The etiology, diagnostics, and treatment of the spasm of the near reflex - a narrative review.

Physiological adaptation of the eye to the visual perception of near objects consists of the "near triad": convergence, accommodation, and pupil miosis. Normally, these tend to revert when one stops fixating on a near object. Spasm of the near reflex (SNR) is a pathological phenomenon, which manifests itself by the persistence of the above-mentioned adjustments, which prevents the eye from returning to its relaxed state. In this narrative review, we aim to summarize the etiology, diagnostics, treatment, and prevention of SNR. The literature review was performed by searching online databases. The clinical presentation of SNR is diverse; it presents as isolated accommodative spasm more frequently than impairment of all three components of the near triad. Patients usually present with fluctuations in visual acuity, blurred vision, diplopia, and asthenopia. The etiology is not fully understood. Potential causes include neuroanatomic, organic, and psychogenic disorders. The diagnosis is clinical, based on the constellation of symptoms and assessment of the near triad. The diagnostic golden standard is a cycloplegic examination of refraction, preferably using cyclopentolate hydrochloride (1%, 0.5%, or 0.1% solution). The first-line treatment requires the administration of a cycloplegic drug in combination with plus lenses, flipper lenses, optical fogging, or miotics. For secondary cases, causal treatment should be implemented. Prevention of SNR should be based on eliminating modifiable risk factors. We propose including screening for SNR symptoms in every ophthalmic examination, especially among patients with psychogenic or neural disorders, after brain trauma, or young adults spending much time in front of computer screens.

Involvement of gut microbiota in multiple sclerosis-review of a new pathophysiological hypothesis and potential treatment target.

Multiple sclerosis (MS) is a chronic inflammatory disease that leads to demyelination and damage to the central nervous system. It is well known, the significance of the involvement and influence of the immune system in the development and course of MS. Nowadays, more and more studies are demonstrating that an important factor that affects the action of the immune system is the gut microbiota. Changes in the composition and interrelationships in the gut microbiota have a significant impact on the course of MS. Dysbiosis affects the disease course mainly by influencing the immune system directly but also by modifying the secreted metabolites and increasing mucosal permeability. The essential metabolites affecting the course of MS are short-chain fatty acids, which alter pro- and anti-inflammatory responses in the immune system but also increase the permeability of the intestinal wall and the blood-brain barrier. Dietary modification alone can have a significant impact on MS. Based on these interactions, new treatments for MS are being developed, including probiotics administration, supplementation of bacterial metabolites, fecal microbiota transplantation, and dietary changes. Further studies may serve to develop new drugs and therapeutic approaches for MS.

Effect of Hematopoietic Stem Cell Transplantation and Post-Transplantation Cyclophosphamide on the Microglia Phenotype in Rats with Experimental Allergic Encephalomyelitis.

Microglia are the resident immune cells of the central nervous system, playing a role in the inflammatory process development and resolution, presenting two main phenotypes, pro-inflammatory M1, and anti-inflammatory M2. Therapies affecting the microglia phenotype may be beneficial in treating inflammatory neurodegenerative diseases. In our experiments, we used the animal multiple sclerosis model, experimental allergic encephalomyelitis (EAE). Rats were treated during the pre- or symptomatic phase of the disease with cyclophosphamide, followed by hematopoietic stem cell transplantation, and with/without post-transplantation cyclophosphamide. Our study aimed to analyze the microglia phenotype in animals subjected to this treatment. The number of M1 cells in the spinal cord, and inducible nitric oxide synthase (iNOS) levels in the brain were similar in all experimental groups. The differences were observed in M2 cells number and arginase 1 (Arg1) levels, which were decreased in EAE animals, and increased after treatment in the symptomatic phase of EAE, and in the pre-symptomatic phase, but only with post-transplantation cyclophosphamide. Analysis of gene expression in the brain showed decreased iNOS expression in EAE animals treated in the symptomatic phase of EAE and no differences in Arg1 expression. Results indicate that treatment applied to experimental animals influences the microglia phenotype, promoting differentiation towards M2 cells.

Communication of gut microbiota and brain via immune and neuroendocrine signaling.

The gastrointestinal tract of the human is inhabited by about 5 × 1013 bacteria (of about 1,000 species) as well as archaea, fungi, and viruses. Gut microbiota is known to influence the host organism, but the host may also affect the functioning of the microbiota. This bidirectional cooperation occurs in three main inter-organ signaling: immune, neural, and endocrine. Immune communication relies mostly on the cytokines released by the immune cells into circulation. Also, pathogen-associated or damage-associated molecular patterns (PAMPs or DAMPs) may enter circulation and affect the functioning of the internal organs and gut microbiota. Neural communication relies mostly on the direct anatomical connections made by the vagus nerve, or indirect connections via the enteric nervous system. The third pathway, endocrine communication, is the broadest one and includes the hypothalamic-pituitary-adrenal axis. This review focuses on presenting the latest data on the role of the gut microbiota in inter-organ communication with particular emphasis on the role of neurotransmitters (catecholamines, serotonin, gamma-aminobutyric acid), intestinal peptides (cholecystokinin, peptide YY, and glucagon-like peptide 1), and bacterial metabolites (short-chain fatty acids).

The Influence of Novel, Biocompatible, and Bioresorbable Poly(3-hydroxyoctanoate) Dressings on Wound Healing in Mice.

The human body's natural protective barrier, the skin, is exposed daily to minor or major mechanical trauma, which can compromise its integrity. Therefore, the search for new dressing materials that can offer new functionalisation is fully justified. In this work, the development of two new types of dressings based on poly(3-hydroxyoctanoate) (P(3HO)) is presented. One of the groups was supplemented with conjugates of an anti-inflammatory substance (diclofenac) that was covalently linked to oligomers of hydroxycarboxylic acids (Oli-dicP(3HO)). The novel dressings were prepared using the solvent casting/particulate leaching technique. To our knowledge, this is the first paper in which P(3HO)-based dressings were used in mice wound treatment. The results of our research confirm that dressings based on P(3HO) are safe, do not induce an inflammatory response, reduce the expression of pro-inflammatory cytokines, provide adequate wound moisture, support angiogenesis, and, thanks to their hydrophobic characteristics, provide an ideal protective barrier. Newly designed dressings containing Oli-dicP(3HO) can promote tissue regeneration by partially reducing the inflammation at the injury site. To conclude, the presented materials might be potential candidates as excellent dressings for wound treatment.

Gender differences in short- vs. long-term impact of maternal depression following pre-gestational chronic mild stress.

Major Depressive Disorder (MDD) with Peripartum Onset was classified in 2013 by the Diagnostic and Statistical Manual, Fifth Edition (DMS-5) and approved in 2019 by the World Health Organization (WHO). These diagnostic revisions call for the development of new animal models of maternal depression, emphasizing the pregnancy period. We have recently described a novel rat model of maternal MDD with a Peripartum Onset. Exposure to pre-gestational chronic mild stress (CMS) with repeated restrain resulted in maternal depressive-like behavior and impacted offspring's neurodevelopment. The present study examined gender differences in short- vs. long-term neurodevelopmental impact of pre-gestational maternal stress. Stress response was assessed in Sprague Dawley CMS-exposed dams (n=7) by metabolic, hormonal, and behavioral changes and compared to controls dams (n=7). Short-term impact of maternal stress on offspring was examined in terms of metabolic, neurodevelopmental, and behavioral tests in male (n=40) and female (n=35) adolescent offspring on a postnatal day (PD) 48; the long-term impact was assessed in adult male (n=13) and female (n=12) offspring on PD 225. Brain tissue was collected from adolescent and adult offspring for biochemical analysis. Maternal stress was associated with decreased body weight and increased urinary corticosterone during the pre-pregnancy period, but depressive-like behavior was delayed until later in pregnancy. No significant neurodevelopmental changes in suckling male or female offspring derived from the stress-exposed dams were observed. However, adolescent male and female offspring of stress-exposed dams displayed an increased depressive-like behavior and gender-dependent increase in anxiety-like behavior in female offspring. These changes were associated with a brain-region-specific increase in brain-derived neurotrophic factor (BDNF) protein and BDNF receptor (TrkB) mRNA in males. Behavioral changes observed in the adolescents receded in adult male and female offspring. However, plasma BDNF was elevated in stress-exposed adult female offspring. These results suggest that pre-gestational maternal stress is associated with gender-dependent short- vs. long-term neurodevelopmental impact in the offspring. Presented data are of significant public health relevance, and there is an urgent need for further research to confirm these findings and probe the underlying mechanisms.

The Anti-Inflammatory Effect of Cabbage Leaves Explained by the Influence of bol-miRNA172a on FAN Expression.

Recently, the possibility of cross-kingdom gene expression regulation by miRNAs from other species ("xenomiRs"), specifically from plants, has acquired scientific meaning. Based on the one of oldest methods for dealing with inflammation via the use of cabbage leaf compresses, we investigated the effects of Brassica oleracea derived miR172a on the potential human target gene encoding FAN (Factor Associated with Neutral Sphingomyelinase Activation) protein. In vitro experiments showed a decrease in FAN protein levels in both human and mouse cells transfected with bol-miRNA172a. As the FAN protein mediates inflammatory responses, the potential of miR172a to mitigate the inflammatory process was tested in a mouse model of rheumatoid arthritis. Animal studies showed the decreased oedema of inflamed paws in mouse with rheumatoid arthritis model induced after treatment with miR172a.

Dietary Antioxidants in Age-Related Macular Degeneration and Glaucoma.

Age-related macular degeneration (AMD) and glaucoma are ophthalmic neurodegenerative diseases responsible for irreversible vision loss in the world population. Only a few therapies can be used to slow down the progression of these diseases and there are no available treatment strategies for reversing the degeneration of the neural retina. In AMD, the pathological process causes the malfunction and damage of the retinal pigmented epithelium and photoreceptors in the macula. In glaucoma, damage of the retinal ganglion cells and their axons is observed and treatment strategies are limited to intraocular pressure lowering. Therefore, other prophylactic and/or therapeutic methods are needed. Oxidative stress is involved in the neurodegenerative process accompanying both AMD and glaucoma; therefore, the use of antioxidant agents would clearly be beneficial, which is supported by the decreased prevalence and progression of AMD in patients adherent to a diet naturally rich in antioxidants. Dietary antioxidants are easily available and their use is based on the natural route of administration. Many preclinical studies both in vitro and using animal models of retinal degeneration showed the efficacy of dietary antioxidants, which was further proved in clinical trials. Resveratrol is beneficial both in AMD and glaucoma animal models, but confirmed only among AMD patients. For AMD, carotenoids and omega-3 fatty acids were also proved to be sufficient in preventing neurodegeneration. For glaucoma, coenzyme Q10 and alpha-lipoic acid showed efficacy for decreasing retinal ganglion cell loss and inhibiting the accompanying destructive processes. Interestingly, the benefits of vitamins, especially vitamin E was not confirmed, neither in preclinical nor in clinical studies.

Anti-CD52 Therapy for Multiple Sclerosis: An Update in the COVID Era.

CD52 is a small surface glycoprotein composed of 12 amino acids. CD52 is found mostly on the surface of mature immune cells, such as lymphocytes, monocytes, eosinophils, and dendritic cells, as well as the male genital tract: within the epididymis and on the surface of mature sperm. Low CD52 expression is also found in neutrophils. CD52 function is not fully understood, although experiments with anti-CD52 antibodies have shown that CD52 is essential for lymphocyte transendothelial migration and may contribute to costimulation of CD4+ T cells and T-cell activation and proliferation. Although knowledge about exact CD52 function is still poor, CD52 presence on the surface of a broad spectrum of immune cells makes it a therapeutic target, especially in immunomediated diseases, such as multiple sclerosis. In multiple sclerosis, alemtuzumab is registered for adult patients with the relapsing-remitting form of the disease defined by clinical and imaging features. Despite the high efficacy of the drug, the main issue is its safety. The main adverse effects of alemtuzumab are associated with drug infusion due to cytokine release and cytotoxic effects of antibodies associated with lymphocyte depletion, which leads to immunosuppression, and secondary autoimmunity that may be the effect of excessive B-cell repopulation and cancer. This review presents current knowledge on the drug's mechanism of action, efficacy and safety data from clinical trials, and real-world observations, including available though scarce data on using alemtuzumab in the COVID era.

Post Transplantation Cyclophosphamide Improves Outcome of Autologous Hematopoietic Stem Cell Transplantation in Animal Model of Multiple Sclerosis.

Experimental allergic encephalomyelitis (EAE) is the animal model of multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (AHSCT) has recently been recognized as the standard treatment for MS. The aim of our experiment was to investigate the effect of AHSCT with the addition of low-dose post-transplantation cyclophosphamide (Cy) on EAE in rats. Low dose post-transplantation Cy is used in haploidentical HSCT to reduce the risk of graft versus host disease. We hypothesized that it could bring additional benefit in autologous HSCT in autoimmune diseases. Rats with evoked EAE were treated with high dose (125 mg/kg) Cy, followed by AHSCT or high dose (125 mg/kg) Cy followed by AHSCT followed by low dose (20 mg/kg) Cy in two-time schedules-with the therapy applied during the pre-symptomatic or symptomatic phase of the disease. Both AHSCT and AHSCT with post-transplantation Cy in accordance with both time schedules reduce the intensity of the inflammatory response in the CNS, in comparison with non-treated EAE rats. The reduction of clinical symptoms was present in all AHSCT treatment protocols, however, it was significantly stronger when post-transplantation Cy was given during the symptomatic phase of the disease. AHSCT with the addition of post HSCT low dose Cy improved the results of AHSCT by not only reducing the intensity of inflammation in the CNS but also by significantly reducing the clinical symptoms in treated animals when compared to AHSCT alone. We provide an experimental rationale that the addition of post-transplantation Cy may improve the outcome of HSCT in MS.

Neuroprotective Factors of the Retina and Their Role in Promoting Survival of Retinal Ganglion Cells: A Review.

Retinal ganglion cells (RGCs) play a crucial role in the visual pathway. As their axons form the optic nerve, apoptosis of these cells causes neurodegenerative vision loss. RGC death could be triggered by increased intraocular pressure, advanced glycation end products, or mitochondrial dysfunction. In this review, we summarize the role of some neuroprotective factors in RGC injury: ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), brain-derived neurotrophic factor, vascular endothelial growth factor, pigment epithelium-derived factor, glial cell line-derived neurotrophic factor, and Norrin. Each, in their own unique way, prevents RGC damage caused by glaucoma, ocular hypertension, ischemic neuropathy, and even oxygen-induced retinopathy. These factors are produced mainly by neurons, leukocytes, glial cells, and epithelial cells. Neuroprotective factors act via various signaling pathways, including JAK/STAT, MAPK, TrkA, and TrkB, which promotes RGC survival. Many attempts have been made to develop therapeutic strategies using these factors. There are ongoing clinical trials with CNTF and NGF, but they have not yet been accepted for clinical use.

The Positive and Negative Outcome of Morphine and Disulfiram Subacute Co-Administration in Rats in the Absence of Ethanol Challenge.

Recently, a well-known anti-alcohol agent, disulfiram (DSF), has gain much interest, as it was found to be effective in the treatment of cocaine abusers, thus also giving hope for patients addicted to opioids and other illicit drugs. Therefore, this study was aimed to investigate the possible outcome that might occur within the subacute co-administration of both morphine (MRF) and DSF in rats, but in the absence of ethanol challenge. As observed, intraperitoneal DSF dose-dependently enhanced MRF-mediated analgesia with the maximal efficacy at a dose of 100 mg/kg. Furthermore, MRF-induced tolerance and aggressive behavior were significantly reduced by DSF (100 mg/kg, i.p.) in comparison to MRF solely. Nonetheless, significant blood biochemical markers of hepatotoxicity were found (i.e., alteration in the levels of glutathione, blood urea nitrogen, etc.), following a combination of both drugs. Likewise, histological analysis of liver tissue revealed severe changes in the group of DSF + MRF, which includes swelling, cell death, damage to certain vessels, and hemorrhages into the liver parenchyma. Our findings indicate that DSF should be used with extreme caution, especially within the course of subacute concomitant use with MRF, as several possible side effects may take place.

Novel opioid-neurotensin-based hybrid peptide with spinal long-lasting antinociceptive activity and a propensity to delay tolerance development.

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration (in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics.

3D bioprinting of hydrogel constructs with cell and material gradients for the regeneration of full-thickness chondral defect using a microfluidic printing head.

Osteochondral (OC) tissue is a biphasic material comprised of articular cartilage integrated atop subchondral bone. Damage to this tissue is highly problematic, owing to its intrinsic inability to regenerate functional tissue in response to trauma or disease. Further, the function of the tissue is largely conferred by its compartmentalized zonal microstructure and composition. Current clinical treatments fail to regenerate new tissue that recapitulates this zonal structure. Consequently, regenerated tissue often lacks long-term stability. To address this growing problem, we propose the development of tissue engineered biomaterials that mimic the zonal cartilage organization and extracellular matrix composition through the use of a microfluidic printing head bearing a mixing unit and incorporated into an extrusion-based bioprinter. The system is devised so that multiple bioinks can be delivered either individually or at the same time and rapidly mixed to the extrusion head, and finally deposited through a coaxial nozzle. This enables the deposition of either layers or continuous gradients of chemical, mechanical and biological cues and fabrication of scaffolds with very high shape fidelity and cell viability. Using such a system we bioprinted cell-laden hydrogel constructs recapitulating the layered structure of cartilage, namely, hyaline and calcified cartilage. The construct was assembled out of two bioinks specifically formulated to mimic the extracellular matrices present in the targeted tissues and to ensure the desired biological response of human bone marrow-derived mesenchymal stem cells and human articular chondrocytes. Homogeneous and gradient constructs were thoroughly characterized in vitro with respect to long-term cell viability and expression of hyaline and hypertrophic markers by means of real-time quantitative PCR and immunocytochemical staining. After 21 days of in vitro culture, we observed production of zone-specific matrix. The PCR analysis demonstrated upregulated expression of hypertrophic markers in the homogenous equivalent of calcified cartilage but not in the gradient heterogeneous construct. The regenerative potential was assessed in vivo in a rat model. The histological analysis of surgically damaged rat trochlea revealed beneficial effect of the bioprinted scaffolds on regeneration of OC defect when compared to untreated control.

Common Genetic Variants Link the Abnormalities in the Gut-Brain Axis in Prematurity and Autism.

This review considers a link between prematurity and autism by comparing symptoms, physiological abnormalities, and behavior. It focuses on the bidirectional signaling between the microbiota and the brain, here defined as the microbiota-gut-vagus-heart-brain (MGVHB) axis and its systemic disruption accompanying altered neurodevelopment. Data derived from clinical and animal studies document increased prevalence of gastrointestinal, cardiovascular, cognitive, and behavioral symptoms in both premature and autistic children and suggest an incomplete maturation of the gut-blood barrier resulting in a "leaky gut," dysbiosis, abnormalities in vagal regulation of the heart, altered development of specific brain regions, and behavior. Furthermore, this review posits the hypothesis that common genetic variants link the abnormalities in the MGVHB axis in premature and autistic pathologies. This hypothesis is based on the recently identified common genetic variants: early B cell factor 1 (EBF1), selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC), and angiotensin II receptor type 2 (AGTR2), in the maternal and infant DNA samples, associated with risk of preterm birth and independently implicated in a risk of autism. We predict that the AGTR2 variants involved in the brain maturation and oxytocin-arginine-vasopressin (OXT-AVP) pathways, related to social behavior, will contribute to our understanding of the link between prematurity and autism paving a way to new therapies.

A rat model to study maternal depression during pregnancy and postpartum periods, its comorbidity with cardiovascular diseases and neurodevelopmental impact in the offspring.

This study aimed to develop an animal model of human depression during pregnancy and lactation to examine the effect of maternal, perinatal depression on offspring development. Maternal depression during pregnancy affects up to 20% of women and is a risk factor for both the developmental and long-term health issues. It is often comorbid with the cardiovascular disease (CVD) that affects the uteroplacental circulation and impacts offspring development. More than half of the expecting mothers with depression use antidepressants that cross the placenta and may interfere with the neurodevelopmental programming. Thus, depressed pregnant mothers face a difficult choice whether "to use or not to use" antidepressant therapy, since both untreated depression and antenatal antidepressant exposure present increased risks of neurodevelopmental pathologies. The ongoing clinical debate presents inconclusive data, while the existing animal models of maternal depression do not include early gestational periods, and, do not monitor depressive-like behavior nor address the cardiovascular abnormalities. The presented model includes pregestational depressive behavior extending into pregnancy and lactation, periods that have not been previously examined. Rat dams exposed to pre-gestational chronic mild stress (CMS) developed a sustained decrease in self-grooming behavior, correlated with hormonal, behavioral, and cardiac changes persisting through the postpartum period. Preliminary data indicate neurodevelopmental delays, behavioral and cardiac abnormalities, and altered levels of both the brain and the heart markers in the offspring of stressed dams. Furthermore, the preliminary data predict that maternal pregnancy during the perinatal period is likely to impact the neurodevelopmental process in a sex-dependent manner. Thus the presented here model (PG-LAC CMS) fulfills both the face and the construct validity criteria for maternal stress-induced depression during pregnancy and postpartum that may facilitate further studies of the relative risks of untreated vs. antidepressant-treated maternal depression during pregnancy to the mother and her offspring.

Vasopressin V1a receptors are present in the carotid body and contribute to the control of breathing in male Sprague-Dawley rats.

Vasopressin (AVP) maintains body homeostasis by regulating water balance, cardiovascular system and stress response. AVP inhibits breathing through central vasopressin 1a receptors (V1aRs). Chemoreceptors within carotid bodies (CBs) detect chemical and hormonal signals in the bloodstream and provide sensory input to respiratory and cardiovascular centers of the brainstem. In the study we investigated if CBs contain V1aRs and how the receptors are involved in the regulation of ventilation by AVP. We first immunostained CBs for V1aRs and tyrosine hydroxylase, a marker of chemoreceptor type I (glomus) cells. In urethane-anesthetized adult Sprague-Dawley male rats, we then measured hemodynamic and respiratory responses to systemic (intravenous) or local (carotid artery) administration of AVP prior and after systemic blockade of V1aRs. Immunostaining of CBs showed colocalization of V1aRs and tyrosine hydroxylase within glomus cells. Systemic administration of AVP increased mean arterial blood pressure (MABP) and decreased respiratory rate (RR) and minute ventilation (MV). Local administration of AVP increased MV and RR without significant changes in MABP or heart rate. Pretreatment with V1aR antagonist abolished responses to local and intravenous AVP administration. Our findings show that chemosensory cells within CBs express V1aRs and that local stimulation of the CB with AVP increases ventilation, which is contrary to systemic effects of AVP manifested by decreased ventilation. The responses are mediated by V1aRs, as blockade of the receptors prevents changes in ventilation. We hypothesize that excitatory effects of AVP within the CB provide a counterbalancing mechanism for the inhibitory effects of systemically acting AVP on the respiration.

Mechanism of action of three newly registered drugs for multiple sclerosis treatment.

Multiple sclerosis (MS) is a disease of suspected autoimmune origin leading to neurodegeneration. The disease pathomechanism is considered to be primarily based on neuroinflammation directed against myelin antigens caused by autoreactive T cells. MS etiology remains still unknown, which makes it difficult to create an efficient therapy, therefore, MS treatment targets mechanisms involved in disease pathology. In this review, we present the mechanism of action of three newly registered drugs for MS. Dimethyl fumarate (DMF) is an agent presenting a broad spectrum of action. Its main activity is based on activating the nuclear factor E2 dependent pathway leading to antioxidant enzyme synthesis. DMF in general suppresses the pro-inflammatory immune activity and exerts a neuroprotective action. Teriflunomide is a more focused drug, acting as an inhibitor of pyrimidines synthesis, important for rapidly dividing cells such as activated lymphocytes. Similarly, alemtuzumab, an anti-CD52 antibody, causes depletion of mainly lymphocytes. Since in MS pathology, T and B cells are involved, this mode of action is promising.

Effect of dimethyl fumarate on heme oxygenase-1 expression in experimental allergic encephalomyelitis in rats.

Multiple sclerosis (MS) is an autoimmunological disease leading to neurodegeneration. The etiology of the disease remains unknown, which strongly impedes the development of effective therapy. Most MS treatments focus on modulating the activity of the immune system. Dimethyl fumarate (DMF) exerts a broad spectrum of action, such as modulating immune cell differentiation towards anti-inflammatory subtypes, influencing cytokine production, regulating immune cell migration into the central nervous system, and activating intracellular antioxidant mechanisms. It is well established that activation of the nuclear factor E2 (Nrf2)-dependent pathway, leading to expression of the second-phase antioxidant enzymes, is influenced by DMF. In our experiments we used female Lewis rats in an animal model of MS - experimental allergic encephalomyelitis (EAE). The rats were fed with dimethyl fumarate to test the expression of heme oxygenase-1 (HO-1), one of the second-phase antioxidant enzymes, at specific time points of the symptomatic phases of the disease: on the first day of the occurrence of clinical symptoms (10th day post immunization, DPI); at the peak of clinical symptoms (14th DPI); and at the end of the relapse (21st DPI). The results showed that HO-1 expression, at both the mRNA and protein level, is influenced by DMF administration only at the very beginning of the symptomatic phase of EAE, and not at the peak of clinical symptoms, nor at the end of the relapse. This indicates that the regulation of the Nrf2-dependent antioxidant pathway by DMF occurs at a certain time interval (early EAE/MS) and strongly underlines the importance of the earliest introduction of the therapy to the patient. .

Increased Activity of the Intracardiac Oxytocinergic System in the Development of Postinfarction Heart Failure.

Aim. The present study was designed to test the hypothesis that the development of postinfarction heart failure is associated with a change of activity of the intracardiac oxytocinergic system. Methods. Experiments were performed on male Sprague-Dawley rats subjected to myocardial infarction or sham surgery. Four weeks after the surgery, blood samples were collected and the samples of the left ventricle (LV) and right ventricle (RV) were harvested for evaluation of the mRNA expression (RT-PCR) of oxytocin (OT), oxytocin receptor (OTR), natriuretic peptides, and the level of OT and OTR protein (ELISA). The concentration of N-terminal B-type natriuretic peptide was measured to determine the presence of heart failure. Results. Plasma NT-proBNP concentration was higher in the infarcted rats. In the infarcted rats, the expression of OT mRNA and the OT protein level were higher in the RV. There were no significant differences between infarcted and noninfarcted rats in the expression of OT mRNA and in the OT protein level in the fragments of the LV. In both the left and the right ventricles, OTR mRNA expression was lower but the level of OTR protein was higher in the infarcted rats. Conclusions. In the present study, we indicate that postinfarction heart failure is associated with an increased activity of the intracardiac oxytocinergic system.