Transdiagnostic features of inflammatory markers and executive function across psychiatric disorders.

Executive dysfunction and dysregulated inflammation are found in patients with different psychiatric disorders. However, whether there are different associations between inflammatory markers and executive performance in patients with different psychiatric diagnoses is unknown. Our study aims were (1) to compare peripheral cytokine expression and executive function in patients with bipolar disorder (BD), substance use disorder (SUD), and schizophrenia (SCZ), and in healthy controls (HC) and (2) to explore the potential association between inflammatory cytokines and executive function in different patient groups and HC.

Fucoidan ameliorates rotenone-induced Parkinsonism in mice by regulating the microbiota-gut-brain axis.

Microbiota-gut-brain axis, the bidirectional relationship between the gut microbiota and the brain, has been increasingly appreciated in the pathogenesis of Parkinson's disease (PD). Fucoidan, a sulphate-rich polysaccharide, has been shown to be neuroprotective by reducing oxidative stress in PD models. However, the role of microbiota-gut-brain axis in the neuroprotective activity of fucoidan has not been revealed.

Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPD.

There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na/K-ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation.

Clozapine-N-oxide protects dopaminergic neurons against rotenone-induced neurotoxicity by preventing ferritinophagy-mediated ferroptosis.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet treatment options are limited. Clozapine (CLZ), an antipsychotic used for schizophrenia, has potential as a PD treatment. CLZ and its metabolite, Clozapine-N-Oxide (CNO), show neuroprotective effects on dopaminergic neurons, with mechanisms needing further investigation.

Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats.

Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy (TLE). We postulated that kainic acid (KA)-Induced status epilepticus triggers microglia-dependent inflammation, leading to neuronal damage, a lowered seizure threshold, and the emergence of spontaneous recurrent seizures (SRS). Extensive evidence from our laboratory suggests that dextromethorphan (DM), even in ultra-low doses, has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease.

Complement receptor 3-mediated neurotoxic glial activation contributes to rotenone-induced cognitive decline in mice.

Microglia-mediated chronic neuroinflammation has been associated with cognitive decline induced by rotenone, a well-known neurotoxic pesticide used in agriculture. However, the mechanisms remain unclear. This work aimed to elucidate the role of complement receptor 3 (CR3), a highly expressed receptor in microglia, in cognitive deficits induced by rotenone.

Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway.

Recent studies showed increased expression of complements in various neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. However, the mechanism regulating the expression of complements and their roles in the pathogenesis of neurodegeneration are unclear. We hypothesized that acute neuroinflammation increases the expression and activation of brain complements, which, in turn, participate in chronic neuroinflammation and progressive neurodegeneration.

Effects of comorbid alcohol use disorder on bipolar disorder: Focusing on neurocognitive function and inflammatory markers.

Background: Alcohol use disorder (AUD) is a highly prevalent comorbid disorder in patients with bipolar disorder (BD). Both BD and AUD were found to be associated with inflammation and cognitive deficits, but few study has been done on BD comorbid with AUD (BD+AUD). We aimed to investigate the impacts of comorbid AUD and BD on cognitive function, inflammatory and neurotrophic markers.

Activation of neuronal NADPH oxidase NOX2 promotes inflammatory neurodegeneration.

Strong evidence indicates critical roles of NADPH oxidase (a key superoxide-producing enzyme complex during inflammation) in activated microglia for mediating neuroinflammation and neurodegeneration. However, little is known about roles of neuronal NADPH oxidase in neurodegenerative diseases. This study aimed to investigate expression patterns, regulatory mechanisms and pathological roles of neuronal NADPH oxidase in inflammation-associated neurodegeneration.

Dysfunction of the noradrenergic system drives inflammation, α-synucleinopathy, and neuronal loss in mouse colon.

Clinical and pathological evidence revealed that α-synuclein (α-syn) pathology seen in PD patients starts in the gut and spreads anatomically connected structures from the gut to the brain. Our previous study demonstrated that depletion of central norepinephrine (NE) disrupted brain immune homeostasis, producing a spatiotemporal order of neurodegeneration in the mouse brain. The purpose of this study was 1) to determine the role of peripheral noradrenergic system in the maintenance of gut immune homeostasis and in the pathogenesis of PD and 2) to investigate whether NE-depletion induced PD-like α-syn pathological changes starts from the gut.

Association Between Inflammatory Cytokines, Executive Function, and Substance Use in Patients With Opioid Use Disorder and Amphetamine-Type Stimulants Use Disorder.

Background: Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored.

Posttranslational S-nitrosylation modification regulates HMGB1 secretion and promotes its proinflammatory and neurodegenerative effects.

Nuclear protein high-mobility group box 1 (HMGB1) can be actively secreted by activated immune cells and functions as a proinflammatory cytokine. Regulation of HMGB1 secretion is critical for treatment of HMGB1-mediated inflammation and related diseases. This study demonstrates that S-nitrosylation (SNO; the covalent binding of nitric oxide [NO] to cysteine thiols) by inducible nitric oxide synthase (iNOS)-derived NO at Cys106 is essential and sufficient for inflammation-elicited HMGB1 secretion.

A novel synthetic peptide SVHRSP attenuates dopaminergic neurodegeneration by inhibiting NADPH oxidase-mediated neuroinflammation in experimental models of Parkinson's disease.

Current treatment of Parkinson's disease (PD) ameliorates symptoms but fails to block disease progression. This study was conducted to explore the protective effects of SVHRSP, a synthetic heat-resistant peptide derived from scorpion venom, against dopaminergic neurodegeneration in experimental models of PD. Results showed that SVHRSP dose-dependently reduced the loss of dopaminergic neuron in the nigrostriatal pathway and motor impairments in both rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse PD models.

Activation of the MAC1-ERK1/2-NOX2 Pathway Is Required for LPS-Induced Sustaining Reactive Microgliosis, Chronic Neuroinflammation and Neurodegeneration.

Recent studies suggest that improper resolution of acute neuroinflammation may lead to long-lasting low-grade chronic neuroinflammation and drive progressive neurodegeneration. However, the molecular mechanism underlying the transition from acute to chronic neuroinflammation remains unclear. The main purpose of this study was to search for potential pathways mediating LPS-elicited chronic neuroinflammation and resultant neurodegeneration.

Early-Released Interleukin-10 Significantly Inhibits Lipopolysaccharide-Elicited Neuroinflammation In Vitro.

Anti-inflammatory cytokine interleukin (IL)-10 is pivotal for limiting excessive inflammation in the central nervous system. Reports show that lipopolysaccharide (LPS)-induced microglial IL-10 emerges in a delayed manner in vitro and in vivo, lagging behind proinflammatory cytokines to facilitate the resolution of neuroinflammation. We hypothesized that IL-10 releases quite quickly based on our pilot investigation.

Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis.

While oxidative stress has been linked to multiple sclerosis (MS), the role of superoxide-producing phagocyte NADPH oxidase (Nox2) in central nervous system (CNS) pathogenesis remains unclear. This study investigates the impact of Nox2 gene ablation on pro- and anti-inflammatory cytokine and chemokine production in a mouse experimental autoimmune encephalomyelitis (EAE) model. Nox2 deficiency attenuates EAE-induced neural damage and reduces disease severity, pathogenic immune cells infiltration, demyelination, and oxidative stress in the CNS.

Microglial Activation Mediates Noradrenergic Locus Coeruleus Neurodegeneration via Complement Receptor 3 in a Rotenone-Induced Parkinson's Disease Mouse Model.

Background: Chronic exposure to the insecticide rotenone can damage dopaminergic neurons and lead to an increased risk of Parkinson's disease (PD). Whereas it is not clear whether rotenone induces neurodegeneration of noradrenergic locus coeruleus (LC/NE) neurons. Chronic neuroinflammation mediated by microglia has been involved in the pathogenesis of PD.

Microglial activation contributes to cognitive impairments in rotenone-induced mouse Parkinson's disease model.

Background: Cognitive decline occurs frequently in Parkinson's disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD.

Add-on memantine may improve cognitive functions and attenuate inflammation in middle- to old-aged bipolar II disorder patients.

Objectives: Chronic inflammation and neuroprogression underlie bipolar disorder (BP) and associated cognitive deficits. Memantine (MM) exerts neuroprotective effects by reducing neuroinflammation. Therefore, we investigated whether add-on low-dose MM (5 mg/day) in BP-II patients may improve cognition and inflammation.

Norepinephrine depleting toxin DSP-4 and LPS alter gut microbiota and induce neurotoxicity in α-synuclein mutant mice.

This study examined the genetic mutation and toxicant exposure in producing gut microbiota alteration and neurotoxicity. Homozygous α-synuclein mutant (SNCA) mice that overexpress human A53T protein and littermate wild-type mice received a single injection of LPS (2 mg/kg) or a selective norepinephrine depleting toxin DSP-4 (50 mg/kg), then the motor activity, dopaminergic neuron loss, colon gene expression and gut microbiome were examined 13 months later. LPS and DSP-4 decreased rotarod and wirehang activity, reduced dopaminergic neurons in substantia nigra pars compacta (SNpc), and SNCA mice were more vulnerable.

Estrogen receptor α phosphorylated at Ser216 confers inflammatory function to mouse microglia.

Background: Estrogen receptor α (ERα) has been suggested to regulate anti-inflammatory signaling in brain microglia, the only resident immune cells in the brain. ERα conserves the phosphorylation motif at Ser216 within the DNA binding domain. Previously, Ser216 was found to be phosphorylated in neutrophils infiltrating into the mouse uterus and to enable ERα to regulate migration.

Combination of dextromethorphan and memantine in treating bipolar spectrum disorder: a 12-week double-blind randomized clinical trial.

Background: The aim of this study is to determine whether adding combination of agents with anti-inflammatory and neurotrophic effects is more efficacious than mood stabilizer alone in improving clinical symptoms, plasma brain-derived neurotrophic factor (BDNF), cytokine levels, and metabolic profiles in patients with bipolar spectrum disorder.

Methods: In a randomized, double-blind, controlled 12-week clinical trial, patients with moderate mood symptoms (HDRS ≥ 18 or YMRS ≥ 14) were recruited. The patients were randomly assigned to a group while still undergoing regular valproate (VPA) treatments: VPA + dextromethorphan (DM) (30 mg/day) + memantine (MM) (5 mg/day) (DM30 + MM5) (n = 66), VPA + DM (30 mg/day) (DM30) (n = 69), VPA + MM (5 mg/day) (MM5) (n = 66), or VPA + Placebo (Placebo) (n = 69).