Vascular cognitive impairment: pathophysiological mechanisms, insights into structural basis, and perspectives in specific treatments

Vladimir A Parfenov,1 Olga D Ostroumova,2,3 Tatiana M Ostroumova,1 Alexey I Kochetkov,2 Victoria V Fateeva,4 Kristina K Khacheva,4 Gulnara R Khakimova,5 Oleg I Epstein61Department of Neurology, Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation; 2Laboratory of Clinical Pharmacology and therapy, Federal State Budgetary Educational Institution of Higher Education “N.I. Pirogov Russian National Research Medical University” of the Ministry of Health of the Russian Federation, Russian Clinical and Research Center of Gerontology, Moscow, Russia; 3Department of Clinical Pharmacology, Internal Medicine and Propaedeutics I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia; 4Medical Information Department, OOO NPF Materia Medica Holding, Moscow, Russian Federation; 5Research and Analytical Division of Scientific Research and Development Department, Moscow, Russian Federation; 6Laboratory of Physiologicaly Active Substances, Department of Molecular and Cellular Pathophysiology, Research Institute of General Pathology and Pathophysiology, Moscow, Russian FederationAbstract: Vascular cognitive impairment (VCI) and vascular dementia are the most common forms of cognitive disorder associated with cerebrovascular disease and related to increased morbidity and mortality among the older population. Growing evidence suggests the contribution of blood-pressure variability, cardiac arrhythmia, hyperactivation of the renin–angiotensin–aldosterone system, endothelial dysfunction, vascular remodeling and stiffness, different angiopathies, neural tissue homeostasis, and systemic metabolic disorders to the pathophysiology of VCI. In this review, we focus on factors contributing to cerebrovascular disease, neurovascular unit alterations, and novel approaches to cognitive improvement in patients with cognitive decline. One of the important factors associated with the neuronal causes of VCI is the S100B protein, which can affect the expression of cytokines in the brain, support homeostasis, and regulate processes of differentiation, repair, and apoptosis of the nervous tissue. Since the pathological basis of VCI is complex and diverse, treatment affecting the mechanisms of cognitive disorders should be developed. The prospective role of a novel complex drug consisting of released–active antibodies to S100 and to endothelial NO synthase in VCI treatment is highlighted.Keywords: vascular cognitive impairment, cerebrovascular disease, neurovascular unit, endothelial dysfunction, S100 protei

Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism

International audienceProgressive degeneration of nigrostriatal dopaminergic (DA-ergic) neurons is a key component in the pathogenesis of Parkinson's disease, which develops for a long time at the preclinical stage with no motor dysfunctions due to the initiation of compensatory processes. The goal of this study was to evaluate the changes in surviving nigrostriatal DA-ergic neurons with focus on tyrosine hydroxylase (TH) in MPTP-treated mice at the presymptomatic and early symptomatic stages of parkinsonism. According to our data, a partial degeneration of DA-ergic neurons at the presymptomatic stage was accompanied by: (i) no change in TH mRNA content in the substantia nigra (SN) suggesting a compensatory increase of TH gene expression in individual neurons; (ii) a decrease of TH protein content in the nigrostriatal system and no change in individual neurons, suggesting a slowdown of TH translation. When comparing DA-ergic neurons at the early symptomatic stage and presymptomatic stage, it becomes evident: (i) a decrease of TH mRNA content in the SN and hence gene expression in individual neurons; (ii) a decrease of TH content in the striatum and its increase in the SN and individual neurons suggesting an acceleration of TH translation. TH activity, an index of the rate of DA synthesis, was unchanged in the SN and decreased in the striatum to the same degree at both stages of parkinsonism. In the meantime, TH activity in individual neurons appeared to be compensatory increased, but to a higher degree at the symptomatic stage than at the presymptomatic one. These data first show that DA depletion, which provokes motor dysfunction, is not a result of the decrease of TH activity and the rate of DA synthesis but is rather related to either a decrease of DA release or an increase of DA uptake in striatal DA-ergic axons.Copyright © 2014 Elsevier B.V. All rights reserved

Characterization of Dopaminergic System in the Striatum of Young Adult Park2−/− Knockout Rats

Abstract Mutations in parkin gene (Park2) are linked to early-onset autosomal recessive Parkinson’s disease (PD) and young-onset sporadic PD. Park2 knockout (PKO) rodents; however, do not display neurodegeneration of the nigrostriatal pathway, suggesting age-dependent compensatory changes. Our goal was to examine dopaminergic (DAergic) system in the striatum of 2 month-old PKO rats in order to characterize compensatory mechanisms that may have occurred within the system. The striata form wild type (WT) and PKO Long Evans male rats were assessed for the levels of DAergic markers, for monoamine oxidase (MAO) A and B activities and levels, and for the levels of their respective preferred substrates, serotonin (5-HT) and ß-phenylethylamine (ß-PEA). The PKO rats displayed lower activities of MAOs and higher levels of ß-PEA in the striatum than their WT counterparts. Decreased levels of ß-PEA receptor, trace amine-associated receptor 1 (TAAR-1), and postsynaptic DA D2 (D2L) receptor accompanied these alterations. Drug-naive PKO rats displayed normal locomotor activity; however, they displayed decreased locomotor response to a low dose of psychostimulant methamphetamine, suggesting altered DAergic neurotransmission in the striatum when challenged with an indirect agonist. Altogether, our findings suggest that 2 month-old PKO male rats have altered DAergic and trace aminergic signaling