Abstract
BackgroundThe NLRP3 inflammasome activation and neuroinflammation are known to be involved in the pathology of depression, whereas autophagy has multiple effects on immunity, which is partly mediated by the regulation of inflammasome and clearance of proinflammatory cytokines. Given the emerging evidence that autophagy dysfunction plays an essential role in depression, it is very likely that autophagy may interact with the inflammatory process in the development and treatment of depression. Salvianolic acid B (SalB), a naturally occurring compound extracted from Salvia miltiorrhiza, contains anti-inflammatory and antidepression properties and has recently been proven to modulate autophagy. In this study, we sought to investigate whether autophagy is involved in the inflammation-induced depression and the antidepressant effects of SalB.MethodsThe effects of prolonged lipopolysaccharide (LPS) treatment and SalB administration on behavioral changes, neuroinflammation, autophagic markers and NLRP3 activation in rat hippocampus were determined by using behavioral tests, real-time PCR analysis, western blot, and immunostaining.ResultsOur data showed that periphery immune challenge by LPS for 2 weeks successfully induced the rats to a depression-like state, accompanied with enhanced expression of pro-inflammatory cytokines and NLRP3 inflammasome activation. Interestingly, autophagic markers, including Beclin-1, and the ratio of LC3II to LC3I were suppressed following prolonged LPS exposure. Meanwhile, co-treatment with SalB showed robust antidepressant effects and ameliorated the LPS-induced neuroinflammation. Additionally, SalB restored the compromised autophagy and overactivated NLRP3 inflammasome in LPS-treated rats.ConclusionsCollectively, these data suggest that autophagy may interact with NLRP3 activation to contribute to the development of depression, whereas SalB can promote autophagy and induce the clearance of NLRP3, thereby resulting in neuroprotective and antidepressant actions.
Highlights
The Nod-like receptor pyrin containing 3 inflammasome (NLRP3) inflammasome activation and neuroinflammation are known to be involved in the pathology of depression, whereas autophagy has multiple effects on immunity, which is partly mediated by the regulation of inflammasome and clearance of proinflammatory cytokines
Salvianolic acid B (SalB) alleviated the enhanced expression of proinflammatory cytokines, IL-1β and IL-6 (Fig. 2b, c), in LPS group except that both SalB and LPS exerted no effect on TNF-α expression (Fig. 2d)
LPS treatment induced significant activation of caspase-1 (Fig. 5e, p < 0.01) and enhanced the protein expression of both pro-IL-1β (Fig. 5f, p < 0.01) and mature IL1β (Fig. 5g, p < 0.01), whereas SalB partly normalized the NLRP3 inflammasome activation with significant decrease of the protein levels NLRP3 inflammasome components (NLRP3, a caspase recruitment domain (ASC), caspase-1 P20) and attenuated IL-1β activation compared with the LPS-treated group. These results suggest that autophagy process may interact with NLRP3 inflammasome to promote depressionlike behaviors and neuroimmune activation, which may actively participate in the molecular mechanisms of antidepressant effects of SalB
Summary
The NLRP3 inflammasome activation and neuroinflammation are known to be involved in the pathology of depression, whereas autophagy has multiple effects on immunity, which is partly mediated by the regulation of inflammasome and clearance of proinflammatory cytokines. We sought to investigate whether autophagy is involved in the inflammation-induced depression and the antidepressant effects of SalB. Autophagy is an evolutionarily homeostatic cellular process, which can sense intracellular stress and rapidly mount a response to cope with the damage through sequestration and degradation of damaged organelles and compromised proteins. This process is orchestrated by a series of autophagy-related genes (Atg genes), such as Beclin-1 and LC3-II (derived from LC3-I upon lipidation), which are reliable biomarkers for assessing autophagy process [2]. The potential mechanisms by which the autophagy process may contribute to both the development and treatment of depression remain equivocal
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