Acrolein scavenger dimercaprol offers neuroprotection in an animal model of Parkinson's disease: implication of acrolein and TRPA1.
Acrolein
/ metabolism
Animals
Behavior, Animal
Cerebral Cortex
/ drug effects
Dimercaprol
/ pharmacology
Dopaminergic Neurons
/ drug effects
Hydroxydopamines
Male
Motor Activity
/ drug effects
Neostriatum
/ drug effects
Neuroprotective Agents
/ pharmacology
Pain
/ etiology
Pain Measurement
/ drug effects
Parkinson Disease, Secondary
/ chemically induced
Rats
Rats, Sprague-Dawley
Substantia Nigra
/ drug effects
TRPA1 Cation Channel
/ metabolism
Acrolein
Dimercaprol
Neuroinflammation
Oxidative stress
Parkinson’s disease
TRPA1
Journal
Translational neurodegeneration
ISSN: 2047-9158
Titre abrégé: Transl Neurodegener
Pays: England
ID NLM: 101591861
Informations de publication
Date de publication:
28 04 2021
28 04 2021
Historique:
received:
11
10
2020
accepted:
16
04
2021
entrez:
29
4
2021
pubmed:
30
4
2021
medline:
21
12
2021
Statut:
epublish
Résumé
The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits. DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein. DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein's ability to upregulate TRPA1 was also verified in vitro using cell lines. These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.
Sections du résumé
BACKGROUND
The mechanisms underlying lesions of dopaminergic (DA) neurons, an essential pathology of Parkinson's disease (PD), are largely unknown, although oxidative stress is recognized as a key factor. We have previously shown that the pro-oxidative aldehyde acrolein is a critical factor in PD pathology, and that acrolein scavenger hydralazine can reduce the elevated acrolein, mitigate DA neuron death, and alleviate motor deficits in a 6-hydroxydopamine (6-OHDA) rat model. As such, we hypothesize that a structurally distinct acrolein scavenger, dimercaprol (DP), can also offer neuroprotection and behavioral benefits.
METHODS
DP was used to lower the elevated levels of acrolein in the basal ganglia of 6-OHDA rats. The acrolein levels and related pathologies were measured by immunohistochemistry. Locomotor and behavioral effects of 6-OHDA injections and DP treatment were examined using the open field test and rotarod test. Pain was assessed using mechanical allodynia, cold hypersensitivity, and plantar tests. Finally, the effects of DP were assessed in vitro on SK-N-SH dopaminergic cells exposed to acrolein.
RESULTS
DP reduced acrolein and reversed the upregulation of pain-sensing transient receptor potential ankyrin 1 (TRPA1) channels in the substantia nigra, striatum, and cortex. DP also mitigated both motor and sensory deficits typical of PD. In addition, DP lowered acrolein and protected DA-like cells in vitro. Acrolein's ability to upregulate TRPA1 was also verified in vitro using cell lines.
CONCLUSIONS
These results further elucidated the acrolein-mediated pathogenesis and reinforced the critical role of acrolein in PD while providing strong arguments for anti-acrolein treatments as a novel and feasible strategy to combat neurodegeneration in PD. Considering the extensive involvement of acrolein in various nervous system illnesses and beyond, anti-acrolein strategies may have wide applications and broad impacts on human health.
Identifiants
pubmed: 33910636
doi: 10.1186/s40035-021-00239-0
pii: 10.1186/s40035-021-00239-0
pmc: PMC8080346
doi:
Substances chimiques
Hydroxydopamines
0
Neuroprotective Agents
0
TRPA1 Cation Channel
0
Trpa1 protein, rat
0
Dimercaprol
0CPP32S55X
Acrolein
7864XYD3JJ
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13Subventions
Organisme : Foundation for the National Institutes of Health
ID : NS090244 and NS115094
Organisme : National Science and Technology Planning Project
ID : 2020YFH0148
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