c-Jun N-Terminal Kinases and Their Pharmacological Modulation in Ischemic and Reperfusion Brain Injury

We present here a review of the literature on the role of c-Jun N-terminal kinases (JNK) and their inhibitors in ischemic and reperfusion brain injuries. The functions of JNK in the signal mechanisms involved in brain damage in ischemia and reperfusion are discussed. Effects linked with inhibition of JNK with synthetic and natural compounds in experimental models of ischemia and reperfusion brain injury are described. Results from experimental studies show that JNK provide potential therapeutic targets for protecting the brain from ischemic stroke. However, the fact that JNK have numerous physiological functions prevents systematic use of nonspecific inhibitors of these kinases for therapeutic purposes. The authors conclude that this task requires a further search for selective JNK3 inhibitors.

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Immune Reconstitution Inflammatory Syndrome and Rebound Syndrome on Withdrawal of Immunomodulatory Drugs for Multiple Sclerosis: Current Understanding and a Case Report

Recent years have seen significant increases in the numbers of patients with multiple sclerosis (MS) receiving treatment with new immunomodulatory drugs. The number of cases in which these drugs are withdrawn because of side effects, intolerance, inadequate efficacy or planned pregnancy also increases. We present here a review of the problem of severe complications associated with the termination of treatment with natalizumab and fingolimod, in the form of immune reconstitution inflammatory syndrome (IRIS) and ricochet syndrome (withdrawal syndrome or rebound syndrome). The history of the term IRIS is considered, along with the diagnostic criteria for this syndrome in patients infected with human immunodeficiency virus. Variants of IRIS in patients interrupting natalizumab treatment are described. The clinical and radiological signs are assessed, as are the possible mechanisms of development of rebound syndrome on withdrawal of natalizumab and fingolimod treatment. The need for developing diagnostic criteria and studying risk factors for the development of IRIS and rebound syndrome in MS patients terminating therapy with new immunomodulatory drugs is emphasized.

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Postnatal Morphogenesis of Purkinje Cells in the Rat Cerebellum

Electron microscopic and histochemical methods were used to obtain a quantitative assessment of the development of organelles in Purkinje cells in the cerebellum of mongrel rats (n = 36) during the postnatal period of ontogeny (days 2, 7, 15, and 45). The nucleus:cytoplasm ratio decreased, while nucleolar area increased, the size and length of mitochondria increased, the quantity of membrane-bound ribosomes and the length of endoplasmic reticular channels increased, the number and sizes of lysosomes increased, and the relative area occupied by lysosomes on sections of the cytoplasm also increased.

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The Functional State of Children Aged 6–8 Years on Testing by Exposure to Different Types of Tension-Inducing Loads

Factor analysis of various measures of functional status identified the key regulatory processes determining psychophysiological reactivity in children aged 6–8 years (n = 102) on performance of mental, sensorimotor, and physical tasks. The characteristics of children's reactivity to additional loads, apparent from the psychophysiological parameters combined to produce different factors, in most cases persisted in all test tasks. Stable patterns of physiological responses were demonstrated in conditions of tension-inducing mental, sensorimotor, and physical loads. The study results indicate that stress responses can be regarded as a psychophysiological process preparing the child's body for tension-inducing activity.

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The Role of Assay of Free Immunoglobulin Light Chains in the Diagnosis of the Onset of Multiple Sclerosis

Objective. To assess the diagnostic value of assaying immunoglobulin (IgG) light chains at the onset of multiple sclerosis (MS). Materials and methods. A total of 226 patients took part in the study; group 1 (n = 111) were patients with clinically isolated syndrome (CIS) with development to MS within the first two years; group 2 (n = 49) were patients with CIS who did not progress to MS in the first two years; group 3 (n = 20) consisted of patients with inflammatory diseases of the central nervous system. The reference group (group 4, n = 46) consisted of patients with noninflammatory CNS diseases. The following immunological indicators were assessed in the patients: the clonal nature of cerebrospinal fluid (CSF) IgG and the concentrations of free ϰ and λ light chains in the CSF and their ratio. Results. Synthesis of free light chains was significantly greater in group 1 than groups 2 and 4. Free light chain synthesis in group 3 was significantly greater than that in groups 2 and 4 but was not significantly different from that in group 1. Free light chain production was significantly greater in patients with oligoclonal IgG synthesis than in patients without oligoclonal synthesis. The level of production of free light chains in patients of group 1 was significantly greater than that in group 2, regardless of whether or not oligoclonal IgG was produced. The most valuable diagnostic markers were the concentration and the coefficient of CSF:serum concentrations of κ light chains. Use of these parameters along with assessment of the clonality of IgG synthesis produced a 50% reduction in number of false negative results. Independently of other factors, increases in κ chain levels led to a 9.718-fold increase in the probability of a diagnosis of MS. Conclusions. Assay of free light chains as a lab marker increases the accuracy of diagnoses of MS and provides an indirect evaluation of the risk that CIS will progress to complete MS in the next two years.

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Molecular Mechanism of Memory Modification

The present review of our own and published data proposes a hypothesis for the molecular mechanisms regulating synaptic efficiency which may underlie long-term changes in behavior and modification of memory on the reactivation. The hypotheses is based on data on role of the atypical protein kinase molecule Mζ in long-term changes in synaptic efficiency by controlling the delivery of AMPA receptors, and on data on the possible nitrosylation of these molecules by nitric oxide, which is produced in synapses when nerve cells are activated.

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Dynamics of Changes in the Expression of the GLUR2 Subunit of the Ionotropic Glutamate Receptor in the Ventrolateral Part of the Solitary Tract Nucleus during the Early Postnatal Period in Health and Prenatal Serotonin Deficiency

Experiments on Wistar rats (n = 18) were performed to study changes in the expression of ionotropic glutamate receptor subunits (GluR2) in the respiratory subnuclei (ventral and lateral) of the solitary tract nucleus (STN). Observations were made during the early postnatal period (days 5, 10, and 20, 5–6 animals per group) in normal conditions and with prenatal decreases in serotonin levels due to inhibition of tryptophan hydroxylase with parachlorophenylalanine. Immunocytochemical detection of GluR2 revealed significant increases in GluR2 expression in the respiratory subnuclei of the STN in the early postnatal period (a 2-fold increase in the lateral subnucleus, 2.6-fold in the ventral). Prenatal serotonin deficiency altered GluR2 expression in the respiratory subnuclei of the STN. There was a significant delay in GluR2 expression in the early period, which increased to control levels by two weeks after birth, though GluR2 expression by juvenile age was lower (twofold) than in controls. Impairments to the glutamatergic receptor networks in the respiratory nuclei may be the basis of respiratory dysfunction.

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