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1.
Article in Russian | MEDLINE | ID: mdl-30335074

ABSTRACT

Parkinson's disease (PD) is one of incurable socially significant diseases. Success in the PD treatment is associated with the development of the technology of preclinical diagnosis and neuroprotective treatment of the disease. In the experimental model of the preclinical PD stage in rats created by intranasal administration of the proteasome inhibitor lactacystin, signs of depression as an anhedonia symptom were detected for the first time. Anhedonia was combined with the death of about one third of dopamine (DA)-ergic neurons in the ventral tegmental area of the midbrain and their axons in the ventral striatum; and a decrease of dopamine concentration in the ventral striatum (by 40%) and the tyrosine hydroxylase level in surviving DA-ergic neurons. The signs of depression may be an early marker of PD, signaling the onset of neurodegeneration in the mesolimbic brain system and increasing functional deficit of the DA-ergic transmission in the ventral striatum. The study results can be applied to the development of the technology of preclinical PD diagnosis and pathogenetic therapy.


Subject(s)
Anhedonia , Parkinson Disease , Ventral Tegmental Area , Animals , Mesencephalon , Parkinson Disease/complications , Parkinson Disease/diagnosis , Rats , Substantia Nigra , Ventral Tegmental Area/pathology
2.
Adv Gerontol ; 31(2): 170-177, 2018.
Article in Russian | MEDLINE | ID: mdl-30080322

ABSTRACT

It is generally accepted that advanced age is the main risk factor for the development and progression of Parkinson's disease (PD). However, data that experimentally confirm the dependence on the age of the rate of neurodegeneration progression and the activity of compensatory processes in the nigrostriatal system in the development of PD are absent in the modern literature. The present study uses a model of neurodegeneration of the nigrostriatal system in rats of different age groups, created by the microinjections of the proteasome inhibitor lactacystin (LC) into the substantia nigra pars compacta (SNpc). The model reproduces the main pathomorphological signs of PD with great reliability. It is shown for the first time that LC administration to old rats, in comparison with young and middle-aged, causes more pronounced neurodegenerative changes in the nigrostriatal system, associated with impairments of fine motor function, a decrease in the growth of the stress-inducible heat shock protein Hsp70 in surviving neurons of SNpc and a decrease in the tyrosine hydroxylase and the vesicular monoamine transporter 2 contents. The data obtained allow us to summarize that the ageing-related weakening of Hsp70 expression combined with a decrease in the efficiency of compensatory processes are significant factors that determine the progression of pathology in the nigrostriatal system in the modeling of PD in old rats. The demonstrated age-related loss of compensatory mechanisms may be one of the reasons for the rapid PD progression in the elderly.


Subject(s)
Aging/pathology , Brain/pathology , Disease Models, Animal , Parkinson Disease/pathology , Animals , Rats , Reproducibility of Results
4.
Ross Fiziol Zh Im I M Sechenova ; 102(6): 647-58, 2016 Jun.
Article in Russian | MEDLINE | ID: mdl-30192489

ABSTRACT

Data on HSP70 involvement in Parkinson's disease (PD) pathogenesis, received in last 10 years, cannot answer the question whether the decrease in stress-inducible Hsp70 brain expression is one of the reasons for progressive neurodegeneration in PD. In the present study, the inhibitor of HSPs expression quercetin was used in a rat model of nigrostriatal system proteasome dysfunction. This model was created by the microinjections of the specific proteasome activity inhibitor lactacystin, that was injected locally to the substantia nigra pars compacta (SNpc). The model reproduces the under-threshold level of nigrostriatal degeneration and neurochemical features characteristic of the preclinical PD stage. It was shown for the first time that quercetin pretreatment inhibited the LC-induced expression of Hsp70 in the SNpc neurons and increased in 1.5 times the dopamine (DA)-ergic neurons death and in 2.7 times the striatal DA-ergic axons degeneration. These changes were accompanied by the depletion of compensatory mechanisms and HSP70 content in the SNpc neurons and the appearance of the motor dysfunctions, typical for the clinical PD stage. The results of this investigation indicate the important role of Hsp70 in mechanisms of the nigrostriatal system protection in proteasome dysfunction, characteristic for the pre-clinical PD stage. The data obtained can be considered as the scientific basis for the development of new technologies for early PD therapy by exogenous Hsp70.


Subject(s)
Corpus Striatum/metabolism , Dopaminergic Neurons/metabolism , Neurodegenerative Diseases/drug therapy , Parkinson Disease, Secondary/drug therapy , Quercetin/pharmacology , Substantia Nigra/metabolism , Acetylcysteine/adverse effects , Acetylcysteine/analogs & derivatives , Acetylcysteine/pharmacology , Animals , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Dopaminergic Neurons/pathology , HSP70 Heat-Shock Proteins/biosynthesis , Male , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/physiopathology , Parkinson Disease, Secondary/metabolism , Parkinson Disease, Secondary/pathology , Parkinson Disease, Secondary/physiopathology , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/adverse effects , Proteasome Inhibitors/pharmacology , Rats , Rats, Wistar , Substantia Nigra/pathology , Substantia Nigra/physiopathology
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