Aminochrome Induces Neuroinflammation and Dopaminergic Neuronal Loss: A New Preclinical Model to Find Anti-inflammatory and Neuroprotective Drugs for Parkinson’s Disease

Araújo, F.; Frota, Annyta Fernandes; Jesus, Lívia Bacelar de; Macedo, Ticiane Caribe; Cuenca‐Bermejo, Lorena; Sánchez-Rodrigo, Consuelo; Ferreira, Kariny Maria Silva; Vr, Oliveira Juciele; Costa, Maria de Fátima Dias; Segura‐Aguilar, Juan; Costa, Sílvia Lima; Herrero, María Trinidad; Silva, Víctor Diógenes Amaral da

doi:10.1007/s10571-021-01173-5

Cited by 4 publications

(3 citation statements)

References 75 publications

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“…These ortho-quinones are potentially neurotoxic but aminochrome is the most stable and neurotoxic [65,66]. Aminochrome induces oxidative stress, mitochondrial dysfunction, formation of neurotoxic alpha-synuclein oligomers, dysfunction of both lysosomal and proteasomal protein degradation systems, neuroinflammation, and endoplasmic reticulum stress [67][68][69][70][71][72].…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…Finally, this redox cycling generates oxidative stress and ATP depletion that is required, among other things, for the neurotransmission of dopamine from monoaminergic vesicles; and (ii) aminochrome is also capable of forming adducts with proteins such as alpha-synuclein, actin, α and β-tubulin, mitochondrial complex 1, ATP13A, and other proteins [62,86,87]. The neurotoxic effects of aminochrome induce oxidative stress, neuroinflammation, formation of neurotoxic alpha-synuclein oligomers, mitochondrial dysfunction, endoplasmic reticulum stress, and dysfunction of both lysosomal and proteasomal protein degradation systems [67][68][69][70][71][72].…”

Section: Dopamine Metabolismmentioning

confidence: 99%

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Targets to Search for New Pharmacological Treatment in Idiopathic Parkinson’s Disease According to the Single-Neuron Degeneration Model

Huenchuguala,

Segura-Aguilar

2024

Biomolecules

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One of the biggest problems in the treatment of idiopathic Parkinson’s disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson’s disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.

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Section: Parkinson's Diseasementioning

confidence: 99%

Section: Dopamine Metabolismmentioning

confidence: 99%

Targets to Search for New Pharmacological Treatment in Idiopathic Parkinson’s Disease According to the Single-Neuron Degeneration Model

Huenchuguala,

Segura-Aguilar

2024

Biomolecules

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“…The loss of dopamine in PD, and subsequent exposure to dopamine replacement therapy, is likely to have complex downstream consequences on neuroglia and on profiles of inflammation, both locally and peripherally. For example, the C57/BL6 mouse and the Wistar rat 6-OHDA models of PD, which are characterised by discrete nigrostriatal dopamine loss, exhibit chronically increased activation of microglia along the nigrostriatal pathway ( De Araújo et al, 2022 ; Mendes-Pinheiro et al, 2021 ). Additionally, significant changes in the gut have been observed in the same mouse model, and also the 6-OHDA model in the Sprague Dawley rat, including reduced dopamine receptor expression, increased dopamine content, and increased inflammatory and oxidative stress markers ( Garrido-Gil et al, 2018 ; Levandis et al, 2015 ).…”

Section: Unknown #4: the Role Of Neuroinflammationmentioning

confidence: 99%

Defining the unknowns for cell therapies in Parkinson's disease

Lane

Lelos

2022

Disease Models &Amp; Mechanisms

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First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD.

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JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species

Santos

Cardim-Pires²,

Shvachiy³

et al. 2022

Neurotox Res

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Aminochrome Induces Neuroinflammation and Dopaminergic Neuronal Loss: A New Preclinical Model to Find Anti-inflammatory and Neuroprotective Drugs for Parkinson’s Disease

Cited by 4 publications

References 75 publications

Targets to Search for New Pharmacological Treatment in Idiopathic Parkinson’s Disease According to the Single-Neuron Degeneration Model

Targets to Search for New Pharmacological Treatment in Idiopathic Parkinson’s Disease According to the Single-Neuron Degeneration Model

Defining the unknowns for cell therapies in Parkinson's disease

JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species

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