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Commentary: Evaluation of Models of Parkinson's Disease.

Muñoz P, Paris I, Segura-Aguilar J - Front Neurosci (2016)

View Article: PubMed Central - PubMed

Affiliation: Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile Santiago, Chile.

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This publication is a review on the preclinical model used today for Parkinson's disease that take in consideration both preclinical model based on neurotoxin or mutations associated to familial Parkinson's disease (PD)... The aim of this commentary is to introduce a new point of view about the actual preclinical models, open discussion, and propose a new preclinical model... The use of correct preclinical model to study the mechanisms and to test possible new therapies is essential to obtain successful results and new therapies... The actual treatment of the disease is based on dopaminergic and anti-cholinergics compounds... The scientific community and pharmaceutical companies have failed to find new drugs to halt the progression of the disease and the worst is that the focus to find new therapies is centered on drugs to alleviate the side effects of L-dopa such as dyskinesia... There are a long list of successful preclinical studies that have failed to translate these positive results to clinical studies and new therapies, for example pioglitazone, topiramate, GDNF, creatine, ubiquinone, cognane, mitoquinone, etc. (Athauda and Foltynie, ; Lindholm et al., ; Olanow et al., ; Park and Stacy, )... The question is why successful results in preclinical studies cannot be translated to clinical studies? Unilateral injection of aminochrome into rat striatum induces a progressive contralateral behavior without loss of nigrostriatal dopaminergic neurons... Instead, aminochrome induces neuronal dysfunction of dopaminergic neurons since the level of dopamine significantly decrease while GABA level significantly increase, generating a neurotransmitter imbalance... The decrease in dopamine release without degeneration of nigrostriatal neurons can be explained by the fact that aminochrome induces mitochondrial dysfunction, significant decrease of ATP level in the striatum and in the number of synaptic vesicles (Herrera et al., )... Interestingly, astrocytes secrete GSTM2 into conditioned medium and dopaminergic model neurons take up GSTM2 and prevent aminochrome-induced neurotoxicity in these neurons (Cuevas et al., )... Therefore, GSTM2 play a protective role against aminochrome both in astrocytes and dopaminergic neurons... The use of animals with DT-diaphorase or GSTM2 knockout injected with aminochrome maybe a new preclinical to study both PD mechanisms and to develop new PD drugs... In conclusion, the failure to translate successful result from preclinical to clinical studies and develop new pharmacological therapies will continue until we found a preclinical model that use an endogenous neurotoxin which is involved in the disease development.

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Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity. Astrocytes secrete GSTM2 which is internalized by dopaminergic neurons in order to increase their protection against aminochrome. Dopamine oxidation to neuromelanin is a harmless pathway due to the presence of DT-diaphorase and GSTM2 that prevent aminochrome-dependent neurotoxicity by inhibiting the formation of alpha-synuclein (SNCA) neurotoxic oligomers, mitochondrial dysfunction, oxidative stress, autophagy, and proteasome dysfunction and endoplasmic reticulum stress.
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Figure 1: Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity. Astrocytes secrete GSTM2 which is internalized by dopaminergic neurons in order to increase their protection against aminochrome. Dopamine oxidation to neuromelanin is a harmless pathway due to the presence of DT-diaphorase and GSTM2 that prevent aminochrome-dependent neurotoxicity by inhibiting the formation of alpha-synuclein (SNCA) neurotoxic oligomers, mitochondrial dysfunction, oxidative stress, autophagy, and proteasome dysfunction and endoplasmic reticulum stress.

Mentions: Aminochrome is the most stable o-quinone formed during dopamine oxidation and it participates on both neurotoxic and neuroprotective reactions. Aminochrome is neurotoxic when it forms adducts with proteins or it is one-electron reduced by flavoenzymes which catalyzes one electron transfer. However, there are two enzymes that prevent aminochrome neurotoxicity (Figure 1): (i) DT-diaphorase prevents aminochrome-induced cell death, mitochondrial dysfunction, oxidative stress, protein degradation dysfunction of both proteasomal and lysosomal systems, and formation of alpha-synuclein neurotoxic oligomers (Segura-Aguilar et al., 2014, 2015); and (ii) glutathione transferase M2-2 (GSTM2) catalyzes the GSH conjugation of both aminochrome and its precursor dopamine o-quinone and it is expressed only in astrocytes. GSTM2 prevent aminochrome toxicity in astrocytes when dopamine takes up from intersynaptic space after neurotransmission and oxidizes to aminochrome in the astrocytes. Interestingly, astrocytes secrete GSTM2 into conditioned medium and dopaminergic model neurons take up GSTM2 and prevent aminochrome-induced neurotoxicity in these neurons (Cuevas et al., 2015). Therefore, GSTM2 play a protective role against aminochrome both in astrocytes and dopaminergic neurons. The protective role of both DT-diaphorase and GSTM2 against aminochrome can explain why dopamine oxidation to neuromelanin is not normally a harmful pathway. The use of animals with DT-diaphorase or GSTM2 knockout injected with aminochrome maybe a new preclinical to study both PD mechanisms and to develop new PD drugs. In conclusion, the failure to translate successful result from preclinical to clinical studies and develop new pharmacological therapies will continue until we found a preclinical model that use an endogenous neurotoxin which is involved in the disease development.


Commentary: Evaluation of Models of Parkinson's Disease.

Muñoz P, Paris I, Segura-Aguilar J - Front Neurosci (2016)

Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity. Astrocytes secrete GSTM2 which is internalized by dopaminergic neurons in order to increase their protection against aminochrome. Dopamine oxidation to neuromelanin is a harmless pathway due to the presence of DT-diaphorase and GSTM2 that prevent aminochrome-dependent neurotoxicity by inhibiting the formation of alpha-synuclein (SNCA) neurotoxic oligomers, mitochondrial dysfunction, oxidative stress, autophagy, and proteasome dysfunction and endoplasmic reticulum stress.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4835501&req=5

Figure 1: Astrocytes protect dopaminergic neurons against aminochrome neurotoxicity. Astrocytes secrete GSTM2 which is internalized by dopaminergic neurons in order to increase their protection against aminochrome. Dopamine oxidation to neuromelanin is a harmless pathway due to the presence of DT-diaphorase and GSTM2 that prevent aminochrome-dependent neurotoxicity by inhibiting the formation of alpha-synuclein (SNCA) neurotoxic oligomers, mitochondrial dysfunction, oxidative stress, autophagy, and proteasome dysfunction and endoplasmic reticulum stress.
Mentions: Aminochrome is the most stable o-quinone formed during dopamine oxidation and it participates on both neurotoxic and neuroprotective reactions. Aminochrome is neurotoxic when it forms adducts with proteins or it is one-electron reduced by flavoenzymes which catalyzes one electron transfer. However, there are two enzymes that prevent aminochrome neurotoxicity (Figure 1): (i) DT-diaphorase prevents aminochrome-induced cell death, mitochondrial dysfunction, oxidative stress, protein degradation dysfunction of both proteasomal and lysosomal systems, and formation of alpha-synuclein neurotoxic oligomers (Segura-Aguilar et al., 2014, 2015); and (ii) glutathione transferase M2-2 (GSTM2) catalyzes the GSH conjugation of both aminochrome and its precursor dopamine o-quinone and it is expressed only in astrocytes. GSTM2 prevent aminochrome toxicity in astrocytes when dopamine takes up from intersynaptic space after neurotransmission and oxidizes to aminochrome in the astrocytes. Interestingly, astrocytes secrete GSTM2 into conditioned medium and dopaminergic model neurons take up GSTM2 and prevent aminochrome-induced neurotoxicity in these neurons (Cuevas et al., 2015). Therefore, GSTM2 play a protective role against aminochrome both in astrocytes and dopaminergic neurons. The protective role of both DT-diaphorase and GSTM2 against aminochrome can explain why dopamine oxidation to neuromelanin is not normally a harmful pathway. The use of animals with DT-diaphorase or GSTM2 knockout injected with aminochrome maybe a new preclinical to study both PD mechanisms and to develop new PD drugs. In conclusion, the failure to translate successful result from preclinical to clinical studies and develop new pharmacological therapies will continue until we found a preclinical model that use an endogenous neurotoxin which is involved in the disease development.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Clinical Pharmacology, Faculty of Medicine, University of Chile Santiago, Chile.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

This publication is a review on the preclinical model used today for Parkinson's disease that take in consideration both preclinical model based on neurotoxin or mutations associated to familial Parkinson's disease (PD)... The aim of this commentary is to introduce a new point of view about the actual preclinical models, open discussion, and propose a new preclinical model... The use of correct preclinical model to study the mechanisms and to test possible new therapies is essential to obtain successful results and new therapies... The actual treatment of the disease is based on dopaminergic and anti-cholinergics compounds... The scientific community and pharmaceutical companies have failed to find new drugs to halt the progression of the disease and the worst is that the focus to find new therapies is centered on drugs to alleviate the side effects of L-dopa such as dyskinesia... There are a long list of successful preclinical studies that have failed to translate these positive results to clinical studies and new therapies, for example pioglitazone, topiramate, GDNF, creatine, ubiquinone, cognane, mitoquinone, etc. (Athauda and Foltynie, ; Lindholm et al., ; Olanow et al., ; Park and Stacy, )... The question is why successful results in preclinical studies cannot be translated to clinical studies? Unilateral injection of aminochrome into rat striatum induces a progressive contralateral behavior without loss of nigrostriatal dopaminergic neurons... Instead, aminochrome induces neuronal dysfunction of dopaminergic neurons since the level of dopamine significantly decrease while GABA level significantly increase, generating a neurotransmitter imbalance... The decrease in dopamine release without degeneration of nigrostriatal neurons can be explained by the fact that aminochrome induces mitochondrial dysfunction, significant decrease of ATP level in the striatum and in the number of synaptic vesicles (Herrera et al., )... Interestingly, astrocytes secrete GSTM2 into conditioned medium and dopaminergic model neurons take up GSTM2 and prevent aminochrome-induced neurotoxicity in these neurons (Cuevas et al., )... Therefore, GSTM2 play a protective role against aminochrome both in astrocytes and dopaminergic neurons... The use of animals with DT-diaphorase or GSTM2 knockout injected with aminochrome maybe a new preclinical to study both PD mechanisms and to develop new PD drugs... In conclusion, the failure to translate successful result from preclinical to clinical studies and develop new pharmacological therapies will continue until we found a preclinical model that use an endogenous neurotoxin which is involved in the disease development.

No MeSH data available.


Related in: MedlinePlus