Nicotinamide mononucleotide mitigates neuroinflammation by enhancing GPX4-mediated ferroptosis defense in microglia.

BACKGROUND: Numerous neurological diseases involving neuroinflammation, particularly microglia, contribute to neuronal death. Ferroptosis is implicated in various diseases characterized by neuronal injury. Studies showed that nicotinamide mononucleotide (NMN) inhibits both neuroinflammation and ferroptosis. However, the mechanisms of NMN in both ferroptosis and neuroinflammation remain unclear. We aimed to explore the effects of NMN on neuroinflammation and the susceptibility of microglia to ferroptosis. METHODS: Ferroptosis markers in macroglia exposed to lipopolysaccharides (LPS) were analyzed using CCK8, flow cytometry, ELISA, and quantitative RT-PCR. The effects of NMN on LPS-induced ferroptosis in microglia were evaluated through flow cytometry, western blot, and immunofluorescence staining. RT-PCR analysis assessed the inflammatory cytokine production of microglia subjected to Ferrostatin-1-regulated ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-involved microglia ferroptosis under LPS induction. In BV2 microglia, an inhibitor of GPX4, RSL3, was employed to suppress GPX4 expression. Intracerebroventricular injection of LPS was performed to evaluate neuroinflammation and microglia activation in vivo. RESULTS: NMN effectively rescued LPS-induced ferroptosis and improved cell viability in microglia. Co-administration of NMN and ferrostatin-1 significantly reduced proinflammatory cytokine production in microglia following the introduction of LPS stimuli. Mechanistically, NMN facilitated glutathione (GSH) production, and enhanced resistance to lipid peroxidation occurred in a manner dependent on GPX4, repressing cytokine transcription and protecting cells from ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-associated microglia ferroptosis under LPS induction. Furthermore, simultaneous injection of NMN ameliorated LPS-induced ferroptosis and neuroinflammation in mouse brains. The data from the present study indicated that NMN enhances GPX4-mediated ferroptosis defense against LPS-induced ferroptosis in microglia by recruiting GSH, thereby inhibiting neuroinflammation. CONCLUSION: Therapeutic approaches to effectively target ferroptosis in diseases using NMN, consideration should be given to both its anti-ferroptosis and anti-inflammatory effects to attain optimal outcomes, presenting promising strategies for treating neuroinflammation-related diseases or disorders.

Integrating Proteomics and Transcriptomics Reveals the Potential Pathways of Hippocampal Neuron Apoptosis in Dravet Syndrome Model Mice.

An important component contributing to the onset of epilepsy is the death of hippocampal neurons. Several studies have shown that Dravet syndrome model mice: Scn1a KO mice have a high number of apoptotic neurons following seizures, but the precise mechanism underlying this remains unclear. The aim of this research was to elucidate the potential molecular mechanism of neuronal apoptosis in Scn1a KO mice by integrating proteomics and transcriptomics, with the ultimate goal of offering better neuroprotection. We found that apoptotic processes were enriched in both proteomic and transcriptomic GO analyses, and KEGG results also indicated that differential proteins and genes play a role in neurotransmission, the cell cycle, apoptosis, and neuroinflammation. Then, we examined the upstream and downstream KGML interactions of the pathways to determine the relationship between the two omics, and we found that the HIF-1 signaling pathway plays a significant role in the onset and apoptosis of epilepsy. Meanwhile, the expression of the apoptosis-related protein VHL decreased in this pathway, and the expression of p21 was upregulated. Therefore, this study suggests that VHL/HIF-1α/p21 might be involved in the apoptosis of hippocampal neurons in Scn1a KO mice.

G protein-coupled estrogen receptor 1 deficiency impairs adult hippocampal neurogenesis in mice with schizophrenia.

OBJECTIVE: This study aimed to confirm that G protein-coupled estrogen receptor 1 (GPER1) deficiency affects cognitive function by reducing hippocampal neurogenesis via the PKA/ERK/IGF-I signaling pathway in mice with schizophrenia (SZ). METHODS: Mice were divided into four groups, namely, KO Con, WT Con, KO Con, and WT SZ (n = 12 in each group). All mice were accustomed to the behavioral equipment overnight in the testing service room. The experimental conditions were consistent with those in the animal house. Forced swimming test and Y-maze test were conducted. Neuronal differentiation and maturation were detected using immunofluorescence and confocal imaging. The protein in the PKA/ERK/IGF-I signaling pathway was tested using Western blot analysis. RESULTS: GPER1 KO aggravated depression during forced swimming test and decreased cognitive ability during Y-maze test in the mouse model of dizocilpine maleate (MK-801)-induced SZ. Immunofluorescence and confocal imaging results demonstrated that GPER1 knockout reduced adult hippocampal dentate gyrus neurogenesis. Furthermore, GPER1-KO aggravated the hippocampal damage induced by MK-801 in mice through the PKA/ERK/IGF-I signaling pathway. CONCLUSIONS: GPER1 deficiency reduced adult hippocampal neurogenesis and neuron survival by regulating the PKA/ERK/IGF-I signaling pathway in the MK-801-induced mouse model of SZ.

Effect of Microvascular Decompression of the Vagus Root Entry/Exit Zone on Blood Pressure in Patients with Hemifacial Spasm Associated with Essential Hypertension: A Retrospective Clinical Analysis.

Background This study aimed to evaluate blood pressure alterations after microvascular decompression (MVD) surgery in patients with hemifacial spasm (HFS) with coexisting hypertension (HTN). Methods A total of 56 patients with HFS with concurrent HTN who underwent MVD surgery in our center between 2015 and 2019 were retrospectively analyzed. Patients were divided into control and experimental groups: patients who received MVD treatment for only the facial nerve and those who received MVD for the affected facial nerve, ipsilateral vagus nerve, and adjacent ventrolateral medulla, respectively. Preoperative (3 days) and postoperative (7 days and 6 months) blood pressure measurements were analyzed. Results No statistically significant differences were observed in gender, age, HFS course, HTN course, HTN grade, and preoperative blood pressure between the two groups. No significant difference was observed between pre- and postoperative blood pressure in the control group. In the experimental group, systolic blood pressure significantly differed between 3 preoperative days and 7 postoperative days ( p < 0.05), as did diastolic blood pressure ( p < 0.05). Measurement at 6 postoperative months also showed significant differences for both systolic blood pressure and diastolic blood pressure compared with that at 3 preoperative days ( p < 0.05). HTN grade according to the World Health Organization classification criteria significantly differed between preoperative and postoperative measurements ( p < 0.05). Conclusion Vascular decompression of the ipsilateral vagus nerve roots may improve blood pressure management in patients with HFS with coexisting HTN who undergo MVD. Laterality of involvement (left vs. right) did not significantly differ.

Up to What Extent Does Dravet Syndrome Benefit From Neurostimulation Techniques?

Background: Dravet syndrome (DS) is a refractory developmental and epileptic encephalopathy (EE) with a variety of comorbidities, including cognitive impairment, autism-like behavior, speech dysfunction, and ataxia, which can seriously affect the quality of life of patients and impose a great burden on society and their families. Currently, the pharmacological therapy is patient dependent and may work or not. Neuromodulation techniques, including vagus nerve stimulation (VNS), deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), responsive neurostimulation (RNS), and chronic subthreshold cortical stimulation (CSCS), have become common adjuvant therapies for neurological diseases, but their efficacy in the treatment of DS is unknown. Methods: We searched Web of Science, PubMed, and SpringerLink for all published cases related to the neuromodulation techniques of DS until January 15, 2022. The systematic review was supplemented with relevant articles from the references. The results reported by each study were summarized narratively. Results: The Web of science, PubMed and SpringerLink search yielded 258 items. A total of 16 studies published between 2016 and 2021 met the final inclusion criteria. Overall, 16 articles (109 cases) were included in this study, among which fifteen (107 patients) were involved VNS, and one (2 patients) was involved DBS. After VNS implantation, seizures were reduced to ≥50% in 60 cases (56%), seizure free were found in 8 cases (7.5%). Only two DS patients received DBS treatment, and the initial outcomes of DBS implantation were unsatisfactory. The seizures significantly improved over time for both DBS patients after the addition of antiepileptic drugs. Conclusion: More than half of the DS patients benefited from VNS, and VNS may be effective in the treatment of DS. However, it is important to note that VNS does not guarantee improvement of seizures, and there is a risk of infection and subsequent device failure. Although DBS is a safe and effective strategy for the treatment of refractory epilepsy, the role of DBS in DS needs further study, as the sample size was small. Thus far, there is no strong evidence for the role of DBS in DS.

Possible Mechanisms Underlying the Effects of Glucagon-Like Peptide-1 Receptor Agonist on Cocaine Use Disorder.

Cocaine use disorder (CUD) is a major public health challenge with a high relapse rate and lack of effective pharmacotherapies; therefore, there is a substantial need to identify novel medications to treat this epidemic. Since the advent of glucagon-like peptide-1 (GLP-1) receptors (GLP-1Rs) agonists (GLP-1RAs), their potential has been extensively explored and expanded. In this review, we first summarized the biological effects of GLP-1, GLP-1Rs, and GLP-1RAs. Subsequently, the recent literature examining the behavioral effects and the possible pharmacological mechanisms of GLP-1RAs on CUD was reviewed. Increasing preclinical evidence suggests that GLP-1RAs are promising in regulating dopamine release, dopamine transporter (DAT) surface expression and function, mesolimbic reward system and GABAergic neurons, and maladaptive behaviors in animal models of self-administration and conditioned place preference. In addition, the emerging role of GLP-1RAs in inhibiting inflammatory cytokines was reported. These findings indicate that GLP-1RAs perform essential functions in the modulation of cocaine-seeking and cocaine-taking behaviors likely through multifaceted mechanisms. Although the current preclinical evidence provides convincing evidence to support GLP-1RA as a promising pharmacotherapy for CUD, other questions concerning clinical availability, impact and specific mechanisms remain to be addressed in further studies.