Abstract
Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has been shown to alleviate neurodegenerative conditions. The present study was to investigate the specific HDAC8 inhibitor WK2-16, especially its effects on the neuroinflammatory responses through glial inactivation. WK2-16 significantly reduced the gelatinolytic activity of MMP-9, and expression of COX-2/iNOS proteins in striatal lipopolysaccharide (LPS)-induced neuroinflammation in C57BL/6 mice. The treatment of WK2-16 markedly improved neurobehavioral deficits. Immunofluorescent staining revealed that WK2-16 reduced LPS-stimulated astrogliosis and microglial activation in situ. Consistently, cellular studies revealed that WK2-16 significantly suppressed LPS-induced mouse microglia BV-2 cell proliferation. WK2-16 was proven to concentration-dependently induce the levels of acetylated SMC3 in microglial BV-2 cells. It also reduced the expression of COX-2/iNOS proteins and TNF-α production in LPS-activated microglial BV-2 cells. The signaling studies demonstrated that WK2-16 markedly inhibited LPS-activated STAT-1/-3 and Akt activation, but not NF-κB or MAPK signaling. In summary, the HDAC8 inhibitor WK2-16 exhibited neuroprotective effects through its anti-neuroinflammation and glial inactivation properties, especially in microglia in vitro and in vivo.
Highlights
Central nervous system (CNS) injuries and neurological diseases, such as head trauma and neurodegenerative diseases, create enormous individual and financial burdens
We further evaluated the anti-inflammatory effects of WK2-16 by measuring inflammatory markers including COX-2, inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) in LPS-activated BV-2 microglia [24]
Our study revealed that WK2-16 dramatically suppressed matrix metalloproteinases (MMPs)-9 activation, which may positively correlate with the protective effect of neurological functions
Summary
Central nervous system (CNS) injuries and neurological diseases, such as head trauma and neurodegenerative diseases, create enormous individual and financial burdens. Microglial activation, astrogliosis, and the release of inflammatory mediators are the major immune components of neuroinflammation. Microglia are the primary immune glial cells in the CNS and predominantly contribute to neuroinflammation. Microglia are activated and mediate neuroinflammatory responses under pathological conditions via phagocytosis, antigen presentation, and the production of proinflammatory mediators, including interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), and oxygen radicals, which results in the propagation of neuronal death and cerebral damage [3,4]. In vivo studies of the toll-like receptor 4 (TLR-4) agonist LPS-induced neuroinflammation model revealed that the presence of microglia is necessary in neuroinflammation-mediated toxicity in brain tissue, in which neurons are vulnerable to injury [5]. Astrocyte activation amplifies the neuroinflammatory responses via the production of neurotoxic factors [6]
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