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Cannabidiol confers neuroprotection against 6-OHDA toxicity by rescuing Nrf2 proteostasis and preserving mitochondrial integrity
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DOI：10.1016/j.freeradbiomed.2026.08.012.png)
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Abstract
En 中文
Oxidative stress and the progressive degeneration of dopaminergic neurons are key features of Parkinson's disease (PD). The intrinsically disordered structure of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which coordinates the main cellular antioxidant response of the body, makes it highly susceptible to misfolding and aggregation under severe oxidative stress, compromising cellular survival. Cannabidiol (CBD) has potent neuroprotective properties, but its exact molecular mechanism within the dopaminergic redox environment remains unclear. In this study, we investigated the protective effects of CBD against 6-hydroxydopamine (6-OHDA)-induced toxicity in both undifferentiated and mature, post-mitotic differentiated SH-SY5Y cells. We found that CBD confers robust Nrf2-dependent neuroprotection against 6-OHDA. Importantly, we uncover a previously unexplored mechanism of neuroprotection by which CBD actively prevents the stress-induced sequestration of Nrf2 into insoluble cytoplasmic inclusions under oxidative stress. We find that CBD keeps Nrf2 in a soluble, functional state, increases Ser40 phosphorylation, restores nuclear localization, and drives the robust transcriptional upregulation of antioxidant enzymes. This targeted activation of Nrf2 effectively reduces intracellular reactive oxygen species (ROS), significantly attenuates mitochondrial fragmentation, and decreases aberrant mitophagic activity. Overall, our results show that rather than merely scavenging reactive oxygen species, CBD directly increases Nrf2 activity during oxidative stress, enabling a sustained cytoprotective response. We thus identify CBD as a highly specific, targeted molecule with a high potential for neuroprotective therapy in PD.
Keywords:
Cannabidiol
Nrf2
Parkinson's disease
6-Hydroxydopamine
Proteostasis
Mitochondrial dynamics
Neuroprotection
5-HT1A
5-hydroxytryptamine subtype 1A
6-OHDA
6-hydroxydopamine
ANOVA
analysis of variance
ARE
antioxidant response element
BDNF
brain-derived neurotrophic factor
BTB
Tramtrack-Bric-a-Brac
CBD
cannabidiol
CCK-8
Cell Counting Kit-8
COX2
cyclooxygenase type 2
CTR
C-terminal domain
DGR
double glycine repeat
DMEM
Dulbecco's Modified Eagle Medium
DMSO
dimethyl sulfoxide
DNs
dopaminergic neurons
DoG
Difference of Gaussians
FBS
fetal bovine serum
GAPDH
glyceraldehyde-3-phosphate dehydrogenase
GFP
green fluorescent protein
GPCRs
G-protein-coupled receptors
HK II
hexokinase II
HMOX1
heme oxygenase-1
HRP
horseradish peroxidase
HSP70
heat shock protein 70
IC50
half-maximal inhibitory concentration
IDP
intrinsically disordered protein
IVR
intervening region
Keap1
Kelch-like ECH-associated protein 1
LAS X
Leica Application Suite X
LDHA
lactate dehydrogenase A
LOX
lipoxygenase
MAP2
microtubule-associated protein 2
MAPK/ERK
mitogen-activated protein kinase/extracellular signal-regulated kinase
MFI
mean fluorescence intensity
MPP+
1-methyl-4-phenylpyridinium
MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NEM
N-ethylmaleimide
NeuN
hexaribonucleotide binding protein-3
NGS
normal goat serum
NQO1
NAD(P)H quinone dehydrogenase 1
Nrf2
nuclear factor erythroid 2-related factor 2
PD
Parkinson's disease
PGC-1α
peroxisome proliferator-activated receptor-gamma coactivator-1alpha
PI3K/Akt
phosphoinositide 3-kinase/protein kinase B
PINK1
PTEN-induced kinase 1
PPAR-γ
peroxisome proliferator-activated receptor gamma
PVDF
polyvinylidene difluoride
RA
retinoic acid
ROS
reactive oxygen species
RPLP0
ribosomal protein lateral stalk subunit P0
RT
room temperature
SD
standard deviation
SDS-PAGE
sodium dodecyl sulfate–polyacrylamide gel electrophoresis
SIRT1
sirtuin 1
SNpc
substantia nigra pars compacta
TBST
Tris-buffered saline with Tween 20
THC
Delta9-tetrahydrocannabinol
TRPV1
transient receptor potential vanilloid 1
UPS
ubiquitin-protease system
WLL
White Light Laser
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