Use of Curcumin, a Natural Polyphenol for Targeting Molecular Pathways in Treating Age-Related Neurodegenerative Diseases

Abstract

Progressive accumulation of misfolded amyloid proteins in intracellular and extracellular spaces is one of the principal reasons for synaptic damage and impairment of neuronal communication in several neurodegenerative diseases. Effective treatments for these diseases are still lacking but remain the focus of much active investigation. Despite testing several synthesized compounds, small molecules, and drugs over the past few decades, very few of them can inhibit aggregation of amyloid proteins and lessen their neurotoxic effects. Recently, the natural polyphenol curcumin (Cur) has been shown to be a promising anti-amyloid, anti-inflammatory and neuroprotective agent for several neurodegenerative diseases. Because of its pleotropic actions on the central nervous system, including preferential binding to amyloid proteins, Cur is being touted as a promising treatment for age-related brain diseases. Here, we focus on molecular targeting of Cur to reduce amyloid burden, rescue neuronal damage, and restore normal cognitive and sensory motor functions in different animal models of neurodegenerative diseases. We specifically highlight Cur as a potential treatment for Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases. In addition, we discuss the major issues and limitations of using Cur for treating these diseases, along with ways of circumventing those shortcomings. Finally, we provide specific recommendations for optimal dosing with Cur for treating neurological diseases.

Substantiation for the Use of Curcumin during the Development of Neurodegeneration after Brain Ischemia

“…On the other hand, curcumin can reduce the brain tissue load of β-amyloid peptide by suppressing RAGE-mediated influx of β-amyloid peptide across the blood-brain barrier from blood and by enhancing the enzymatic degradation of β-amyloid peptide. In addition, curcumin may stimulate phagocytosis [108] and increase the presence of phagocytic cells around deposits of β-amyloid peptide, as observed in various experimental models [150], as well as with amyloid plaques in sections of post-mortem human brain exposed to primary rodent microglia [151]. Curcumin stimulates amyloid phagocytosis by activating microglial cells and enzymatic breakdown of amyloid [108].…”

“…Therefore, targeting these pathways may be the basic strategy for developing post-ischemic neurodegeneration therapy. In this context, the use of curcumin in the treatment of post-ischemic neurodegeneration has certain advantages, namely (1) it easily crosses the blood-brain barrier [103,104], (2) binds and disaggregates oligomers and fibrils of amyloid proteins [105,106], (3) increases the clearance of amyloid [107], (4) reduces chronic inflammation, (5) acts as a powerful antioxidant, (6) stimulates neurogenesis, (7) removes metal from amyloid, (8) can be taken in relatively high doses without side effects [108].…”

Deuterated Curcuminoids: Synthesis, Structures, Computational/Docking and Comparative Cell Viability Assays against Colorectal Cancer

“…Given recent reports on the efficacy of some curcumin–BF 2 adducts for two‐photon imaging and as cross‐linking inhibitors for β‐amyloid species in Alzheimer's disease (AD), it is likely that CUR–BF 2 compounds could also serve as chemotherapeutic agents for colorectal cancer.…”

“…Comparison of the anticancer activity between the CUR-BF 2 adducts and the corresponding CUR derivatives (e.g., 1 vs. 2, 1a vs. 2a), clearly shows that BF 2 complex-ation remarkably enhances the anticancer potency of the CUR compounds ( Figure 9). Given recent reports on the efficacy of some curcumin-BF 2 adducts for two-photon imaging and as cross-linking inhibitors for b-amyloid speciesi nA lzheimer's disease( AD), [24,25] it is likely that CUR-BF 2 compounds could also serve as chemotherapeutic agents for colorectal cancer.…”

The Potential for Natural Antioxidant Supplementation in the Early Stages of Neurodegenerative Disorders

“…For example, some studies in vitro on microglia stressed that curcumin, administered in low doses (0-20 µM), promotes the expression of the Heme Oxygenase (HO)-1 antioxidant proteins and peroxiredoxin 6 (Prdx6), minimises neuroinflammation and the production of cytokines (IL-1β, IL-6, TNFα) induced by lipopolysaccharide (LPS) [88], reduces the stress of the endoplasmic reticulum through the inhibition of UPR as well as of the pro-apoptotic pathway associated with the C/EBP homologous protein (CHOP) transcription factor [89], which, once activated, induces the secretion of IL-1β and caspase 1. As supported by evidence, curcumin prevents the brain stress induced by oxidative damage by increasing the GSH levels and the activity of the superoxide dismutase (SOD), GSH-peroxidase (GPx), GSH-reductase (GR) and catalase (CAT) antioxidant enzymes [90]. The anti-inflammatory property of curcumin manifests itself by increasing the levels of anti-inflammatory cytokines as well as the expression of the NF-κB transcription factor [91].…”