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.

A novel curcumin derivative for the treatment of diabetic neuropathy

“…For example, past studies have demonstrated that curcumin may prevent the onset of diabetes (Rouse et al, 2014) and can also impact neuropathy independent of glycemic control (Sharma et al, 2007). Curcumin, while showing some promising therapeutic properties, has distribution and bioavailability issues that restrict its development as a clinically-viable therapy (Hu et al, 2015). We have therefore developed the curcumin derivative J147 using a medicinal chemistry approach that improves bioavailability sufficiently to make it a viable oral drug candidate (Chen et al, 2011; Prior et al, 2014).…”

“…STZ is toxic to beta cells within the first 24 h after delivery (Eleazu et al, 2013) and J147 was not given until 5 days after STZ, so it is unlikely that J147 impeded the acute diabetogenic properties of STZ. Curcumin has been reported to enhance beta cell function (Hu et al, 2015) and it is plausible that J147 also enhanced the function of residual beta cells. Indeed, plasma insulin levels at death were elevated in J147-treated diabetic mice, albeit not statistically significantly.…”

The Essential Medicinal Chemistry of Curcumin

“…35 In concert with this boom in nutraceutical applications of curcumin, DSHEA (Dietary Supplement Health and Education Act) legislation establishing the legalities of dietary supplements in the United States (1994) and advents in in vitro testing likely contributed significantly to a sharp upturn in the publication of manuscripts regarding the use of curcumin in biological studies in the late 1990s (Figure 2). Since that time, curcumin has been reported to have activity for the following indications: anti-inflammatory, anti-HIV, antibacterial, antifungal, nematocidal, antiparasitic, antimutagenic, antidiabetic, antifibrinogenic, radioprotective, wound healing, lipid lowering, antispasmodic, 36 antioxidant, 37 immunomodulating, anticarcinogenic, 38 and Alzheimer’s disease, 39 among others. In many scientific and medicinal circles, these reported effects of curcumin have marked it as a source of future breakthrough therapeutics for complex diseases that are thought to require potent but nonselective therapeutics.…”

Curcumin Modulates Molecular Chaperones and Autophagy-Lysosomal Pathways In Vitro after Exposure to Aβ42

“…The SLCP has greater cellular permeability and neuro protection as described previously [26,33,34]. Therefore, to compare the HSPs response, we treated the N2a cells with 1 μM of Cur and or SLCP for 24 h after exposed with Aβ42 (10 μM).…”

“…However, recently, a solid lipid Cur particles (SLCP) formulation has been shown to increase its solubility, stability and bioavailability [22,26,32,33].This SLCP formula (also known as Longvida) is considered one of the most promising strategies for restoration and up regulation of several synaptic markers and maintenance of protein degradation pathways in transgenic mouse models of AD [11,22,26,28,33]. This formulation can penetrate 65 times greater into the brain tissue and can bind to Aβ plaques more effectively than dietary Cur, a finding that may lead to mitigating the deleterious effects of Aβ and p-tau aggregates in AD [22,26,33]. Given this, the present study was designed to investigate whether dietary Cur, THC and/or SLCP can affect molecular chaperones, ALPs, on neuronal cell lines which have been exposed to Aβ42.…”