Activation of expression of brain-derived neurotrophic factor at the site of implantation of allogenic and xenogenic neural stem (progenitor) cells in rats with ischemic cortical stroke.

Ischemic stroke was modeled in the sensorimotor zone of the brain cortex in adult rats. Rat embryonic nervous tissue, neural stem cells from human olfactory epithelium, and rat fibroblasts (cell control) were implanted into the peri-infarction area of rats of different groups immediately after stroke modeling. Expression of BDNF mRNA was analyzed 7 days after surgery by real-time PCR. BDNF expression in cell preparation before their implantation was minimum. The expression of BDNF mRNA increased by 5-6 times in the areas of implantation of rat fibroblasts and human olfactory epithelium and by 23 times in the area of implantation of rat embryonic nervous tissue compared to periinfarction areas without cell implantation. These findings confirm the possibility of realization of the therapeutic effects of neural stem cells via expression of trophic factors.

[Ofatumumab - a new drug for the treatment of multiple sclerosis]. / Ofatumumab ­ novyi preparat dlya lecheniya rasseyannogo skleroza.

Recently anti-B-cell therapy has been increasingly integrated into the treatment of multiple sclerosis (MS). This review is devoted to ofatumumab, a new drug of this line. Ofatumumab, an all-human monoclonal antibody used to treat chronic leukemia, binds to a different region than the binding site of other CD20 antibodies, including both a small and large loop in the CD20 receptor structure. This monoclonal antibody provides favorable results for MS by reducing the frequency of exacerbations and the risk of disability progression, significantly more pronounced when compared with teriflunomide. The drug can be used in patients with active relapsing MS and SPMS with exacerbations, with the ineffectiveness of first-line drugs as one of the options for second-line therapy, in patients with highly active MS, especially with a high risk of PML (transfer from natalizumab), as well as if there are difficulties in organizing intravenous courses in day hospitals (produced as outpatient injections).

[New tools for early detection of multiple sclerosis progression: MSProDiscuss questionnaire]. / Novye instrumenty dlya rannego vyyavleniya progressirovaniya rasseyannogo skleroza. Oprosnik MSProDiscuss.

Diagnosis of secondary progressive multiple sclerosis (SPMS) is based on a history of gradual worsening of neurological symptoms within 6-12 months without exacerbations following an initial relapsing-remitting (RRMS) disease course. In the absence of reliable MRI, immunological and clinical markers, it is hardly possible to achieve objectivity in determining the transition of MS to a progressive stage. This often leads to a long period of diagnostic uncertainty, which prevents timely therapeutic decisions. Physicians expressed an unmet need for a tool that could be used in routine clinical practice to assess the risks of progression to SPMS quickly and reliably, in an easy-to-interpret output for a joint discussion with the patient. From a wide range of disease symptoms and lifestyle factors reflecting the progression to SPMS and obtained by analysis of large clinical data (3294 cases) and a survey of patients and specialists, significant were identified and ranked by categories according to combined expert opinion. A mathematical model was developed and validated, and an electronic version of the MSProDiscuss questionnaire created. Test sensitivity for SPMS diagnosis is 0.82, specificity 0.84, interrater reliability 0.95. Median time for completion of the questionnaire was 2.16 minutes per patient. Physicians of the Russian Federation who used the questionnaire confirmed its high feasibility. Thus, the methodology of the questionnaire development based on the combined opinion of patients and physicians, along with the large clinical data, made it possible to obtain high sensitivity, specificity and reproducibility of the test and takes little time with a clear output. MSProDiscuss may be useful not only in the differential diagnosis of RRMS and SPMS, but also to determine the risks of progression to SPMS, which is of great clinical importance.

[The pegylated form of interferon beta in the treatment of multiple sclerosis]. / Pegilirovannaia forma interferona beta v terapii rasseiannogo skleroza.

Interferons-beta (IFN-ß) along with glatiramer acetate is one of the most commonly used disease modifying treatment (DMT) of multiple sclerosis (MS) associated with effectiveness and acceptable safety profile. At the same time, therapy with IFN-ß has a number of limitations associated with a high frequency of injections and production of neutralizing antibodies. The development of the pegylated form of IFN-ß (PEG-IFN-ß) is aimed at resolving these issues. This article reviewed the mechanism of action, efficacy, safety and tolerability of PEG-IFN-ß in the treatment of MS.

[The translocation of macromolecules via the hematoencephalic barrier].

The solution to the problem of transportation of high-molecular substances via the hematoencephalic barrier (HEB) is a necessary condition for the development of theoretical and applied aspects of selective transport of biologically active substances (neurotrops, medications) from blood into the brain. In the last decades, views on the possibility of macromolecular transport through intact HEB have changed substantially. Under physiological conditions, translocation of macromolecular substances via HEB is performed with the help of specific molecular transport systems and by endocytosis. The former mechanism prevails both in intensity and the nomenclature of the substances transported. The permeability of the intact (unchanged) HEB for macromolecules exists to an extent necessary for normal CNS functioning. Destruction of dense contacts in the HEB, local retraction and death of endotheliocytes, destruction of the basal membrane take place in pathological processes in the nervous tissue under the influence of inflammatory factors (cytokines, metalloproteinases etc) induced by activated endotheliocytes, T-lymphocytes, macrophages and glial cells; this in fact opens the paracell way for macromolecular components of blood.

[Elimination of neurospecific proteins from CNS: pathogenetic and methodical aspects].

Appearance of neurospecific proteins (NSP) outside the brain plays a certain pathogenetic role in the development of autosensitization occurring in many kinds of CNS injuries and diseases. Analysis of modern views of cerebrospinal fluid (CSF) exchange allows us to suppose that NSP are eliminated from the brain tissue within CSF, moving from the subarachnoid space into cranial veins, and by lymphatic way, into deep cervical lymph nodes. Elevation of NSP level in CSF indicates an actual neudegenerative process. Serum levels of NSP are determined by the balance between the elimination of NSP from the brain, on the one hand, and their metabolism and the response of the immune system to the appearance of these autoantigenes in the blood stream, on the other. Basing on their own data on the dynamics of NSP (NSE, GFAR, and MBP) concentrations and the proportions of these proteins in CSF and serum (coefficient of elimination) in rats after ischemic, hypoxic, and autoimmune cerebral lesions, the authors offer an algorithm of pathogenetic evaluation, including, on the one part, a conclusion on the presence or absence of a neurodegenerative process, and, on the other, a conclusion on a normal or lowered rate of NSP elimination (metabolism). The results of such an analysis may have a clinical significance in terms of the development of a pathogenetic therapy, including, in every individual case, not only neuroprotectors, but also pharmaceuticals directed towards correction of the functional condition of the immune system.

[The effect of a combined vitamin--antioxidants preparations on hemostasis in rats with experimental hyperperoxidation].

Experiments on a group of 308 rats showed that prooxidant (lead acetate) introduced per os with daily meals decreases the antioxidant potential (increases lipid peroxidation, LPO) and reduces tolerance with respect to thrombin (increases the level of intravascular blood coagulation markers). For the same treatment on the background of a vitamin - antioxidants preparations (complivit or selmevit), the level of changes was significantly decreased and the resistance to thrombin was increased. Selmevit (containing selenium) was more effective. It is concluded that complex vitamin--antioxidants preparations can be used for correcting hemostatic changes in cases of hyperoxidation.

[Antacid bifilact and its effectiveness in the treatment of chronic gastroduodenitis and ulcer disease in children]. / Antatsidnyi bifilakt i ego éffektivnost' v terapii khronicheskogo gastroduodenita i iazvennoi bolezni u detei.

Antacid bifilact was applied for the first time to the treatment of 30 patients with gastroduodenitis and peptic ulcer. This enabled one to remove the disease clinical manifestations within the shortest time possible, to normalize the acid-forming function of the stomach and upset microecology of the intestine, lysozyme activity of alimentary secretions. The formulation and know how for antacid bifilact, a new dietetic product, are described.

[Capsaicin in treatment of neuropathic pain].

Treatment of neuropathic pain (NP) is a serious medical problem. Antiepileptic drugs and antidepressants, used to relief pain, act on the central pain mechanisms and cause several side-effects, thus substantially restricting possibilities of their clinical application.At the same time, NP often has a peripheral component. Ligand-associated channels, including vanilloid receptors TRPV1, play a key role in the development of regional NP syndromes. Capsaicin, a component of chili pepper and several other plants, is a highly selective ligand of TRPV1 receptors and has long been used in treatment of pain syndromes. However, its using is limited by short-term action and relatively low efficacy. Recently it has been shown that the local use of single high doses of capsaicin during 30-60 min causes a marked stable(> 12 weeks) effect. The decrease in NP (>50%) is seen in about half of patients. Current studies will allow to single out groups of patients with the maximal treatment effect of capsaicin.

[Neurological deficit following cortical stroke in rats with functional hemispheric asymmetry].

We evaluated the effect of "sidedness" of focal stroke induced by pial blood vessel devascularization in sensorimotor cortex of right or left hemisphere on neurological deficit in rats. Animals were preliminary examined for paw preference (hemispheric "dominance") by means of food reaching test. Data of cylinder-test, vibrissae-elicited forelimb placing test and swimming task (forepaw inhibition test) were assessed to monitor functional deficit weekly for 8 weeks after stroke. No difference between rats with right or left cortical damage was observed during the experiment. Rats with ischemia in "dominant" hemisphere performed significantly better than those with "nondominant" hemisphere lesion. The revealed effect of functional brain asymmetry on the neurological rehabilitation after stroke should be considered in design of preclinical investigation of new therapeutic approaches to stroke.

[Influence of the neural stem cell transplantation on the restoration of CNS functions in rats with cortical stroke].

Ischemic stroke was modeled in white pedigreeless rats by the superficial blood vessel devascularization in the sensorimotor cortex. The preparations of neural progenitors--rat embryonic neural stem cells (rENSC) and human olfactory epithelium-derived neural stem cells (hOENSC) and differentiated fibroblasts ("cell control") were transplanted at the perimeter of the devascularized region. These cells marked with vital tracer stayed alive in the brain parenchyma for at least 16 days. The monitoring of contralateral forepaw motor deficit during 8 weeks demonstrated that only rats with rENSC transplantation had the stable and significant improvement of performance in cylinder test and swimming test (forepaw inhibition test) in comparison to "cell controls" and rats without cell transplantation. The maximal difference in the relative values (the efficacy) was 25% to the end of the experiment. There was no difference in the indicators of vibrissae-elicited forelimb placing test between experimental groups. The methodological approach used makes it possible to broaden the study of mechanisms of neural stem cells' therapeutic effect in stroke.

Selective accumulation of monoclonal antibodies against neurospecific enolase in brain tissue of rats with middle cerebral artery occlusion.

Preparations of I(125)-labeled monoclonal antibodies against neurospecific enolase and mouse plasma IgG1 were injected intravenously to rats immediately after unilateral occlusion of the middle cerebral artery. Radioactivity of I(125)-labeled monoclonal antibodies against neurospecific enolase in the brain tissue progressively increased, reached a maximum by the 48th hour, and remained practically unchanged after 72 h. At the same time radioactivity of labeled IgG1 in the brain tissue and radioactivity of both preparations in the blood, liver, spleen, kidneys, heart, and lungs decreased over 72 h. Selective accumulation of I(125)-labeled monoclonal antibodies against neurospecific enolase was less significant in the brain tissue of the contralateral hemisphere and cerebellum not exposed to ischemia.