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

Schizophrenia is a complex neuropsychiatric disorder characterized by a spectrum of symptoms including cognitive impairments and psychotic episodes. Clozapine, an atypical antipsychotic drug, is a widely recognised treatment option for patients with drug-resistant schizophrenia, due to it having the highest efficacy out of all the antipsychotic drugs. Despite its efficacy, clozapine's impact on cognition and brain structure in schizophrenia patients remains a subject of ongoing research and debate, with accumulating evidence indicating negative impacts on cognitive performance and changes in brain volume. Changes in the immune system are linked to variations in cognitive functioning in schizophrenia. Previous research has indicated that microglia, the primary innate immune cells of the brain, have been associated with decreased cognitive performance when dysfunctional. Evidence suggests that brain structure may mediate the observed relationship between microglia and cognition. Microglial exosomes, integral to neuroinflammation and cellular communication, could provide insight into the neurobiological mechanisms underpinning the effects of clozapine treatment. This review focuses on the proposition that alterations in microglial exosome composition, particularly miRNAs, are involved in mediating clozapine's diverse effects on cognition by influencing brain macrostructure. This review aims to highlight new directions for future research that could lead to more effective and targeted therapeutic approaches in the management of schizophrenia.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome typically diagnosed in childhood that may persist into adulthood. Its etiology encompasses both genetic and environmental factors, with genetic studies indicating catecholamine dysfunction and epidemiological evidence emphasizing neuroinflammation as a potential trigger. To investigate the roles of inflammation and development processes in ADHD, we conducted a longitudinal behavioral study using female Swiss mice with a dopamine deficit model. We explored the impact of neonatal dopaminergic lesions, treatment with abscisic acid (ABA)-an anti-inflammatory hormone-and developmental changes by comparing behavioral patterns in juvenile and adult mice. Postmortem analyses assessed neuroinflammation through microglial morphology, NLRP3, cytokine expression, and the excitatory/inhibitory (E/I) ratio in specific brain regions. Neonatal dopaminergic lesions induced hyperactivity and hypersensitivity in juvenile mice that persisted into adulthood. In adults, increased social interaction and memory impairment were observed in lesioned mice. Brain development mitigated impulsivity, while ABA treatment reduced locomotor activity, downregulated pain sensitivity, and influenced social interaction, although it did not completely resolve cognitive deficits in lesioned adult mice. In brain regions such as the anterior cingulate cortex (ACC), posterior insular cortex (pIC), and hippocampus, lesions significantly altered microglial morphology. In the ACC, lesions increased IL-1β and TNFα levels, decreased Arg1 mRNA levels, and disrupted the E/I balance. Importantly, ABA treatment restored microglial morphology, normalized IL-1β and Arg1 expression and upregulated vGAT levels. This study demonstrates that dopamine deficits lead to microglia alterations and E/I imbalance, contributing to ADHD symptoms. While some symptoms improve with brain development, targeting microglial health in specific brain regions emerges as a promising therapeutic approach for managing ADHD.

Fatty acid-binding protein 4 (FABP4) is a key lipid binding protein expressed in microglia, which has been demonstrated to play a critical role in microglial-mediated neuroinflammation, a component of many neurodegenerative diseases. Compounds able to inhibit the function of FABP4 have shown promise in reducing microglial-mediated neuroinflammation, however, their physicochemical properties would prevent their ability to be easily formulated and traverse the blood-brain barrier (BBB) in order to access microglial FABP4. To this end, this study assessed the ability of a series of FABP4 inhibitors, with more desirable physicochemical properties, to attenuate microglial inflammation in an in vitro setting. Four inhibitors with varying affinity to FABP4, as measured by isothermal titration calorimetry (MFP-0011462, MFP-0012314, MFP-0012318, and MFP-0012328), were assessed for their ability to induce toxicity and attenuate reactive oxygen species (ROS) generation and tumour necrosis factor-α (TNF-α) release from lipopolysaccharide (LPS)-activated BV-2 microglia. All FABP4 inhibitors were determined to be soluble in the aqueous buffers at the highest concentration used in the assays (100 µM). Isothermal titration calorimetry demonstrated that the compounds had varying affinities for FABP4 (K_D values of 316 nM to > 100 µM). The ability of FABP4 inhibitors to reduce LPS-mediated ROS production aligned with their K_D for FABP4, with the most effective inhibitor (MFP-0012328) also able to reduce TNF-α production (by RT-qPCR) and TNF-α release from LPS-activated BV-2 cells by 17% and 25%, respectively. These studies have demonstrated that a series of FABP4 inhibitors with more appropriate physicochemical properties for BBB penetration are able to reduce microglial-mediated inflammation, which may be of benefit in diseases where overactivation of microglia leads to neurodegeneration.

Fingolimod (FYN) is one of the approved medicines for treatment of multiple sclerosis (MS) while exhibiting several side effects such as liver enzyme elevation and cardiac damage. This study was aimed to prepare the mixed micelles of ascorbyl palmitate (AP) and alpha-tocopherol polyethylene glycol succinate (TPGS) as a delivery system for FYN. The mixed micelles were prepared by thin film hydration method at different ratios of AP/TPGS. Saturation solubility of the micelles was compared with the pure drug. The optimized formulation was characterized by scanning electron microscopy (SEM) and subjected for stability study at 5 ± 3 °C for 3 months. The effect of the prepared fingolimod loaded micelles (FYN-Micelle) was finally assessed by experimental autoimmune encephalomyelitis (EAE) model at the dose of 0.3, 1, and 3 mg/kg of fingolimod, which was administrated intraperitoneally. The results indicated that the prepared mixed micelles at the AP/TPGS ratio of 1:5 showed a particle size, zeta potential, and an entrapment efficiency of 116.86 ± 2.41 nm, 23.61 ± 4.56 mV, and 63.28 ± 5.31%, respectively. Also, this formulation was stable after a 3-month incubation at 5 ± 3 °C. SEM images displayed an amorphous state of the drug in the micelles. Animal studies confirmed that this formulation at the dose of 1 mg/kg could enhance the myelin density of the brain while reducing cardiac and hepatic impairment. Therefore, these findings suggested that FYN-Micelle could be exploited as an effective delivery system for fingolimod hydrochloride to treat MS.

Fibromyalgia syndrome (FMS) is characterized by prolonged, widespread musculoskeletal pain accompanied by various physical and psychological disturbances. Modafinil, a wake-promoting drug, manages pain symptoms in several diseases by inhibiting dopamine reuptake and exhibiting anti-inflammatory and immunomodulatory effects, including the impairment of cytokine production, microglia, and mast cell activation. Central inflammation may involve microglial activation, which is correlated with mast cell activation. Restoring dopamine levels and modulating the communication between mast cells and microglia may represent a promising approach to managing pain symptoms in FMS. Thus, this study intended to explore the interplay between brain mast cells and microglia as an underlying mechanism in the pathophysiology of FMS and how this interaction is controlled by modafinil, with a focus on dopamine/SP/MRGPRX2/histamine and PI3K/p-Akt/NF-κB signaling pathways. Rats were arbitrarily distributed between 4 groups. Group 1 served as normal control. Reserpine (1 mg/kg/day; s.c) was injected into the remaining groups for three consecutive days. In groups 3 and 4, modafinil (100 mg/kg/day; p.o) was administered either alone or in conjunction with haloperidol (1 mg/kg/day; ip), respectively, for the following 21 days. Modafinil ameliorated reserpine-induced thermal/mechanical allodynia (1.3-fold, 2.3-fold) and hyperalgesia (0.5-fold), attenuated depression (0.5-fold), and enhanced motor coordination (1.2-fold). It mitigated the histopathological alterations and increased dopamine levels in the thalamus of rats by 88.5%. Modafinil displayed anti-inflammatory effects via inhibiting mast cells and microglia activation, manifested by reductions in SP/MRGPRX2/IL-17/histamine (52%, 58%, 56.7%, and 63.7%) and PI3K/p-Akt/t-Akt/NF-κB/TNF-α/IL-6 (31.7%, 55.5%, 41%, 47.6%, and 76.9%), respectively. Ultimately, modafinil alleviated FMS behavioral, histopathological, and biochemical abnormalities and suppressed mast cell-microglial neuroinflammation in the thalamus of rats exposed to reserpine. This study highlights the potential of repurposing modafinil to improve FMS symptoms.

Multiple Sclerosis (MS) is the leading inflammatory and non-traumatic cause of disability in young adults, with late-onset MS emerging in middle-aged patients often resulting in poorer treatment responses and worse prognoses. The calcium-binding protein S100B is elevated in MS patients, and its targeting has shown promise in reducing disease severity in experimental autoimmune encephalomyelitis (EAE) models. However, most studies on MS pathology have focused on young animal models, leaving a gap in understanding the effects of age and S100B ablation on disease progression throughout the lifespan. This study aimed to characterize EAE in mice of different ages, examining demyelination, inflammation, and immune responses to determine whether S100B ablation could mitigate MS pathogenesis across the lifespan. EAE was induced in six cohorts of C57BL/6 mice: young adults (3 months), older adults (6 months), and middle-aged (12 months), including corresponding S100B knockout (KO) groups, followed for 23 days. Upon sacrifice, spinal cords were assessed via immunohistochemistry and Real-Time qPCR, while splenocytes were analyzed for immune cell characterization. Results indicated a more severe disease course in 12-month-old mice, marked by increased gliosis, inflammation, and impaired microglial phagocytic activity. Notably, S100B absence reduced gliosis and inflammatory markers across all ages, with 12-month-old S100B KO mice showing increased regulatory T cells. These findings highlight the exacerbating role of age and elevated S100B in MS progression, underscoring the importance of identifying age-specific MS markers and therapeutic targets.

Overproduction of reactive oxygen species occurs when inflammation induces oxidative stress in macrophages and microglia, leading to a self-sustaining cycle of cellular damage and neuroinflammation. Oxidative stress and neuroinflammation are well-established contributors to the pathophysiology of autism spectrum disorders, which are associated with impaired neuronal function, neuronal loss, and behavioral deficits. Damaged cells, through microglial activation, release additional inflammatory mediators under conditions of oxidative stress, exacerbating neuronal damage. Quercetin, a powerful dietary antioxidant, has been shown to scavenge free radicals, reduce oxidative stress, and inhibit inflammatory pathways. Given these properties, we hypothesize that quercetin may improve learning and social skills in individuals with autism spectrum disorders by alleviating oxidative stress and reducing brain levels of inflammatory cytokines. In this study, an autism model was established in 30 rats by intraperitoneal injection of 250 mg/kg/day propionic acid (PPA) for five days. The study groups were as follows: Group 1: Normal ontrol (n = 10); Group 2: PPA + saline (PPAS, n = 10); Group 3: PPA + Quercetin (PPAQ, n = 10). All treatments were administered for 15 days. At the end of the treatment, histological and biochemical analyses of brain tissue and behavioral tests related to autistic-like behaviors were performed. Malondialdehyde, tumor necrosis factor-alpha, and interleukin-13 levels in brain homogenates were significantly higher in the PPAS group compared to the control group, indicating elevated oxidative stress and inflammation following PPA exposure. The PPAQ group significantly reduced oxidative stress parameters and inflammatory biomarkers, demonstrating its antioxidant and anti-inflammatory effects. This biochemical improvement was accompanied by preserving Purkinje cells and neuronal populations, significantly reduced in the PPAS group. Moreover, quercetin-treated rats exhibited improved social behavior and learning, which were severely impaired in the PPAS group. These findings, when interpreted together, suggest that quercetin exerts its neuroprotective effects by targeting oxidative stress and neuroinflammation, thereby preventing neuronal cell loss and alleviating behavioral deficits associated with autism spectrum disorders.

Post-stroke depression (PSD) poses a serious impact on patients' life quality. Effective drugs to treat this annoying disease are still being sought. Yi-nao-jie-yu (YNJY) prescription has been found to relieve PSD; however, the underlying mechanisms remain unelucidated. This work elucidated the therapeutic effects and mechanisms underlying YNJY prescription in PSD. PSD rat model was treated with YNJY prescription and ML385. Depression-like behaviors of rats was appraised. Hematoxylin-eosin, Nissl, and NeuN immunofluorescence staining were performed to observe hippocampal neuronal damage. Transmission electron microscopy was used to assess hippocampal mitochondrial damage. Commercial kits and western blotting were adopted to research ferroptosis-related factors and Nrf2/GPX4/SLC7A11 signals. In vitro experiments were performed using rat hippocampal neurons to explore the mechanism by which YNJY prescription relieves PSD. In PSD rats, YNJY prescription relieved depression-like behaviors, attenuated hippocampal neuronal damage, mitigated hippocampal ferroptosis and mitochondrial damage, and activated hippocampal Nrf2/GPX4/SLC7A11 pathway. By in vitro experiments, erastin treatment exacerbated hippocampal neuronal damage, ferroptosis, mitochondrial damage, and lipid peroxidation; however, YNJY prescription abolished these erastin-induced effects. In the erastin-treated hippocampal neuronal model of PSD, ML385 treatment increased ferroptosis, hippocampal neuronal damage, and lipid peroxidation; however, YNJY prescription counteracted these ML385-induced effects. By in vivo study, ML385 reversed the relief of YNJY prescription on depressive-like behaviors of PSD rats, and the inhibition on ferroptosis in PSD rats' hippocampus. YNJY prescription relieves PSD by blocking ferroptosis via activating the Nrf2/GPX4/SLC7A11 pathway. It may be a promising agent for treating PSD clinically.

Cognitive impairment following surgical procedures, termed postoperative cognitive dysfunction (POCD), is a significant complication affecting the central nervous system. This condition stems from the combined impacts of anesthesia and surgical intervention, with microglial-induced neuroinflammation identified as the primary pathological mechanism. Irisin, a recently identified hormone released during physical exercise, has shown remarkable anti-inflammatory and neuroprotective properties, largely through its ability to modulate microglial activation in various central nervous system disorders. In this study, we explored the protective effects of irisin and its underlying mechanisms in a mouse model of POCD and BV2 microglial cells. Our results demonstrated that irisin effectively mitigated hippocampal-dependent cognitive deficits in mice subjected to exploratory laparotomy. Additionally, irisin facilitated the phenotypic shift of microglia from the pro-inflammatory M1 state to the anti-inflammatory and reparative M2 state. Furthermore, irisin upregulated the expression of Sirt3 in the postoperative hippocampus of mice. Importantly, pharmacological inhibition of Sirt3 activity using 3-TYP nullified the neuroprotective effects of irisin. In vitro studies revealed that irisin increased the expression of Sirt3 and autophagy-related proteins in lipopolysaccharide-activated BV2 microglial cells. Notably, Sirt3 knockout impeded irisin-induced autophagy enhancement and inhibited the polarization of microglia toward the M2 phenotype. Collectively, these findings highlight irisin's ability to attenuate POCD by driving the phenotypic transition of microglia from M1 to M2 through a mechanism involving Sirt3-mediated autophagy. This novel pathway underscores the therapeutic potential of irisin as a promising candidate for managing POCD.

The aim of this research endeavor was to explore the therapeutic potential of ( +)-catechin in mitigating neuropathic pain. A total of thirty-two Sprague‒Dawley rats were randomly allocated into four groups: the sham group, the chronic constriction injury (CCI) group, the CCI + ibuprofen group, and the CCI + ( +)-catechin group. The results of the in vivo experiment show that ( +)-catechin has the potential to improve mechanical hyperalgesia induced by CCI and reduce the infiltration of inflammatory cells in the injured sciatic nerve. CCI induces the upregulation of nNOS, iNOS, IL-1β, and COX-2 within the rat sciatic nerve and leads to an elevation in the levels of IL-1β, PGE2, and TNF-α in the serum of rats, while simultaneously diminishing the secretion of IL-10. Moreover, immunofluorescence analysis reveals that CCI enhances the expression of CD32 (an M1 polarization marker) in the rat spinal cord, while diminishing the expression of CD206 (an M2 polarization marker). However, the administration of ( +)-catechin effectively counteracts these effects. Western blot analysis further demonstrates that ( +)-catechin significantly reduces the protein expression of IBA-1, IL-1β, MyD88, p-NF-κB, p-JNK, p-ERK, p-p38MAPK, COX-2, and TLR4 within the spinal cord. The findings of the BV2 cell experiment revealed the attenuating effects of ( +)-catechin on M1 polarization markers (such as IL-1β, TNF-α, iNOS, and CD32), while concurrently boosting the levels of M2 polarization markers (including CD206, IL-10, and Arg-1). Notably, administration of LPS significantly heightened the accumulation of IBA-1, IL-1β, MyD88, p-NF-κB, p-JNK, p-ERK, p-p38MAPK, TLR4, COX-2, and iNOS, while concurrently suppressing Arg-1 expression. However, the administration of ( +)-catechin effectively reversed these alterations. Overall, these findings suggest that ( +)-catechin alleviates neuropathic pain by modulating the M1 and M2 phenotypes of microglia through the TLR4/MyD88/NF-κB pathway.