Induction of ferroxidase enzymatic activity by copper reduces MPP+-evoked neurotoxicity in rats

Rubio-Osornio, Moisés; Montes, Sergio; Heras‐Romero, Yessica; Guevara, Jorge; Rubio, Carmen; Aguilera, Penélope; Rivera-Mancía, Susana; Floriano-Sánchez, Esaú; Monroy-Noyola, Antonio; Rı́os, Camilo

doi:10.1016/j.neures.2012.12.003

Cited by 17 publications

(14 citation statements)

References 29 publications

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“…To test this, we administered the PD toxin, MPTP, to WT and CP KO mice, which causes loss of CP expression and consequent iron elevation [4,23]. If the surviving SN neurons in CP KO mice at 5 months of age were comparatively resistant to iron toxicity, MPTP should not exaggerate nigral neuronal loss.…”

Section: Resultsmentioning

confidence: 99%

Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease

Ayton

Lei

Adlard

et al. 2014

Mol Neurodegeneration

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BackgroundThe substantia nigra (SN) midbrain nucleus is constitutively iron rich. Iron levels elevate further with age, and pathologically in Parkinson’s disease (PD). Iron accumulation in PD SN involves dysfunction of ceruloplasmin (CP), which normally promotes iron export. We previously showed that ceruloplasmin knockout (CP KO) mice exhibit Parkinsonian neurodegeneration (~30% nigral loss) by 6 months, which is prevented by iron chelation. Here, we explored whether known iron-stressors of the SN (1) aging and (2) MPTP, would exaggerate the lesion severity of CP KO mice.FindingsWe show that while 5 month old CP KO mice exhibited nigral iron elevation and loss of SN neurons, surprisingly, aging CP KO mice to 14 months did not exacerbate iron elevation or SN neuronal loss. Unlike young mice, iron chelation therapy in CP KO mice between 9–14 months did not rescue neuronal loss. MPTP exaggerated iron elevation in young CP KO mice but did not increase cell death when compared to WTs.ConclusionsWe conclude that there may exist a proportion of substantia nigra neurons that depend on CP for protection against iron neurotoxicity and could be protected by iron-based therapeutics. Death of the remaining neurons in Parkinson’s disease is likely caused by parallel disease mechanisms, which may call for additional therapeutic options.

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Section: Resultsmentioning

confidence: 99%

Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease

Ayton

Lei

Adlard

et al. 2014

Mol Neurodegeneration

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“…Recently, using the same paradigm, we found that copper pretreatment increased ceruloplasmin expression and prevented the MPP + -induced loss of ceruloplasmin ferroxidase activity and the concomitant increase in lipid peroxidation. Additionally, a slight decrease in ferrous iron was found in the striatum and mesencephalon [149]. We consider that the increased ferroxidase activity is responsible for the decline in ferrous iron content and the concomitant prevention of lipid peroxidation.…”

Section: Copper-related Therapiesmentioning

confidence: 99%

Copper and Copper Proteins in Parkinson’s Disease

Montes

Rivera-Mancía

Dı́az-Ruiz

et al. 2014

Oxidative Medicine and Cellular Longevity

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160

107

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Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson's disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found in substantia nigra and caudate nucleus of Parkinson's disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson's disease; for instance, it is known that CTR1 is decreased in substantia nigra pars compacta in Parkinson's disease and that a mutation in ATP7B could be associated with Parkinson's disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology.

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“…Algunos estudios han encontrado que la prolongada exposición a metales pesados está asociada al desarrollo de la enfermedad de Parkinson, estas correlaciones han sido validadas en modelos animales y en estudios in-vitro (Jinsmaa et al, 2014;Kumudini et al, 2014;Rubio-Osornio et al, 2013;Meloni & Vasak, 2011;Lu, Prudent, Fauvet, Lashuel, & Girault, 2011). Todos los hallazgos apuntan a que la muerte neuronal dopaminérgica en el sistema nigroestriatal es producida por exposición continua durante años a agentes tóxicos y no sólo por la exposición a un único agente en ocasiones esporádicas.…”

Section: Factores Ambientalesunclassified

La Enfermedad de Parkinson: Etiología, Tratamientos y Factores Preventivos

Hurtado

Cárdenas

et al. 2017

Univ Psychol

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RESUMENLa enfermedad de Parkinson (EP) es la patología neurodegenerativa motora con mayor incidencia a nivel mundial, cuyas causas aún no son claras. Actualmente no existe cura, pero es posible contar con diferentes tratamientos que permiten aliviar algunos de sus síntomas y enlentecer su curso. Debido a la gran cantidad de informaciones, en ocasiones contradictorias sobre los llamados "factores de riesgo" (entendidos éstos como situaciones que pueden exacerbar la posibilidad de aparición de la enfermedad, incluyendo desde la predisposición familiar hasta la exposición prolongada a substancias exógenas), en esta revisión se pretende ofrecer una panorámica actual sobre factores asociados a la aparición de EP. Se revisan también algunos tratamientos que buscan contrarrestar la pérdida de la función dopaminérgica de la substancia nigra (SN) y algunas de las aproximaciones terapéuticas tanto farmacológicas, como por estimulación cerebral profunda (ECP) o por implante celular. Se revisan también investigaciones sobre el potencial terapéutico de compuestos con alta especificidad a receptores colinérgicos (nAChRs) y antagonistas de receptores de adenosina, específicamente del subtipo A2A. Posiblemente durante las próximas décadas, nuestro conocimiento en epigenética pueda arrojar nuevas luces sobre esta interacción, así como sobre las relaciones entre ciertas líneas de microbios intestinales y aparición de EP. En este momento, la alternativa terapéutica que ofrece mayor eficacia es la ECP, sin embargo, a futuro se espera que el desarrollo de nuevas estrategias de implante cerebral pueda ofrecer una cura real de la EP. Palabras claveEnfermedad de Parkinson (EP); estimulación cerebral profunda (ECP); sustancia nigra (SN); núcleo subtálamico (NST); globo pálido interno (GPi). ABSTRACTParkinson's disease (PD) is the most prevalent neurodegenerative motor pathology worldwide, the causes of which are still unclear. Currently there is no cure, but it is possible to have different treatments that allow to alleviate some of its symptoms and slow its course. Due to the large amount of information, sometimes contradictory, about the

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Induction of ferroxidase enzymatic activity by copper reduces MPP+-evoked neurotoxicity in rats

Cited by 17 publications

References 29 publications

Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease

Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease

Copper and Copper Proteins in Parkinson’s Disease

La Enfermedad de Parkinson: Etiología, Tratamientos y Factores Preventivos

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