TY - JOUR
T1 - Apomorphine Reduces A53T α-Synuclein-Induced Microglial Reactivity Through Activation of NRF2 Signalling Pathway
AU - Heurtaux, Tony
AU - Kirchmeyer, Melanie
AU - Koncina, Eric
AU - Felten, Paul
AU - Richart, Lorraine
AU - Uriarte Huarte, Oihane
AU - Schohn, Herve
AU - Mittelbronn, Michel
N1 - Funding Information:
We sincerely thank Dr Lasse Sinkkonen for his diligent proofreading of the manuscript. Michel Mittelbronn would like to thank the Luxembourg National Research Fond (FNR) for the support (FNR PEARL P16/BM/11192868 grant).
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Apomorphine
KW - Inflammation
KW - Mutant alpha-synuclein
KW - Primary microglia
KW - Transcription factor recruitment
UR - http://www.scopus.com/inward/record.url?scp=85113186022&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/34415465
U2 - 10.1007/s10571-021-01131-1
DO - 10.1007/s10571-021-01131-1
M3 - Article
C2 - 34415465
AN - SCOPUS:85113186022
SN - 0272-4340
VL - 42
SP - 2673
EP - 2695
JO - Cellular and Molecular Neurobiology
JF - Cellular and Molecular Neurobiology
IS - 8
ER -