Neuroprotective Potential of the Natural Bioactive Compound Calebin A against Endogenous Neurotoxins

Abstract

With the rapid aging of the global population, neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have become increasingly prevalent and represent major public health challenges. These disorders share several common pathological mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, dysregulated neurotransmission, and activation of apoptotic pathways, which ultimately lead to progressive neuronal loss. Due to the largely irreversible nature of neuronal damage, current therapeutic strategies mainly provide symptomatic relief rather than targeting the underlying neurodegenerative processes. Therefore, there is a critical need to identify multifunctional neuroprotective compounds capable of modulating multiple pathogenic pathways. Curcumin, a natural polyphenolic compound derived from Curcuma longa, has attracted attention due to its antioxidant, anti-inflammatory, and neuroprotective properties. However, its clinical application is limited by poor aqueous solubility, structural instability, and low bioavailability. Calebin A, a naturally occurring curcumin-derived metabolite, possesses structural modifications that may improve chemical stability and pharmacological properties. Previous studies suggested that Calebin A may exert neuroprotective effects through inhibition of β-amyloid aggregation; however, its role in cholinergic and dopaminergic neurodegeneration remains unclear.

In this study, in silico ADME analysis and molecular docking were employed to evaluate the physicochemical and pharmacokinetic properties of Calebin A. The results suggested that structural differences between Calebin A and curcumin may contribute to improved pharmacokinetic features. Molecular docking further indicated favorable binding interactions with neurotransmitter-regulating enzymes. To experimentally evaluate its neuroprotective potential, hippocampal HT22 neurons and dopaminergic N27 neurons were used. Hydrogen peroxide was applied to induce oxidative neuronal injury. In HT22 neurons, Calebin A significantly increased intracellular glutathione (GSH) levels, activated interleukin-1β converting enzyme (ICE-1), and inhibited caspase-3 activity, suggesting selective modulation of apoptotic signaling. In N27 neurons, Calebin A exhibited complementary effects, including inhibition of monoamine oxidase (MAO), suppression of ICE-1 activity, and inhibition of caspase-3 activation. Collectively, these findings demonstrate that Calebin A exerts neuroprotective effects through modulation of oxidative balance, inflammatory proteases, and neurotransmitter-degrading enzymes, supporting its potential as a multifunctional natural compound for targeting neurodegenerative mechanisms.