The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing-remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis.

Local Administrations of Iron Oxide Nanoparticles in the Prefrontal Cortex and Caudate Putamen of Rats Do Not Compromise Working Memory and Motor Activity.

Iron oxide nanoparticles (IONPs) have come into focus for their use in medical applications although possible health risks for humans, especially in terms of brain functions, have not yet been fully clarified. The present study investigates the effects of IONPs on neurobehavioural functions in rats. For this purpose, we infused dimercaptosuccinic acid-coated IONPs into the medial prefrontal cortex (mPFC) and caudate putamen (CPu). Saline (VEH) and ferric ammonium citrate (FAC) were administered as controls. One- and 4-week post-surgery mPFC-infused animals were tested for their working memory performance in the delayed alternation T-maze task and in the open field (OF) for motor activity, and CPu-infused rats were tested for their motor activity in the OF. After completion of the experiments, the brains were examined histologically and immunohistochemically. We did not observe any behavioural or structural abnormalities in the rats after administration of IONPs in the mPFC and the CPu. In contrast, administration of FAC into the CPu resulted in decreased motor activity and increased the number of microglia in the mPFC. Perls' Prussian blue staining revealed that FAC- and IONP-treated rats had more iron-containing ramified cells than VEH-treated rats, indicating iron uptake by microglia. Our results demonstrate that local infusions of IONPs into selected brain regions have no adverse impact on locomotor behaviour and working memory.

Blockade of the orexin 1-receptors and 'cocaine- and amphetamine-regulated transcript' in the nucleus accumbens shell alters impulse control in rats.

Impulsivity is a multifaceted construct and alterations in impulsiveness are often associated with psychiatric diseases, including drug addiction and binge eating disorder. Impulse control involves several brain regions. The present study assessed the role of the orexigenic, appetite stimulating neuropeptide orexin (OX) and the anorexigenic, appetite reducing neuropeptide cocaine- and amphetamine-regulated transcript (CART) within the nucleus accumbens shell (NAcSh) in impulse control in rats. The animals were ranked for their trait impulsivity based on a screening in the 5-choice serial reaction time task (5-CSRTT). The rats' performances were analysed after bilateral infusions of the OX 1-receptor antagonist SB-334867 (SB) and CART-antibodies (CART-ABs) into the NAcSh. After SB infusions, there was no change in premature responses observed on average. Further analysis revealed a negative linear correlation between the effect of intra-NAcSh SB infusions on premature responses and trait impulsivity. The effect of SB ranged from an increase, no change to a decrease in premature responses in the individual animals with increasing trait impulsivity. Infusions of CART-ABs led to consistently enhanced impulse control with fewer irrelevant actions, independent of trait impulsivity. These data suggest that both OX, especially OX A, and CART in the NAcSh, can be considered endogenous regulators of impulsive action, dependent on underlying impulsivity in the case of OX and independent from trait impulsivity in the case of CART.

Investigating a role of orexin and 'cocaine- and amphetamine-regulated transcript' in the nucleus accumbens shell in binge eating of male rats and the relationship with impulsivity.

Binge eating disorder (BED) is the most prevalent eating disorder in the adult population. It is characterized by recurrent episodes of uncontrollable overconsumption of palatable food (PF). BED is connected to several comorbidities such as obesity, major depression, and substance use disorder, and was linked to heightened levels of impulsivity. The neurobiological basis of BED is however still vaguely known. Binge eating (BE) occurs without homeostatic needs, and therefore, relates to hedonic consumption of PF. A major brain structure in the control of hedonic feeding, and part of the network regulating impulsive action, is the nucleus accumbens shell (NAcSh). The present study in rats assessed the influence of trait impulsivity on the development of BE-like feeding and the role of the orexigenic neuropeptide orexin (OX) and the anorexigenic neuropeptide cocaine- and amphetamine-regulated transcript (CART) within the NAcSh in a BE-model. The rats were initially ranked for their trait impulsivity based on a screening in the 5-choice serial reaction time task. They were subsequently introduced into a limited access-model to establish BE-like feeding with pure vegetable fat to examine a correlation between trait impulsivity and the development of BE-like feeding. The effect of bilateral infusions of the OX 1-receptor (OX1R) antagonist SB-334867 (SB) and CART-antibodies (CART-ABs) into the NAcSh was examined in relation to trait impulsivity. Further, accumbal OX1R density was evaluated by immunohistochemical staining in rats with normal and BE-like feeding behavior. We found that all animals developed stable BE-like PF intake, independent of trait impulsivity and without differences in the dynamics. The blockade of accumbal OX1Rs effectively reduced PF intake only in the control group that had daily access to PF, with impulsivity trait as a decisive factor, pointing towards alterations in orexinergic transmission in the NAcSh of rats bingeing on pure fat. This was corroborated by a lower density of OX1Rs in the NAcSh of rats with BE-like feeding behavior, precisely, in low-impulsive bingeing rats. Regardless of impulsivity trait, antagonizing CART in the NAcSh did not affect PF intake of control or bingeing animals. This suggests that endogenous accumbal CART does not influence consummatory behavior in ad libitum-fed rats with access to fat, under both normal and BE-like feeding patterns.

Vaccine-based clinical protection against SARS-CoV-2 infection and the humoral immune response: A 1-year follow-up study of patients with multiple sclerosis receiving ocrelizumab.

Introduction: Given the varying severity of coronavirus disease 2019 (COVID-19) and the rapid spread of Severe-Acute-Respiratory-Syndrome-Corona-Virus-2 (SARS-CoV-2), vaccine-mediated protection of particularly vulnerable individuals has gained increasing attention during the course of the pandemic. Methods: We performed a 1-year follow-up study of 51 ocrelizumab-treated patients with multiple sclerosis (OCR-pwMS) who received COVID-19 vaccination in 2021. We retrospectively identified 37 additional OCR-pwMS, 42 pwMS receiving natalizumab, 27 pwMS receiving sphingosine 1-phosphate receptor modulators, 59 pwMS without a disease-modifying therapy, and 61 controls without MS (HC). In OCR-pwMS, anti-SARS-CoV-2(S)-antibody titers were measured prior to the first and after the second, third, and fourth vaccine doses (pv2/3/4). The SARS-CoV-2-specific T cell response was analyzed pv2. SARS-CoV-2 infection status, COVID-19 disease severity, and vaccination-related adverse events were assessed in all pwMS and HC. Results: We found a pronounced and increasing anti-SARS-CoV-2(S)-antibody response after COVID-19 booster vaccinations in OCR-pwMS (pv2: 30.4%, pv3: 56.5%, and pv4 90.0% were antibody positive). More than one third of OCR-pwMS without detectable antibodies pv2 developed positive antibodies pv3. 23.5% of OCR-pwMS had a confirmed SARS-CoV-2 infection, of which 84.2% were symptomatic. Infection rates were comparable between OCR-pwMS and control groups. None of the pwMS had severe COVID-19. An attenuated humoral immune response was not associated with a higher risk of SARS-CoV-2 infection. Discussion: Additional COVID-19 vaccinations can boost the humoral immune response in OCR-pwMS and improve clinical protection against COVID-19. Vaccines effectively protect even OCR-pwMS without a detectable COVID-19 specific humoral immune response, indicating compensatory, e.g., T cell-mediated immunological mechanisms.

Effects of Local Administration of Iron Oxide Nanoparticles in the Prefrontal Cortex, Striatum, and Hippocampus of Rats.

Iron oxide nanoparticles (IONPs) are used for diverse medical approaches, although the potential health risks, for example adverse effects on brain functions, are not fully clarified. Several in vitro studies demonstrated that the different types of brain cells are able to accumulate IONPs and reported a toxic potential for IONPs, at least for microglia. However, little information is available for the in vivo effects of direct application of IONPs into the brain over time. Therefore, we examined the cellular responses and the distribution of iron in the rat brain at different time points after local infusion of IONPs into selected brain areas. Dispersed IONPs or an equivalent amount of low molecular weight iron complex ferric ammonium citrate or vehicle were infused into the medial prefrontal cortex (mPFC), the caudate putamen (CPu), or the dorsal hippocampus (dHip). Rats were sacrificed 1 day, 1 week, or 4 weeks post-infusion and brain sections were histologically examined for treatment effects on astrocytes, microglia, and neurons. Glial scar formation was observed in the mPFC and CPu 1 week post-infusion independent of the substance and probably resulted from the infusion procedure. Compared to vehicle, IONPs did not cause any obvious additional adverse effects and no additional tissue damage, while the infusion of ferric ammonium citrate enhanced neurodegeneration in the mPFC. Results of iron staining indicate that IONPs were mainly accumulated in microglia. Our results demonstrate that local infusions of IONPs in selected brain areas do not cause any additional adverse effects or neurodegeneration compared to vehicle.

Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety.

We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB) coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania, and attention deficit hyperactivity disorder (ADHD) share hyperactivity symptom, we systematically examined LAB mice with respect to unique and overlapping endophenotypes of the three diseases. To this end Venn diagrams were used as an instrument for discrimination of possible models. We arranged the endophenotypes in Venn diagrams and translated them into different behavioral tests. LAB mice showed elevated levels of locomotion in the open field (OF) test with deficits in habituation, compared to mice bred for normal (NAB) and high anxiety-related behavior (HAB). Cross-breeding of hypoactive HAB and hyperactive LAB mice resulted in offspring showing a low level of locomotion comparable to HAB mice, indicating that the HAB alleles are dominant over LAB alleles in determining the level of locomotion. In a holeboard test, LAB mice spent less time in hole exploration, as shown in patients with schizophrenia and ADHD; however, LAB mice displayed no impairments in social interaction and prepulse inhibition (PPI), implying a unlikelihood of LAB as an animal model of schizophrenia. Although LAB mice displayed hyperarousal, active coping styles, and cognitive deficits, symptoms shared by mania and ADHD, they failed to reveal the classic manic endophenotypes, such as increased hedonia and object interaction. The neuroleptic haloperidol reduced locomotor activity in all mouse lines. The mood stabilizer lithium and the psychostimulant amphetamine, in contrast, selectively reduced hyperactivity in LAB mice. Based on the behavioral and pharmacological profiles, LAB mice are suggested as a novel rodent model of ADHD-like symptoms.