PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats: Highlights on HMGB1/RAGE/TLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1

Abstract

Ample evidence has pointed to a close link between cardiovascular diseases (CVD) and depression. Inflammatory pathways including the high-mobility-group-box-1 protein, receptor-for-advanced-glycation-end-products and toll-like-receptor-4 (HMGB1/RAGE/TLR4) and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathways are thought to be crucial players in this link. Activation of these pathways ends by releasing of different inflammatory mediators involved in CVD and depression pathophysiology. In the brain, this inflammatory process enhanced indoleamine2,3-dioxygenase-1 (IDO-1) activation with subsequent alteration in kynurenine/tryptophan levels causing depression. Based on the favorable anti-inflammatory effects of Alirocumab, the proprotein-convertase-subtilisin/kexin-type-9 (PCSK9) inhibitor, used in different CVD, this study was designed to investigate its potential antidepressant effect. The behavioral and neurochemical effects of concomitant treatment of Alirocumab at doses of (4, 8 and 16 mg/kg/week subcutaneously) in Wistar rats exposed to chronic unpredictable mild stress (CUMS) for 6 weeks were assayed. Alirocumab prevented CUMS-induced depressive-like-behaviors exhibited in open-field and forced-swimming tests, and hypothalamus–pituitary–adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Alirocumab prevented CUMS-induced alteration in hippocampal kynurenine/tryptophan levels and pro-inflammatory cytokines tumor-necrosis-factor-alpha, interleukin-1beta (IL-1β), IL-2 and IL-6. Western blot and PCR analysis showed that Alirocumab favorably modulated the HMGB1/RAGE/TLR4 axis, nuclear-factor-kappa-beta, NLRP3 inflammasome complex and IDO-1 in the hippocampus of CUMS rats. These effects were correlated to the level of PCSK9 expression. The behavioral and biochemical findings indicated the potential antidepressant effect of PCSK9 inhibition by Alirocumab. Graphical Abstract

Punicalagin’s Protective Effects on Parkinson’s Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway

“…Consequently, NF-KB inhibition by PUN resulted in the suppression of NLRP3 release and the formation of pro-inflammatory mediators. This preventedNLRP3 activation and consequently blocked the activity of caspase-1, thereby reducing the maturation of IL-1β, in agreement with previous studies [89,90]. Additionally, PUN attenuated the expression of pro-inflammatory mediators, which contributed to the suppression of the JAK-2/STAT-3 signaling pathway and reduced astroglial activation.…”

Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

“…Alirocumab, an inhibitor of PCSK9 which is a protein correlated to TLR4 regulation, prevented CUMS-induced depression-like-behaviors in Wistar rats. This effect of PCSK9 inhibition was associated with the inhibition of the hippocampal HMGB1/RAGE/TLR4 pathway [86]. The same antidepressant effect was observed in CUMS mice with the KD of Follistatin-like protein 1, identified as a novel inflammatory protein that alleviated depressive symptoms and microglia hyperactivation through the inhibition of the TLR4/MyD88/NF-κB pathway [87].…”

Anti-Glycation Properties of Zinc-Enriched Arthrospira platensis (Spirulina) Contribute to Prevention of Metaflammation in a Diet-Induced Obese Mouse Model

“…In response to AGE binding, RAGE activates a wide range of signals leading to activation of pro-inflammatory transcription factors, including NFkB. NFkB in turn induces the transcription of proinflammatory cytokines and primes the assembling and activation of the NLRP3 inflammasome, one of the most characteristic pro-inflammatory molecular platforms involved in metaflammation onset [ 61 , 62 , 63 ]. Interestingly, the effective prevention of RAGE upregulation by Zn-SP was paralleled by robust reduction in both nuclear translocation of the NFκB-p65 and expression of NLRP3 inflammasome complex in the liver as well as by significant reduction in the systemic concentrations of NFκB- and NLRP3-dependent cytokines, IL-6/IFN-γ and IL-1β, respectively.…”