Clinical development of curcumin in neurodegenerative disease

Abstract

Curcumin, a polyphenolic antioxidant derived from the turmeric root has undergone extensive preclinical development, showing remarkable efficacy in wound repair, cancer and inflammatory disorders. This review addresses the rationale for its use in neurodegenerative disease, particularly Alzheimer’s disease. Curcumin is a pleiotropic molecule, which not only directly binds to and limits aggregation of the β-sheet conformations of amyloid characteristic of many neurodegenerative diseases but also restores homeostasis of the inflammatory system, boosts the heat shock system to enhance clearance of toxic aggregates, scavenges free radicals, chelates iron and induces anti-oxidant response elements. Although curcumin corrects dysregulation of multiple pathways, it may exert many effects via a few molecular targets. Pharmaceutical development of natural compounds like curcumin and synthetic derivatives have strong scientific rationale, but will require overcoming various hurdles including; high cost of trials, concern about profitability and misconceptions about drug specificity, stability, and bioavailability.

Keywords:

• activator protein 1
• Alzheimer’s disease
• amyloid
• amyloid-binding
• antioxidant
• brain derived neurotrophic factor
• c-jun N terminal kinase
• heat shock proteins
• heat shock proteins
• misfolded proteins
• neurodegeneraton
• neuroinflammation
• non-steroidal anti-inflammatory drugs
• nuclear factor kappa B
• polyphenolic antioxidants

Financial & competing interests disclosure

The paper was supported by Veterans Affairs RX000669, BX001257, NIH RO1AG021975, NIH U01AG28583. SA Frautschy and G Cole are co-inventors of a UCLA and Veterans Affairs patent on a curcumin formulation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Curcumin affects both causal and downstream mediators in Alzheimer’s disease pathogenesis and stimulates repair mechanisms but has not been adequately developed clinically.

• Curcumin is an amyloid-binding probe, which reduces chronic inflammation and facilitates resolution of inflammation and reduces lipid peroxidation that correlates with synapse loss.

• For age-related diseases like Alzheimer’s, which have long prodromal periods and multiple dysregulated signaling pathways, pleiotropic molecules may be more effective than highly specific drugs.

• A concerted effort is necessary to identify the key major yet still elusive molecular targets and to develop mathematical models to predict synergistic interactions between these targets to optimize drug cocktails, with a major focus on FDA-approved drugs proven to be safe with chronic use.

• Government and private funds dedicated to translational research are insufficient, which make it virtually impossible to identify dose, gender, and ApoE isoform-dependent effects of drugs with limited patent protection, including curcumin.

• Increase funding for translational research in Alzheimer’s is necessary, and for the pharmaceutical industry to envision development of natural compounds as a profitable approach, as has been the case for many natural compounds beginning with aspirin.