Figure - available from: Journal of Immunology Research
This content is subject to copyright. Terms and conditions apply.
Source publication
Depression is one of the most important mental illnesses and is closely related to inflammation. Betaine is a natural product with an anti-inflammatory and antioxidant activities. However, the mechanism by which betaine ameliorates depression-like behaviors induced by lipopolysaccharide (LPS) is poorly understood. The purpose of this study was to i...
Citations
... anti-inflammatory properties [9]. Recently, there have been advancements in pharmacological approaches that aim to modulate microglial polarization, offering potential therapeutic options for reducing the recurrence of psychiatric disorders [10][11][12]. In combination, the preponderance of evidence indicates a strong association between microglial abnormalities and the development of depression. ...
Depression is a prevalent and debilitating psychiatric disorder, imposing substantial societal and individual burdens. This study aims to investigate the involvement of ferroptosis and microglial polarization in the pathogenesis of depression, as well as the underlying mechanism. Increased protein arginine methyltransferase 2 (PRMT2) expression was observed in BV2 cells and the hippocampus following lipopolysaccharide (LPS) stimulation. Mechanistically, alkylation repair homolog protein 5 (ALKBH5)-mediated m6A modification enhanced the stability of PRMT2 mRNA. PRMT2 promoted arginine methylation of β-catenin and induced proteasomal degradation of β-catenin proteins, resulting in transcriptional inhibition of glutathione peroxidase 4 (GPX4). The upregulation of PRMT2 further accelerated microglia polarization by activating ferroptosis through the β-catenin-GPX4 axis. Depletion of PRMT2 improved LPS-induced depressive- and anxiety-like behaviors as well as cognitive impairment by inhibiting ferroptosis and M1 polarization of microglia. Our findings underscore the crucial involvement of the ALKBH5-PRMT2-β-catenin-GPX4 axis in ferroptosis and M1 polarization of microglia, thereby offering novel insights into the pathogenesis interventions for depression.
... The activation of microglia and the consequent induction of neuroin ammation have been tied to the pathogenesis of major depressive disorders. Broadly speaking, activated microglia are classi ed into proin ammatory M1 cells and anti-in ammatory regenerative M2 cells [10,11]. Higher levels of M1 microglia polarization and activity are associated with phagocytic and in ammatory activity, and an elevated M1/M2 ratio is related to impaired neurological function and depression in rat [12,13]. ...
Background
Microglial polarization and associated inflammatory activity are key mediators of depression pathogenesis. The natural Smilax glabra rhizomilax derivative engeletin has been reported to exhibit robust anti-inflammatory activity, but no studies to date have examined the mechanisms through which it can treat depressive symptoms.
Purpose
This study was designed to assess the therapeutic efficacy of engeletin in a murine chronic stress social defeat stress (CSDS) model system and to clarify the underlying mechanisms, with a particular focus on microglial polarization.
Methods
CSDS model mice were used to test the potential antidepressant effects of engeletin. Following a 21-day engeletin treatment period, a range of assays including the sucrose preference test (SPT), social interaction test (SIT), tail suspension test (TST), forced swim test (FST), and open field test (OFT) were used to measure depressive-like behaviors in these mice. Following the completion of such behavioral testing, 3.0 T multifunctional magnetic resonance imaging brain scans including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), T2 mapping, and diffusion tensor imaging (DTI) were performed. In addition, quantitative real-time PCR (qRT-PCR), and western blotting were used to measure levels of inflammatory cytokines including interleukin (IL)-6, IL-10, IL-1β, and TNF-α. Microglia activation was further evaluated through western blotting and immunohistochemical staining for markers of M1 (CD86, iNOS) and M2 (Arg1, CD206) polarization. The lipocalin-2 (LCN2)/ C-X-C motif chemokine ligand 10 (CXCL10) signaling pathway was additionally assessed via whole transcriptomic sequencing, qRT-PCR, and western blotting. Adeno-associated virus (AAV) particles encoding LCN2-EGFP were then infused into CSDS model mice to evaluate the effects of LCN2 overexpression and engeletin treatment in greater detail.
Results
Treatment for 21 days with engeletin significantly alleviated depressive-like behaviors in CSDS model mice. T1WI and T2WI imaging revealed no significant differences between groups, but the bilateral prefrontal cortex of CSDS mice exhibited significant increases in apparent diffusion coefficient (ADC) and T2 values relative to normal control mice, with a corresponding reduction in fractional anisotropy (FA), while engeletin reversed all of these changes. CSDS resulted in higher levels of IL-1β, IL-6, and TNF-a production, enhanced microglial activation, and greater M1 polarization with a concomitant decrease in M2 polarization in the mPFC, whereas engeletin treatment effectively abrogated these CSDS-related pathological changes. Engeletin was further found to suppress the LCN2/CXCL10 signaling axis such that AAV-induced LCN2 overexpression ablated the antidepressant effects of engeletin and reversed its beneficial effects on the M1/M2 polarization of microglia. These data suggest that the antidepressant effects of engeletin are correlated with the polarization of microglia, highlighting a potential avenue for future design of antidepressant strategies that specifically target the microglia.
Conclusion
Engeletin can alleviate CSDS-induced depressive-like behaviors by regulating the LCN2/CXCL10 pathway and thereby altering the polarization of microglia.
... It is subsequently distributed to different organs, including the brain [15,16]. BT exhibits various pharmacological effects, including antioxidant and anti-inflammatory activities, as well as the ability to mitigate endoplasmic reticulum stress and apoptosis [13,15,[17][18][19][20][21][22]. Due to these properties, it is anticipated that BT may possess neuroprotective characteristics suitable for addressing behavioral impairments induced by ischemia, toxins, and stress, such as seizures, depressive-like symptoms, motor dysfunction, and memory deficits [22][23][24][25][26][27]. ...
... BT exhibits various pharmacological effects, including antioxidant and anti-inflammatory activities, as well as the ability to mitigate endoplasmic reticulum stress and apoptosis [13,15,[17][18][19][20][21][22]. Due to these properties, it is anticipated that BT may possess neuroprotective characteristics suitable for addressing behavioral impairments induced by ischemia, toxins, and stress, such as seizures, depressive-like symptoms, motor dysfunction, and memory deficits [22][23][24][25][26][27]. However, despite extensive research on the beneficial effects of BT, there is currently a dearth of knowledge regarding its potential therapeutic use as a neuroprotectant against HP-induced OD and the underlying mechanisms involved in its ameliorative effects. ...
... Consequently, it is expected that BT administration can subsequently impede the development of OD in animals. This hypothesis is based on the well-documented and robust anti-oxidative, anti-inflammatory, and anti-apoptotic properties exhibited by BT in previous studies conducted by our laboratory and others [13,15,[17][18][19][20][21][22]24,26,27]. The purpose of the present study was designed to explore the possible effects of BT on HP-induced OD using a well-established rat model of neurotoxicity. ...
With its pathophysiological characteristics strongly similar to patients with tardive dyskinesia (TD), haloperidol (HP)-induced neurotoxicity and orofacial dyskinesia (OD) in animal models have long been used to study human TD. This study aimed to explore the potential protective effects of betaine (BT), a vital biochemical compound present in plants, microorganisms, animals, and various dietary sources. The study focused on investigating the impact of BT on haloperidol (HP)-induced orofacial dyskinesia (OD) in rats, as well as the underlying neuroprotective mechanisms. To induce the development of OD, which is characterized by increased vacuous chewing movement (VCM) and tongue protrusion (TP), rats were administered HP (1 mg/kg i.p.) for 21 consecutive days. BT was administered intraperitoneally (i.p.) at doses of 30 and 100 mg/kg, 60 min later, for 21 successive days. On the 21st day, after evaluating OD behavior, the rats were sacrificed, and various measurements were taken to assess the nitrosative and oxidative status, antioxidant capacity, mitochondrial function, neuroinflammation, and apoptotic markers in the striatum. The results demonstrated that (1) HP induced OD development, and (2) BT was found to prevent most of the HP-induced OD; decrease oxidative stress levels; increase anti-oxidation power; prevent mitochondrial dysfunction; and reduce the levels of neuroinflammatory and apoptotic markers in the striatum. Our results demonstrate that the neuroprotective effects of BT against HP-induced OD are credited to its antioxidant prevention of mitochondrial dysfunction, anti-neuroinflammatory effects, and anti-apoptotic effects, suggesting that BT may be a novel therapeutic candidate in delaying or treating human TD in clinical settings. However, further studies will be warranted to extrapolate preclinical findings into clinical studies for a better understanding of the role of BT.
Microglial polarization and associated inflammatory activity are the key mediators of depression pathogenesis. The natural Smilax glabra rhizomilax derivative engeletin has been reported to exhibit robust anti‐inflammatory activity, but no studies to date have examined the mechanisms through which it can treat depressive symptoms. We showed that treatment for 21 days with engeletin significantly alleviated depressive‐like behaviours in chronic stress social defeat stress (CSDS) model mice. T1‐weighted imaging (T1WI), T2‐weighted imaging (T2WI) imaging revealed no significant differences between groups, but the bilateral prefrontal cortex of CSDS mice exhibited significant increases in apparent diffusion coefficient and T2 values relative to normal control mice, with a corresponding reduction in fractional anisotropy, while engeletin reversed all of these changes. CSDS resulted in higher levels of IL‐1β, IL‐6, and TNF‐a production, enhanced microglial activation, and greater M1 polarization with a concomitant decrease in M2 polarization in the mPFC, whereas engeletin treatment effectively abrogated these CSDS‐related pathological changes. Engeletin was further found to suppress the LCN2/C‐X‐C motif chemokine ligand 10 (CXCL10) signalling axis such that adeno‐associated virus‐induced LCN2 overexpression ablated the antidepressant effects of engeletin and reversed its beneficial effects on the M1/M2 polarization of microglia. In conclusion, engeletin can alleviate CSDS‐induced depressive‐like behaviours by regulating the LCN2/CXCL10 pathway and thereby altering the polarization of microglia. These data suggest that the antidepressant effects of engeletin are correlated with the polarization of microglia, highlighting a potential avenue for future design of antidepressant strategies that specifically target the microglia.
Previous studies have demonstrated a bidirectional relationship between inflammation and depression. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and NLR family pyrin domain-containing 3 (NLRP3) inflammasomes is closely related to the pathogenesis of various neurological diseases. In patients with major depressive disorder, NLRP3 inflammasome levels are significantly elevated. Understanding the role that NLRP3 inflammasome-mediated neuroinflammation plays in the pathogenesis of depression may be beneficial for future therapeutic strategies. In this review, we aimed to elucidate the mechanisms that lead to the activation of the NLRP3 inflammasome in depression as well as to provide insight into therapeutic strategies that target the NLRP3 inflammasome. Moreover, we outlined various therapeutic strategies that target the NLRP3 inflammasome, including NLRP3 inflammatory pathway inhibitors, natural compounds, and other therapeutic compounds that have been shown to be effective in treating depression. Additionally, we summarized the application of NLRP3 inflammasome inhibitors in clinical trials related to depression. Currently, there is a scarcity of clinical trials dedicated to investigating the applications of NLRP3 inflammasome inhibitors in depression treatment. The modulation of NLRP3 inflammasomes in microglia holds promise for the management of depression. Further investigations are necessary to ascertain the efficacy and safety of these therapeutic approaches as potential novel antidepressant treatments.
Depression, a prevalent psychiatric malady, afflicts a substantial global demographic, engendering considerable disease burden due to its elevated morbidity and mortality rates. Contemporary therapeutic approaches for depression encompass the administration of serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants, albeit these pharmaceuticals potentially induce adverse neurological and gastrointestinal effects. Traditional Chinese Medicine (TCM) natural products proffer the benefits of multi-target, multi-level, and multi-channel depression treatment modalities. In this investigation, we conducted a comprehensive literature review of the past 5 years in PubMed and other databases utilizing the search terms "Depression," "Natural medicines," "Traditional Chinese Medicine," and "hypothalamic-pituitary-adrenal axis." We delineated the 5 most recent and pertinent signaling pathways associated with depression and hypothalamic-pituitary-adrenal (HPA) axis dysregulation: nuclear factor kappa light-chain-enhancer of activated B cell, brain-derived neurotrophic factor, mitogen-activated protein kinase, cyclic AMP/protein kinase A, and phosphoinositide 3-kinase/protein kinase B. Additionally, we deliberated the antidepressant mechanisms of natural medicines comprising alkaloids, flavonoids, polyphenols, saponins, and quinones via diverse pathways. This research endeavor endeavored to encapsulate and synthesize the progression of TCMs in modulating HPA axis-associated signaling pathways to mitigate depression, thereby furnishing robust evidence for ensuing research in this domain.
