Abstract
Excessive cerebral inflammation plays a key role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Berberine, an isoquinoline alkaloid isolated from Chinese herb Coptis chinensis, possesses anti-inflammatory, and neuroprotective effects. Here we evaluated the beneficial effects of berberine against SAH-induced inflammatory response and the subsequent brain injury. Our data showed that berberine treatment significantly inhibited microglia activation and proinflammatory cytokines release. Concomitant with suppressed cerebral inflammation, berberine mitigated the subsequent brain injury as demonstrated by improved neurological behavior, reduced brain edema, and decreased neural apoptosis. Moreover, berberine significantly inhibited high mobile group box 1 (HMGB1)/nuclear factor-κB (Nf-κB)-dependent pathway and enhanced sirtuin 1 (SIRT1) expression after SAH. Treatment with ex527, a selective SIRT1 inhibitor, reversed berberine-induced SIRT1 activation and inhibitory effects on HMGB1/Nf-κB activation. In addition, ex527 pretreatment abated the anti-inflammatory and neuroprotective effects of berberine on SAH. Taken together, these findings suggest that berberine provides beneficial effects against SAH-triggered cerebral inflammation by inhibiting HMGB1/Nf-κB pathway, which may be modulated by SIRT1 activation.
Highlights
Subarachnoid hemorrhage (SAH) remains a fata neurological emergency with high mortality and morbidity rates (Macdonald and Schweizer, 2017; Chen F. et al, 2018; Li et al, 2019)
All procedures in this study were approved by the Animal Care and Use Committee of Capital Medical University and Abbreviations: BBB, blood-brain barrier; CNS, central nervous system; DMSO, dimethylsulfoxide; EBI, early brain injury; enzymelinked immunosorbent assays (ELISA), enzyme-linked immunosorbent assays; Hematoxylin and Eosin (H&E), hematoxylin and eosin; HMGB1, high mobile group box 1; HRP, horseradish peroxidase; ICAM-1, intercellular adhesion molecule 1; IL-1b, interleukin-1b; IL-6, interleukin-6; Myd88, medullary differentiation factor 88; NAD+, nicotinamide adenine dinucleotide; Nf-kB, nuclear factor-kB; SAH, subarachnoid hemorrhage; SIRT1, sirtuin 1; TLR4, toll-like receptor 4; TNF-a, tumor necrosis factor-a
Consistent with previous researches (Lu et al, 2018; Tao et al, 2019), we found that activation of microglia and expression of inflammatory cytokines were markedly increased after SAH, which were associated with the aggravated brain edema, neural apoptosis, and neurological impairment
Summary
Subarachnoid hemorrhage (SAH) remains a fata neurological emergency with high mortality and morbidity rates (Macdonald and Schweizer, 2017; Chen F. et al, 2018; Li et al, 2019). Excessive neuroinflammation is a key pathogenic cascade that contributes to neuronal injury and cell death after SAH (Fan et al, 2017; Lu et al, 2018; Tao et al, 2019; Zhang et al, 2019b). High mobile group box 1 (HMGB1) plays a critical role in triggering neuroinflammation after SAH (Sun et al, 2014). Sirtuin 1 (SIRT1) is a type of histone deacetylase and plays an important role in endogenous neuroprotection after SAH (Zhang et al, 2016b). SIRT1 plays a key role in regulating HMGB1/Nf-kB activation (Chen F. et al, 2018; Zhang et al, 2019b)
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