Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer's disease: Limitations, and current and future perspectives.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of cognitive impairment and dementia worldwide. The pathobiology of the disease has been studied in the form of several hypotheses, ranging from oxidative stress, amyloid-beta (Aß) aggregation, accumulation of tau forming neurofibrillary tangles (NFT) through metal dysregulation and homeostasis, dysfunction of the cholinergic system, and to inflammatory and autophagic mechanism. However, none of these hypotheses has led to confirmed diagnostics or approved cure for the disease. OBJECTIVE: This review is aimed as a basic and an encyclopedic short course into metals in AD and discusses the advances in chelation strategies and developments adopted in the treatment of the disease. Since there is accumulating evidence of the role of both biometal dyshomeostasis (iron (Fe), copper (Cu), and zinc (Zn)) and metal-amyloid interactions that lead to the pathogenesis of AD, this review focuses on unraveling therapeutic chelation strategies that have been considered in the treatment of the disease, aiming to sequester free and protein-bound metal ions and reducing cerebral metal burden. Promising compounds possessing chemically modified moieties evolving as multi-target ligands used as anti-AD drug candidates are also covered. RESULTS AND CONCLUSION: Several multidirectional and multifaceted studies on metal chelation therapeutics show the need for improved synthesis, screening, and analysis of compounds to be able to effectively present chelating anti-AD drugs. Most drug candidates studied have limitations in their physicochemical properties; some enhance redistribution of metal ions, while others indirectly activate signaling pathways in AD. The metal chelation process in vivo still needs to be established and the design of potential anti-AD compounds that bi-functionally sequester metal ions as well as inhibit the Aß aggregation by competing with the metal ions and reducing metal-induced oxidative damage and neurotoxicity may signal a bright end in chelation-based therapeutics of AD.

Luteolin-Supplemented diets ameliorates Bisphenol A-Induced toxicity in Drosophila melanogaster.

Bisphenol A (BPA) is an industrial chemical used in the production of various plastic materials. It is associated with reproductive, immunological and neurological disorders. Luteolin, a flavonoid found in fruits and vegetables, possesses anti-oxidative, anti-inflammatory and free radical scavenging properties. Here, we carried out studies to ascertain if Luteolin would ameliorate BPA-induced toxicity in Drosophila melanogaster. Firstly, flies were treated separately with Luteolin (0, 50, 100, 150 and 300 mg/kg diet) and BPA (0, 0.01, 0.05 and 0.1 mM) for 28 days survival assessments. Consequently, Luteolin (150 and 300 mg/kg diet) and/or BPA (0.05 mM) were exposed to D. melanogaster for 7 days for the evaluation of nitric oxide level, eclosion rate, viability assay, histology of fat body, antioxidant (Glutathione-S-transferase, catalase and total thiol), oxidative stress (hydrogen peroxide) and behavioural (negative geotaxis and acetylcholinesterase) markers. The results showed that BPA induced antioxidant-oxidative stress imbalance and behavioural deficit in flies. Luteolin increased survival rate and augmented antioxidant markers in flies. Importantly, Luteolin ameliorated BPA-induced degeneration in the fat body around the rostral, thorax and abdominal regions, oxidative stress, behavioural deficit, reduction in cell viability and eclosion rate of D. melanogaster (p < 0.05). Overall, this study offered further insights on the antioxidative and chemopreventive properties of Luteolin against BPA-induced toxicity.