Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway

The chiral molecule, apomorphine, is currently used for the treatment of Parkinson’s disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphin...

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Published in:Cellular and molecular neurobiology 2022-11, Vol.42 (8), p.2673-2695
Main Authors: Heurtaux, Tony, Kirchmeyer, Melanie, Koncina, Eric, Felten, Paul, Richart, Lorraine, Uriarte Huarte, Oihane, Schohn, Herve, Mittelbronn, Michel
Format: Article
Language:English
Subjects:
Anti-inflammatory agents
Apomorphine
Biomedical and Life Sciences
Biomedicine
Cell Biology
Dopamine
Enantiomers
Inflammation
Life Sciences
Lipophilic
Microglia
Movement disorders
Neurobiology
Neurodegenerative diseases
Neurosciences
Original Research
Oxidative stress
Parkinson's disease
Patients
Phagocytes
Signal transduction
siRNA
Synuclein
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Summary:The chiral molecule, apomorphine, is currently used for the treatment of Parkinson’s disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphine has also antioxidant and free radical scavenger activities. Neuroinflammation, oxidative stress, and microglia reactivity have emerged as central players in PD. Thus, modulating microglia activation in PD may be a valid therapeutic strategy. We previously reported that murine microglia are strongly activated upon exposure to A53T mutant α-synuclein. The present study was designed to investigate whether apomorphine enantiomers could modulate this A53T-induced microglial activation. Taken together, the results provided evidence that apomorphine enantiomers decrease A53T-induced microgliosis, through the activation of the NRF2 signalling pathway, leading to a lower pro-inflammatory state and restoring the phagocytic activity. Suppressing NRF2 recruitment (trigonelline exposure) or silencing specifically Nfe2l2 gene (siRNA treatment) abolished or strongly decreased the anti-inflammatory activity of apomorphine. In conclusion, apomorphine, which is already used in PD patients to mimic dopamine activity, may also be suitable to decrease α-synuclein-induced microglial reactivity.
ISSN:0272-4340
1573-6830
DOI:10.1007/s10571-021-01131-1