Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases

Abstract

With the global population aging, the incidence of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, has been progressively increasing. However, effective therapeutic strategies and clinical drugs for these disorders remain scarce. Curcumin, a natural polyphenolic compound primarily derived from the herbaceous plant Curcuma longa L., has been proposed as a promising candidate for ND treatment based on the excellent antioxidant, anti-inflammatory and neuroprotective properties. Its pharmacological activities encompass scavenging reactive oxygen species, mitigating toxic protein aggregation and cytotoxicity, repairing mitochondrial dysfunction, and inhibiting excessive neuronal apoptosis. Compared with synthetic drugs, curcumin demonstrates a more favorable safety profile with fewer side effects. Nevertheless, its clinical application is substantially hindered by poor bioavailability, which stems from low aqueous solubility, inefficient intestinal absorption, and rapid metabolism and systemic elimination. Conventional administration methods often fail to achieve effective concentrations in vivo. Further clinical trials are also required to validate the therapeutic efficacy and potential adverse effects in human subjects. This article systematically reviews the pathogenesis of NDs and the knowledge on curcumin including pharmacological effects, neuroprotective mechanisms, functions across specific NDs and advanced strategies to enhance the bioavailability, with the aim of promoting the development and clinical translation of curcumin-based therapeutics for NDs.

Keywords: bioavailability; curcumin; natural medicine; neurodegenerative disease; pharmacological activity.

FIGURE 1

Mechanism of curcumin exerting the neuroprotective effect. (1) Antioxidation: Ⅰ. Direct scavenging of ROS; Ⅱ. Enhancement of antioxidant enzyme activity, such as SOD, CAT and GPx; Ⅲ. Promoting the dissociation of Nrf2 from Keap1 to bind to antioxidant response elements (ARE), inducing the expression of antioxidant genes. (2) Anti-inflammation: Ⅰ. Inhibition of the activities of cyclooxygenase (COX), lipoxygenase (LOX), etc.; Ⅱ. Inhibition of the activation of the inflammasome NLRP3; Ⅲ. Inhibiting the activity of the IκB kinase (IKK) complex, thereby suppressing NF-κB, and consequently reducing the expression of NF-κB-mediated pro-inflammatory factors such as IL-1β, IL-6, TNF-α, etc.; Ⅳ. Reduced abnormal activation of astrocytes and microglia; Ⅴ. Promoting the production of short-chain fatty acids (SCFAs) of intestinal microbes to regulate the brain-gut axis, maintaining the integrity of the blood-brain barrier and indirectly protecting the nervous system. (3) Removal of toxic proteins: Ⅰ. Inhibition of the formation of toxic protein aggregates; Ⅱ. Prevention of tau phosphorylation; Ⅲ. Activating the PI3K/AKT/mTOR pathway to promote autophagic clearance of formed toxic proteins and damaged cells. (4) Maintenance of metal homeostasis: Ⅰ. Chelating heavy metal ions to alleviate neurotoxicity; Ⅱ. Prevention of intracellular calcium overload. (5) Inhibition of excessive apoptosis: Upregulating Bcl-2 and downregulating Bax to reduce mitochondrial cytochrome C release and inhibit caspase-9/6/3 activation, suppressing excessive apoptosis. (6) Promotion of regeneration and repair of neurons: Ⅰ. Increasing the expression of brain-derived neurotrophic factor (BDNF); Ⅱ. Upregulation of Wnt/β-catenin (WβC) pathway.