Cholinergic activity plays a vital role in cognitive function, and is reduced in individuals with
neurodegenerative diseases.
Scopolamine, a
muscarinic cholinergic antagonist, has been employed in many studies to understand, identify, and characterize therapeutic targets for
Alzheimer's disease (AD).
Scopolamine-induced
dementia is associated with impairments in memory and cognitive function, as seen in patients with AD. The current study aimed to investigate the molecular mechanisms underlying
scopolamine-induced
cholinergic neuronal dysfunction and the
neuroprotective effect of
lactucopicrin, an inhibitor of
acetylcholine esterase (AChE). We investigated apoptotic cell death,
caspase activation, generation of
reactive oxygen species (ROS),
mitochondrial dysfunction, and the expression levels of anti- and
pro-apoptotic proteins in
scopolamine-treated C6 cells. We also analyzed the expression levels of
antioxidant enzymes and nuclear factor (erythroid-derived 2)-like 2 (NRF2) in C6 cells and neurite outgrowth in N2a
neuroblastoma cells. Our results revealed that 1 h
scopolamine pre-treatment induced cytotoxicity by increasing apoptotic cell death via oxidative stress-mediated
caspase 3 activation and
mitochondrial dysfunction.
Scopolamine also downregulated the expression the
antioxidant enzymes superoxide dismutase,
glutathione peroxidase, and
catalase, and the
transcription factor NRF2.
Lactucopicrin treatment protected C6 cells from
scopolamine-induced toxicity by reversing the effects of
scopolamine on those markers of toxicity. In addition,
scopolamine attenuated the secretion of neurotrophic
nerve growth factor (
NGF) in C6 cells and neurite outgrowth in N2a cells. As expected,
lactucopicrin treatment enhanced
NGF secretion and neurite outgrowth. Our study is the first to show that
lactucopicrin, a potential
neuroprotective agent, ameliorates
scopolamine-induced
cholinergic dysfunction via NRF2 activation and subsequent expression of
antioxidant enzymes.