Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology最新文献

Hematopoiesis is a tightly regulated process taking place in specialized bone marrow structures called hematopoietic niches. In these structures, hematopoietic stem cells produce all hematopoietic lineages by their self-renewal and differentiation abilities. Sympathetic nerve fibers, entering the bone marrow in association with blood vessels, regulate on a circadian basis the hematopoietic stem cells and leukocytes migration in and out the bone marrow. This cellular traffic, that is mainly regulated by beta-adrenergic receptors expressed on mesenchymal stem cells, is needed to maintain an efficient hematopoietic niche and for immunosurveillance against infections. Both alpha- and beta-adrenergic receptors seem involved in the regeneration of hematopoiesis after myeloablative treatments. Likewise, the effects of psychogenic stress and of ageing on the hematopoietic system are also mediated by adrenergic signals. Yet, the exact mechanisms regulating hematopoietic regeneration and the differentiation ratio between lymphoid and myeloid cells are still obscure. A comprehensive understanding of the adrenergic influence on hematopoiesis holds the potential for novel therapeutic approaches in a variety of hematological diseases.

Identifying the specific bioactive molecules produced by mesenchymal stem cells (MSCs) and the signaling pathways and cell types upon which they act is critical to developing MSC-based therapeutics for inflammatory diseases with high unmet needs. Our study aimed to investigate the impact of extracellular vesicle (EV)-derived TNF-Stimulated Gene-6 (TSG-6, from adipose tissue-derived mesenchymal stem cell concentrated conditioned medium, ASC-CCM or TSG-6 overexpression in ASC using ORF expression-ready clone) on microglia and its potential anti-inflammatory effects. EV but not non-vesicular secretome prepared by ultracentrifugation confirmed the expression of TSG-6 exclusively in the small EV (sEV) fraction. sEV ranged from 50-150 nm as determined by Zetasizer, demonstrated bilipid membrane evidenced by transmission electron microscopy, expressed positive exosomal (e.g. CD63) markers, and were endocytosed by BV2 cells confirmed by DiI fluorescently labeled exosomes. BV2 microglia cultured under serum-free conditions stimulated with TLR4 agonists (LPS and IFNγ) for 12 h in the presence of p-ASC-EV (sEV derived from ASC after cytokine stimulation) and TSG-6-ORF-EV significantly reduced nitrite release (p < 0.001), phagocytic activity (p < 0.001) and reduced CD44 expression (p < 0.05). CD44 knockdown in BV2 cells ablated TSG-6-ORF-EV mediated nitrite release, IL1β downregulation, and phagocytosis with TLR4 agonists. Our results revealed that under cytokine stimulation, the EV portion of ASC-CCM becomes enriched with TSG-6. Overexpressing TSG-6 in ASC leads to an increased concentration of TSG-6 in sEVs. This enriched EV fraction, containing TSG-6, regulates microglial dynamics through a feedback loop with CD44. EV-associated TSG-6 can influence immune cell behavior and signaling, mitigating excessive inflammation or immune dysfunction.

Necroptosis is a novel mode of cell death that differs from traditional apoptosis, characterized by distinct molecular mechanisms and physiopathological features. Recent research has increasingly underscored the pivotal role of necroptosis in various neurological diseases, including stroke, Alzheimer's disease and multiple sclerosis. A defining hallmark of these conditions is neuroinflammation, a complex inflammatory response that critically influences neuronal survival. This review provides a comprehensive analysis of the mechanistic underpinnings of necroptosis and its intricate interplay with neuroinflammation, exploring the interrelationship between the two processes and their impact on neurological disorders. In addition, we discuss potential therapeutic strategies that target the intervention of necroptosis and neuroinflammation, offering novel avenues for intervention. By deepening our understanding of these interconnected processes, the development of more effective treatments approaches holds significant promise for improving patient outcomes in neurological disorders.

Mania-like episodes are neuropsychiatric disturbances associated with bipolar disorder (BD). Autophagic flux disturbance evolved as one of the molecular mechanisms implicated in mania. Recently, Dapagliflozin (DAPA) has corrected autophagic signaling in several neurological disorders. Yet, no endeavours examined the autophagic impact of DAPA in mania-like behaviours. This study aimed to investigate the effect of DAPA on disrupted autophagic pathways in a mouse model of mania-like behaviour. Mania-like behaviour was induced through paradoxical sleep deprivation (PSD) using the multiple-platform method for a duration of 36 h. Mice were divided into three groups, with DAPA (1 mg/kg/day, orally) administered for one week. Behavioural assessments were conducted on the 7th day. DAPA mitigated anxiety-like behaviour in the open field test and improved motor coordination and muscle tone in the rotarod test. Mechanistically, DAPA activated hippocampal autophagy-related markers; liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway, autophagy related gene 7 (ATG7), and microtubule-associated protein light chain 3II (LC3II). This was associated with reduced levels of the autophagosome receptor p62 protein, which subsequently enhanced GABA_A receptor-associated protein (GABARAP), facilitating the surface presentation of GABA_A receptors. Additionally, DAPA upregulated the GABA_B receptor R2 subunit through trophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Furthermore, DAPA mitigated elevated serum stress hormones and restored the balance between proinflammatory and anti-inflammatory cytokines in both cortical and hippocampal tissues. These findings highlight the role of autophagic flux modulation by DAPA and its therapeutic potential in mitigating mania-like behaviours.

Several preclinical and clinical studies have shown that SARS-CoV-2 infection is associated with new-onset Parkinson's disease (PD). The overall goal of this study is to uncover how the COVID-19 severity gradient impacts the conventional pathological pathway of PD to inform the identification of at-risk patients and the development of personalized treatment strategies. Transcriptomics analysis of 43 PD pathogenic genes was conducted on nasopharyngeal swabs from 50 COVID-19 patients with varying severity including 17 outpatients, 16 non-ICU, and 17 ICU patients, compared to 13 SARS-CoV-2 negative individuals. The study shows that COVID-19 severity gradient differentially dysregulates PD pathological genes. Dysfunctional lysosomal and mitochondrial processes in outpatients and non-ICU COVID-19 patients was identified as the convergent network of COVID-19-PD interactions. These dysfunctions were later abrogated by the upregulation of the ubiquitin-proteasome system and autophagy-lysosome system in ICU COVID-19 patients. A potential synergistic co-expression and clustering of protein clearance pathway genes with other pathological genes was observed in ICU patients, indicating a possible overlap in biological pathways. Dysregulation of the PD pathopharmacogene, SLC6A3 was observed in ICU patients, suggesting potential COVID-19-gene-drug interactions. Nasopharyngeal swabs express major PD pathological genes as well as clinically relevant drug processing genes, which could advance studies on PD, including diagnosis, pathogenesis, and the development of disease-modifying treatments. Outpatients and non-ICU COVID-19 patients may face a higher risk of developing new-onset PD, whereas ICU COVID-19 patients may be more susceptible to COVID-19-gene-drug interactions.

Neuroinflammation plays a vital role in the etiology and pathogenesis of Tourette syndrome (TS). The postmortem report of TS patients clarified that IL-2 is elevated in the basal ganglia region, supporting neuroinflammation of TS. α₂ receptor agonist (clonidine) is one of the primary drugs for treating tic disorders; supported by clinical and animal experiments, α₂ receptor agonists have potential anti-inflammatory effects. This article aims to explore the impact of clonidine on neuroinflammation with TS and to reveal the possible mechanism of clonidine-mediated neuroinflammation with TS. Thirty P21 SD rats were randomly divided into a TS rat group (n = 20) and a normal control group (n = 10). After successful TS modelling, rats were randomly divided into the clonidine intervention group (n = 10) and the TS group (n = 10). The clonidine intervention group received clonidine 0.1 mg/kg by gavage daily for seven consecutive days. After behavioural evaluation on day 8, the brain was removed from the head. The striatum was separated from one side of the brain and subjected to ELISA to detect cytokines. The other side of the brain was subjected to immunohistochemical detection for microglial activation, and the integral optical density value was calculated using image software for comparison between the groups. Compared to the normal group, IL-2 cytokine levels in TS rats were significantly higher (P < 0.05). In the clonidine group, IL-2 levels (213.82 ± 121.48 pg/ml) were significantly lower than in the TS group (322.61 ± 79.27 pg/ml) (P < 0.05) but not significantly different from the normal control group (257.40 ± 95.80 pg/ml) (P > 0.05). Immunohistochemical analysis showed significant microglial activation in TS rats (IOD = 22.10 ± 6.67) compared to the normal group (IOD = 11.58 ± 4.36) (P < 0.05). Clonidine administration reduced microglial activation, with a significant difference between the TS + clonidine group (IOD = 15.97 ± 8.03) and TS rats (P < 0.05). Clonidine can suppress the neuroinflammatory response in Tourette syndrome, and its inhibitory effect on the neuroinflammatory response may be a potential beneficial effect of this treatment.

Sporadic Alzheimer's disease (SAD) represents one of the major memory deficits that is characterized by tau hyperphosphorylation and amyloid beta (Aβ) deposition in the brain. Both are considered AD hallmarks which are mediated through neuroinflammation, oxidative stress, and cholinergic circuit interruption. This study aimed to show how limettin and PD98059 exert a neuroprotective effect against SAD and the possible role of the extracellular regulated kinase (p-ERK1/2) and glycogen synthase kinase-3 beta (p-GSK-3β) (Ser9)/cAMP-response element binding protein (p-CREB) (Ser133)/brain derived neurotrophic factor (BDNF) pathway. Control animals (Group I) received the vehicles, group II received PD98059 (10 mg/kg/i.p), while group III was administered limettin (15 mg/kg/i.p). Additionally, the other three groups received a single dose of streptozotocin (STZ; 3 mg/kg/ICV), where group IV served as the SAD group, while groups V and VI received PD98059 and limettin daily for 3 weeks, respectively. The SAD animals receiving PD98059 and limettin increased the number of arm entries, % alternations in Y-maze, with reduction in mean escape latency, increase in time spent in target quadrant and platform crossing in Morris Water Maze, compared to the SAD group. Additionally, PD98059 and limettin administration to the STZ group downregulated persistent activation of p-ERK1/2 which in turn increased p-GSK-3β (Ser9), leading to enhanced p-CREB (Ser133) and BDNF expressions, as well as reducing inflammatory markers viz., nuclear factor-kappa B and interleukin-6, leading to decreased Aβ deposition. Both treatments reduced immunohistochemical p-tau expression, brain edema, and increased intact neuron cells remarkably. Thus, based on these findings, PD98059 and limettin may have promising effects in protecting against SAD. Using blockers/inhibitory molecules are recommended to confirm effect through the corresponding pathway.

Patients with advanced cancer often have bone metastases, causing bone destruction and cancer-induced bone pain (CIBP). The CCAAT/enhancer binding protein β (c/EBPβ) mediated the regulation of various pro-inflammatory molecules in microglia. To investigate the specific effect and regulatory mechanism of c/EBPβ in CIBP, a mice model of Lewis lung cancer (LLC) cells implantation was constructed. Our data demonstrated that the c/EBPβ was remarkably elevated in the spinal cord of CIBP mice. Specific knocking down c/EBPβ relieved the mechanical allodynia and thermal hyperalgesia of CIBP mice by suppressing the microglia activation and pro-inflammatory cytokines generation. Besides, overexpressing c/EBPβ could prompt severe pain behaviors with spinal neuroinflammation in naïve mice. Notably, the upstream regulator constitutive photomorphogenic 1 (COP1) was gradually reduced in the spinal cord of CIBP mice. Upregulating the expression of COP1 effectively alleviated the nociceptive behaviors of CIBP mice by inhibiting the accumulation of c/EBPβ and subsequent neuroinflammation. However, knocking down COP1 caused the rapid increase of c/EBPβ and exacerbation of spinal neuroinflammation, ultimately leading to behavioral damage in naïve mice. In conclusion, the absence of COP1 promoted the accumulation of c/EBPβ and neuroinflammatory molecules in the spinal cord of CIBP mice, which extends the future therapeutic approach for CIBP.

During or after chemotherapy, cognitive impairments characterized by forgetfulness, difficulty concentrating, and depressive and anxiety-like symptoms are observed. There is limited research examining the effects of rosuvastatin (RVS), an HMG-CoA reductase inhibitor, in the context of neuroinflammation-related cognitive disruption. Here, we aimed to investigate the neuroprotective potential of RVS against doxorubicin (DOX)-induced cognitive impairments. Experimental groups were planned as control (normal saline, intraperitoneal), DOX (total cumulative dose 10 mg/kg, intraperitoneal), RVS (10 mg/kg, oral, 20 days), and RVS + DOX. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, genetic, histopathological, and immunohistochemical examinations. Results from Morris water maze (MWM), passive avoidance, locomotion activity, and elevated plus maze (EPM) tests showed that DOX administration caused behavioral disorders. Moreover, DOX increased the levels of inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α), while decreasing the levels of interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase, catalase (SOD), endothelial nitric oxide (eNOS), and catalase (CAT). Co-treatment with RSV significantly attenuated DOX-induced behavioral changes and oxidative stress markers. In addition, similar to the immunohistochemical results, we determined that it increased the expression levels of extracellular signal-related kinases 1/2 (ERK1/2), cyclic adenosine monophosphate response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF) and restored the histopathological structure of the brain. Therefore, these results indicated that RSV has a neuroprotective effect against DOX-induced cognitive impairment by reducing neurobehavioral impairments, exerting antioxidant and anti-inflammatory effects, and modulating brain growth factors.

Extracellular vesicles released from mesenchymal stem cells (MSCs-EV) have shown anti-inflammatory effects in Parkinson's disease (PD). This study was designed to assess the neuroprotective effects of human umbilical cord MSCs (hucMSCs) and the possible mechanisms involved. SH-SY5Y cells were induced with MPP⁺, and the impact of hucMSCs-EV on the damage to SH-SY5Y cells was examined. Mice were induced with PD-like symptoms by MPTP and the effects of hucMSCs-EV on neurological damage in mouse brain tissue were detected as well. HucMSCs-EV inhibited apoptosis and oxidative stress in MPP⁺-induced SH-SY5Y cells. HucMSCs-EV suppressed behavioral deficits and neuronal apoptosis in MPTP-induced mice, with an increased number of dopamine neurons in brain tissues and decreased p-alpha-syn expression in dopamine neurons. The expression of ribosomal protein S27A (RPS27A) in SH-SY5Y cells was elevated after co-culture of neurons and hucMSCs-EV, and RPS27A silencing abated the effect of hucMSCs-EV in vivo and in vitro. RPS27A bound to the MDM2 promoter, thus promoting P53 ubiquitination and degradation. MDM2 overexpression strengthened the therapeutic effect of hucMSCs-EV. We conclude that hucMSCs-EV promote the interaction between RPS27A and MDM2 by delivering RPS27A, which regulates the MDM2-P53 axis to promote degradation of P53 to ameliorate neurological damage in PD.