microglial cells at various concentrations of HMA with or without LPS (100 ng/mL)
Summary
Lacking an effective treatment, increased environmental exposure of chemicals, and predisposing genetic factors, neurodegenerative diseases, have always been of prime interest to researchers. Various types of neurodegenerative disorders have their own specific set of neuronal circuitry that undergoes degeneration, resulting in specific disease symptoms [1,2,3]. Sustained or prolonged immune response in the central nervous system (CNS) will cause excessive neuroinflammation, leading to damage to the adjacent neurons [3]. Microglial cells have sensitive reactions (infectious diseases and oxidative stress) and high mobility [7]. These antigen-presenting cells, upon activation, produce various intermediate mediators (proinflammatory cytokines, chemokines, and reactive oxygen species) which are capable of destroying pathogens, but can induce toxicity in neurons, leading to the occurrence of various inflammatory-mediated neurodegenerative disorders [8]
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