Experimental modeling of preclinical and clinical stages of Parkinson’s disease

Abstract

Degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system is the key stage in the pathogenesis of Parkinson's disease. The first symptoms of this disease are observed after degeneration of 70-80% neurons, which occurs over 20-30 years. The clinical stage of Parkinson's disease begins after this period. Late diagnostics of Parkinson's disease contributes to low efficiency of therapy for this disorder. Detailed study of the pathogenesis and development of preclinical diagnostic methods for Parkinson's disease are the urgent problems. This work was designed to develop a new experimental model of the preclinical and clinical stages of the disease. Experimental modeling was performed on C57Bl/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This agent is converted into the MPP(+)-neurotoxin in brain DAergic neurons. We showed that MPTP in a dose of 4 mg/kg has no effect on the nigrostriatal DAergic system. MPTP in a dose of 8-16 mg/kg produced the toxic effect only on DAergic axons, which simulates the preclinical stage of Parkinson's disease. MPTP in a dose of 20-40 mg/kg had the toxic effect on neuronal axons and bodies, which simulates the clinical stage of Parkinson's disease. The data suggest that progressive degeneration of DAergic neurons is accompanied by activation of compensatory mechanisms for functional deficiency of these cells.

Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis

“…The entire experimental model for Parkinson's disease used exogenous neurotoxins such as 6-hydroxydopamine [111], MPTP [112], paraquat [113], rotenone [114] and dithiocarbamates [115]. Most likely, the degeneration of dopaminergic neurons containing neuromelanin is primarily dependent on an endogenous neurotoxin(s), such as (i) the o-quinones (dopamine o-quinone, aminochrome and 5,6-indolequinone) generated during dopamine oxidation; (ii) 3,4-dihydroxyphenylacetaldehyde generated by the oxidative deamination of dopamine catalyzed by MAO [116]; (iii) salsolinol, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, the condensation product of dopamine with aldehyde [86].…”

Complex Network-Driven View of Genomic Mechanisms Underlying Parkinson’s Disease: Analyses in Dorsal Motor Vagal Nucleus, Locus Coeruleus, and Substantia Nigra

“…In PD, the compensatory mechanisms at cellular and molecular levels are centered in protection against neurotoxicity [ 105 , 106 ] and neurogenesis and reinnervation of affected areas [ 107 ]. These mechanisms are more active in the initial and intermediate stages of PD, declining in the final stages [ 108 , 109 ].…”

Análise de redes de interação transcricional na substância nigra, locus cerúleo e núcleo dorsal do nervo vago na Doença de Parkinson

“…Esse perfil de rede é muito diferente do observado em LC-CT. Em LC-DP predominam: i) genes envolvidos na regulação da expressão gênica e processos ligados à membrana plasmática (endocitose, exocitose); ii) genes ligados a processos de desenvolvimento neuronal, controle do extresse oxidativo e degradação de proteínas. Esse cenário sugere que no locus cerúleo a DP induziria a ativação de mecanismos compensatórios (Khaindrava et al, 2011;van Nuenen et al, 2012) para a degeneração neuronal, o que será discutido com maior detalhe nas seções V-4 e VI.…”

“…Na DP os mecanismos compensatórios ao nível molecular e celular centram-se em proteção contra neuroxicidade (Bajo-Grañeras et al, 2011a e b) e neurogênese e reinervação de áreas afetadas (Domenger et al, 2012). Esses mecanismos são mais ativos em estágios iniciais e intermediários da doença e declinam nos estágios finais (Khaindrava et al, 2011;Nandhagopal et al, 2011). Por sua vez, a análise de redes de intereração transcricional feita neste trabalho mostra (como se verá mais claramente adiante) que os hubs relacionados à manutenção/regulação da homeostase vão sendo suplantados, na qualidade de hubs principais nas redes, por outros ligados a mecanismos claramente compensatórios e, finalmente, por aqueles ligados à degeneração neuronal, conforme a sequência nervo vago -locus cerúleo -substância nigra.…”