Deferoxamine and Curcumin Loaded Nanocarriers Protect Against Rotenone-Induced Neurotoxicity

Abstract

Introduction: Reduced glutathione and excess free iron within dopaminergic, substantia nigra neurons in Parkinson's disease (PD) can drive accumulation of toxic hydroxyl radicals resulting in sustained oxidative stress and cellular damage. Factors such as brain penetrance and bioavailability have limited the advancement of potential antioxidant and iron chelator therapies for PD. Objective: This study aimed to develop novel nanocarrier delivery systems for the antioxidant curcumin and/or iron chelator deferoxamine (DFO) to protect against rotenoneinduced changes in cell viability and oxidative stress in SH-SY5Y cells. Method: Nanocarriers of curcumin and/or DFO were prepared using Pluronic F68 (P68) with or without dequilinium (DQA) by modified thin-film hydration. Cell viability was assessed using an MTT assay and oxidative stress was measured using Thiobarbituric acid reactive substances (TBARS) and cellular antioxidant activity (CAA) assays. Results: All formulations demonstrated high encapsulation efficiency (65-96%) and nanocarrier size was <200nm. 3h-pretreatment with P68 or P68+DQA nanocarriers containing various concentrations of curcumin and/or DFO significantly protected against rotenone-reduced cell viability. The addition of DFO to curcumin-loaded P68+DQA nanocarriers resulted in increased protection by at least 10%. All nanoformulations significantly protected against rotenone-induced lipid peroxidation (p < 0.0001). The addition of DQA, which targets mitochondria, resulted in up to 65% increase in cellular antioxidant activity. In nearly all preparations, the combination of 10uM curcumin and 100uM DFO had the most antioxidant activity. Conclusion: This study demonstrates for the first time the formulation and delivery using P68 and P68+DQA curcumin and/or DFO nanocarriers to protect against oxidative stress induced by a rotenone PD model. This strategy to combine antioxidants with iron chelators may provide a novel approach to fully utilise their therapeutic benefit for PD.

Co-Administration of Iron and a Bioavailable Curcumin Supplement Increases Serum BDNF Levels in Healthy Adults

“…Compared to conventional curcumin, Briskey et al [58] showed that a formulated curcumin form resulted in significantly greater increases in total plasma curcuminoid concentration in a human volunteer study. Furthermore, formulated curcumin has been shown to be more likely to cross the blood-brain barrier [44,54,85] and express neuroprotective effects due to improved bioavailability and targeted delivery, in both cellular and murine studies [44,85,86]. This could therefore explain how the addition of curcumin to iron supplementation consistently resulted in increased BDNF levels in the current study.…”

“…Curcumin, a non-flavonoid polyphenol, is the most biologically active antioxidant component in the rhizomatous spice Curcuma longa Linnaeus (L.) or turmeric [42]. Curcumin is a pleiotropic compound with wide ranging beneficial properties including antioxidative, anti-inflammatory and neuroprotective effects [43,44]. Curcumin and its analogue curcuminoids, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), can exist in two different forms depending on their environment; keto and enol [45].…”

“…It acts as a free-radical chain breaker, capable of donating hydrogen to ROS due to the presence of a hydroxyl group in its structure [51]. Furthermore, studies examining the neuroprotective properties of curcumin have shown that it has potential as a treatment for neurological disorders, such as depression, bipolar disorders and neurodegenerative diseases [44,52]. Since curcumin is lipophilic in nature, it is assumed to be able to cross the BBB [53].…”

“…The pharmacological use of curcumin has therefore been limited due to its poor bioavailability, limited bio-distribution, poor stability and short half-life [55]. Formulation science strategies have shown that nanocarrier delivery systems such as liposomes and micelles may address these limitations and enhance curcumin's therapeutic potential [44,56,57]. A recent study by Briskey and colleagues [58] demonstrated that formulation of curcumin using a novel delivery system comprising a mixture of surfactants, polar lipids and solvents (known as LipiSperse ® ) significantly increases the plasma concentration of curcumin in human volunteers, further highlighting the application of delivery systems to increase the bioavailability of poorly absorbed molecules.…”

Enhanced accumulation of reduced glutathione by Scopoletin improves survivability of dopaminergic neurons in Parkinson’s model

“…A large number of antioxidant based strategies focusing on ascorbic acid, deferoxamine, cucurmin etc has been investigated for management of the PD symptoms but without any translatable benefits 47,48 ; thus requiring elucidation of better alternatives with robust antioxidant capabilities to promote neuronal health in PD. Natural derivatives have been increasingly appreciated for their potency in prevention and management of neurodegenerative diseases 35,49,50 .…”