Systemic inflammation often induces neuroinflammation and disrupts neural functions, ultimately causing cognitive impairment. Furthermore, neuronal inflammation is the key cause of many neurological conditions. It is particularly important to develop effective neuroprotectants to prevent and control inflammatory brain diseases. Baicalin (BAI) has a wide variety of potent neuroprotective and cognitive enhancement properties in various models of neuronal injury through antioxidation, anti-inflammation, anti-apoptosis, and stimulating neurogenesis. Nevertheless, it remains unclear whether BAI can resolve neuroinflammation and cognitive decline triggered by systemic or distant inflammatory processes. In the present study, intraperitoneal lipopolysaccharide (LPS) administration was used to establish neuroinflammation to evaluate the potential neuroprotective and anti-inflammatory effects of BAI. Here, we report that BAI activated silent information regulator 1 (SIRT1) to deacetylate high-mobility group box 1 (HMGB1) protein in response to acute LPS-induced neuroinflammation and cognitive deficits. Furthermore, we demonstrated the anti-inflammatory and cognitive enhancement effects and the underlying molecular mechanisms of BAI in modulating microglial activation and systemic cytokine production, including tumor necrosis factor- (TNF-) α and interleukin- (IL-) 1β, after LPS exposure in mice and in the microglial cell line, BV2. In the hippocampus, BAI not only reduced reactive microglia and inflammatory cytokine production but also modulated SIRT1/HMGB1 signaling in microglia. Interestingly, pretreatment with SIRT1 inhibitor EX-527 abolished the beneficial effects of BAI against LPS exposure. Specifically, BAI treatment inhibited HMGB1 release via the SIRT1/HMGB1 pathway and reduced the nuclear translocation of HMGB1 in LPS-induced BV2 cells. These effects were reversed in BV2 cells by silencing endogenous SIRT1. Taken together, these findings indicated that BAI reduced microglia-associated neuroinflammation and improved acute neurocognitive deficits in LPS-induced mice via SIRT1-dependent downregulation of HMGB1, suggesting a possible novel protection against acute neurobehavioral deficits, such as delayed neurocognitive recovery after anesthesia and surgery challenges.
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Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1–7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1–7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1–7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1–7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.
Delayed neurocognitive recovery (dNCR) is a major complication after anesthesia and surgery in older adults. Alpha-synuclein (α-syn; encoded by the gene, SNCA) has recently been shown to play an important role in hippocampus-dependent working memory. Aggregated forms of α-syn are associated with multiple neurotoxic mechanisms, such as mitochondrial dysfunction and cell death. In this study, we found that blocking α-syn improved both mitochondrial function and mitochondria-dependent neuronal apoptosis in a mouse model of dNCR. Various forms of α-syn (including total α-syn, phosphorylated-Ser129-α-syn, and oligomers) were upregulated in hippocampal tissue and extracted mitochondria after surgical challenge. Clenbuterol is a novel transcription modulator of Scna. Clenbuterol significantly attenuated surgery-induced progressive accumulation of various toxic α-syn forms in the hippocampus, as well as mitochondrial damage and memory deficits in aged mice following surgery. We also observed excessive mitochondrial α-syn accumulation and increased mitochondria-mediated apoptosis in vitro using nerve growth factor-differentiated PC12 cells and primary hippocampal neurons exposed to lipopolysaccharide. To further validate the neuroprotective effect of α-syn inhibition, we used a lentiviral Snca-shRNA (Lv-shSnca) to knockdown Snca. Of note, Lv-shSnca transfection significantly inhibited neuronal apoptosis mediated by the mitochondrial apoptosis pathway in neurons exposed to lipopolysaccharide. This α-syn inhibition improved the disruption to mitochondrial morphology and function, as well as decreased levels of apoptosis. Our results suggest that targeting pathological α-syn may achieve neuroprotection through regulation of mitochondrial homeostasis and suppression of apoptosis in the aged hippocampus, further strengthening the therapeutic potential of targeting α-syn for dNCR.
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