Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine.

Introduction: Currently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand - RTL1000), comprised of the extracellular α1 and ß1 domains of MHC class II molecules linked covalently to myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, can address the neuroimmune effects of methamphetamine addiction through its ability to bind to and down-regulate CD74 expression, block macrophage migration inhibitory factor (MIF) signaling, and reduce levels of pro-inflammatory chemokine ligand 2 (CCL2). The present study evaluated the effects of our third-generation pMHC II construct, DRmQ, on cognitive function and concentration of inflammatory cytokines in the frontal cortex, a region critical for cognitive functions such as memory, impulse control, and problem solving. Methods: Female and male C57BL/6J mice were exposed to methamphetamine (or saline) via subcutaneous (s.c.) injections administered four times per day every other day for 14 days. Following methamphetamine exposure, mice received immunotherapy (DRmQ or ibudilast) or vehicle s.c. injections daily for five days. Cognitive function was assessed using the novel object recognition test (NORT). To evaluate the effects of immunotherapy on inflammation in the frontal cortex, multiplex immunoassays were conducted. ANOVA was used to compare exploration times on the NORT and immune factor concentrations. Results: Post hoc analysis revealed increased novel object exploration time in MA-DRmQ treated mice, as compared to MA-VEH treated mice (non-significant trend). One-way ANOVA detected a significant difference across the groups in the concentration of macrophage inflammatory protein-2 (MIP-2) (p = 0.03). Post hoc tests indicated that mice treated with methamphetamine and DRmQ or ibudilast had significantly lower levels of MIP-2 in frontal cortex, as compared to mice treated with methamphetamine and vehicle (p > 0.05). Discussion: By specifically targeting CD74, our DRQ constructs can block the signaling of MIF, inhibiting the downstream signaling and pro-inflammatory effects that contribute to and perpetuate methamphetamine addiction.

Inflammatory and mental health sequelae of COVID-19.

The COVID-19 pandemic has caused significant negative consequences to mental health. Increased inflammatory factors and neuropsychiatric symptoms, such as cognitive impairment ("brain fog"), depression, and anxiety are associated with long COVID [post-acute sequelae of SARS-CoV-2 infection (PASC), termed neuro-PASC]. The present study sought to examine the role of inflammatory factors as predictors of neuropsychiatric symptom severity in the context of COVID-19. Adults (n = 52) who tested negative or positive for COVID-19 were asked to complete self-report questionnaires and to provide blood samples for multiplex immunoassays. Participants who tested negative for COVID-19 were assessed at baseline and at a follow-up study visit (∼4 weeks later). Individuals without COVID-19 reported significantly lower PHQ-4 scores at the follow-up visit, as compared to baseline (p = 0.03; 95% CI-1.67 to -0.084). Individuals who tested positive for COVID-19 and experienced neuro-PASC had PHQ-4 scores in the moderate range. The majority of people with neuro-PASC reported experiencing brain fog (70% vs. 30%). Those with more severe COVID-19 had significantly higher PHQ-4 scores, as compared to those with mild disease (p = 0.008; 95% CI 1.32 to 7.97). Changes in neuropsychiatric symptom severity were accompanied by alterations in immune factors, particularly monokine induced by gamma interferon (IFN-γ) (MIG, a. k.a. CXCL9). These findings add to the growing evidence supporting the usefulness of circulating MIG levels as a biomarker reflecting IFN-γ production, which is important because individuals with neuro-PASC have elevated IFN-γ responses to internal SARS-CoV-2 proteins.

Point-of-Care Noninvasive Technology for Pediatric Dehydration Assessment.

OBJECTIVE: Dehydration is a commonly encountered problem worldwide. Current clinical assessment is limited by subjectivity and limited provider training with children. The objective of this study is to investigate a new noninvasive, point-of-care technology that measures capillary refill combined with patient factors to accurately diagnose dehydration. METHODS: This is a prospective observational study at a tertiary care children's hospital in Buenos Aires, Argentina. Patients were eligible if younger than 10 years who presented to the emergency department with vomiting and/or diarrhea whom the triage nurse deems to be potentially dehydrated. Patients had the digital capillary refill device done on presentation in addition to standard of care vital signs and weight. Patients had serial weights measured on hospital scales throughout their stay. The primary outcome was dehydration, which was calculated as a percent change in weight from admission to discharge. RESULTS: Seventy-six children were enrolled in the study with 56 included in the final analysis. A stepwise forward method selection chose malnutrition, temperature, and systolic blood pressure for the multivariable model. The area under the curve for the final model was fair (0.7431). To further look into the utility of such a device in the home setting where blood pressure is not available often, we reran the model without systolic blood pressure. The area under the curve for the final model was 0.7269. CONCLUSIONS: The digital capillary refill point-of-care device combined with readily available patient-specific factors may improve the ability to detect pediatric dehydration and facilitate earlier treatment or transfer to higher levels of care.

Yoga for veterans with PTSD: Cognitive functioning, mental health, and salivary cortisol.

Objective: Research indicates that cognitive functioning is negatively impacted by exposure to chronic stress due to overactivation of the stress response. Yoga has demonstrated benefits when practiced by individuals diagnosed with posttraumatic stress disorder (PTSD). This quasi-experimental pilot study examined the impact of a yoga intervention on cognitive functioning, symptoms of PTSD, and the biological stress response in Veterans diagnosed with PTSD. Method: Cognitive functioning, self-report measures of mental health symptoms, and salivary cortisol were measured within two weeks prior to beginning and following completion of a 10-week yoga protocol. Veterans with PTSD participated in gender-specific groups of the yoga intervention. Paired t tests and correlational analyses were used to analyze quantitative data. Results: Statistically significant improvements were observed between baseline and postintervention scores on measures of response inhibition, PTSD, depression, sleep, quality of life, and subjective neurocognitive complaints. Positive correlations were found between baseline and postintervention changes in sleep and depression, and between change in cortisol output and a measure of life satisfaction. Statistically significant differences (baseline to postintervention) for other objective measures of cognitive performance and cortisol were not detected. Conclusions: Results provide preliminary support for the practice of yoga to improve cognitive functioning (response inhibition) related to symptoms of PTSD while also improving mental health symptoms, sleep, and quality of life. Positive correlations affirm the role of sleep in mood symptoms and indicate the need for further examination of the role of cortisol in life satisfaction. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Partial MHC/neuroantigen peptide constructs attenuate methamphetamine-seeking and brain chemokine (C-C motif) ligand 2 levels in rats.

There are no medications that target the neurotoxic effects or reduce the use of methamphetamine. Recombinant T-cell receptor ligand (RTL) 1000 [a partial major histocompatibility complex (pMHC) class II construct with a tethered myelin peptide], addresses the neuroimmune effects of methamphetamine addiction by competitively inhibiting the disease-promoting activity of macrophage migration inhibitory factor to CD74, a key pathway involved in several chronic inflammatory conditions, including substance use disorders. We previously reported that RTL constructs improve learning and memory impairments and central nervous system (CNS) inflammation induced by methamphetamine in mouse models. The present study in Lewis rats evaluated the effects of RTL1000 on maintenance of self-administration and cue-induced reinstatement using operant behavioral methods. Post-mortem brain and serum samples were evaluated for the levels of inflammatory factors. Rats treated with RTL1000 displayed significantly fewer presses on the active lever as compared to rats treated with vehicle during the initial extinction session, indicating more rapid extinction in the presence of RTL1000. Immunoblotting of rat brain sections revealed reduced levels of the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) in the frontal cortex of rats treated with RTL1000, as compared to vehicle. Post hoc analysis identified a positive association between the levels of CCL2 detected in the frontal cortex and the number of lever presses during the first extinction session. Taken together, results suggest that RTL1000 may block downstream inflammatory effects of methamphetamine exposure and facilitate reduced drug seeking-potentially offering a new strategy for the treatment of methamphetamine-induced CNS injury and neuropsychiatric impairments.

Neuroinvasion and cognitive impairment in comorbid alcohol dependence and chronic viral infection: An initial investigation.

Viruses that invade the central nervous system (CNS) can cause neuropsychiatric impairments. Similarly, chronic alcohol exposure can induce inflammatory responses that alter brain function. However, the effects of a chronic viral infection and comorbid alcohol use on neuroinflammation and behavior are not well-defined. We investigated the role of heavy alcohol intake in regulating inflammatory responses and behavioral signs of cognitive impairments in mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13. LCMV-infected mice exposed to alcohol had increased peripheral inflammation and impaired cognitive function (as indicated by performance on the novel object recognition test). Initial findings suggest that brain region-specific dysregulation of microglial response to viral infection may contribute to cognitive impairments in the context of heavy alcohol use.

S100B and Inflammatory Cytokine Levels in Blood as Potential Markers of Blood-Brain Barrier Damage and Psychiatric Impairment in Comorbid Hepatitis C Viral Infection and Alcohol Use Disorder.

BACKGROUND: Hepatitis C virus (HCV) infection and alcohol use disorder (AUD) both adversely affect the immune system resulting in alterations in immune cell signaling and inflammatory processes. The aim of this study was to investigate how comorbid AUD contributes to abnormalities in inflammatory mediators and psychiatric impairments in adults with HCV. METHODS: Alcohol use, mood, and inflammatory factors were evaluated at 3 time points (baseline, week 4, and week 12) in Veterans with HCV, with (n = 42) and without (n = 13) comorbid AUD. Peripheral indices of immune activation, blood-brain barrier (BBB) damage (S100 calcium-binding protein B [S100B]), liver function, and viral load were measured using immunoassays and polymerase chain reaction assays. RESULTS: Comorbid AUD was associated with increased symptoms of depression and anxiety, elevated levels of liver enzymes, and altered expression of inflammatory factors. Alcohol consumption was positively correlated with the severity of psychiatric symptoms. Univariate analysis identified significant group differences in interleukin (IL)-8 (p = 0.006), IL-10 (p = 0.03), and S100B (p = 0.048), with increased levels in participants with AUD, which persisted over time despite reductions in alcohol use and no significant change in HCV viral load. Statistically significant effects of study group or time were not found for the other immune factors assessed. Exploratory receiver operating characteristic curve analysis evaluated the ability of IL-8, IL-10, and S100B to differentiate between levels of alcohol consumption and generated biomarker cutoff values used to identify low risk and unhealthy alcohol use groups. CONCLUSIONS: These results demonstrate that HCV and comorbid AUD are associated with greater psychiatric impairments, potentially resulting from increased inflammation, dysregulated cytokine expression, and compromised BBB function. Alcohol-induced BBB damage may increase the risk of neuropathological consequences within the context of chronic HCV infection.

Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake.

BACKGROUND: Methamphetamine (MA) abuse causes immune dysfunction and neuropsychiatric impairment. The mechanisms underlying these deficits remain unidentified. METHODS: The effects of MA on anxiety-like behavior and immune function were investigated in mice selectively bred to voluntarily consume high amounts of MA [i.e., MA high drinking (MAHDR) mice]. MA (or saline) was administered to mice using a chronic (14-day), binge-like model. Performance in the elevated zero maze (EZM) was determined 5 days after the last MA dose to examine anxiety-like behavior. Cytokine and chemokine expressions were measured in the hippocampus using quantitative polymerase chain reaction (qPCR). Human studies were also conducted to evaluate symptoms of anxiety using the General Anxiety Disorder-7 Scale in adults with and without a history of MA dependence. Plasma samples collected from human research participants were used for confirmatory analysis of murine qPCR results using an enzyme-linked immunosorbent assay. RESULTS: During early remission from MA, MAHDR mice exhibited increased anxiety-like behavior on the EZM and reduced expression of chemokine (C-C motif) ligand 3 (ccl3) in the hippocampus relative to saline-treated mice. Human adults actively dependent on MA and those in early remission had elevated symptoms of anxiety as well as reductions in plasma levels of CCL3, relative to adults with no history of MA abuse. CONCLUSIONS: The results highlight the complex effects of MA on immune and behavioral function and suggest that alterations in CCL3 signaling may contribute to the mood impairments observed during remission from MA addiction.