Metal ions, Alzheimer's disease and chelation therapy

Abstract

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease, clinically characterized by memory and cognitive dysfunctions. It is primarily a disease of old age (1) and is the most prevalent cause of dementia in elderly people (2). AD affects about 35 million people worldwide today (3) and it is estimated to nearly double every 20 years, to reach 66 million in 2030, and 115 million in 2050 (3). There is no known cause and no cure for AD and these numbers makes finding a cure or rational treatment for AD an urgent priority. Despite significant advances in understanding the neuropathological and neurochemical events taking place in AD, the etiopathogenesis of progressive and mental cognitive dysfunction associated with aging remains largely unclear.Pathologically, AD is characterized by neuronal degeneration. The brains of AD patients are mainly characterized by extracellular proteic (or neuritic) deposits (amyloid or senile plaques) surrounded by dystrophic neuritic and intracellular neurofibrillary tangles (NFT) (4). The plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behavior such as the entorhinal cortex, hippocam- In the last few years, various studies have been providing evidence that metal ions are critically involved in the pathogenesis of major neurological diseases (Alzheimer, Parkinson). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. Neurodegeneration is an excellent target for exploiting the metal chelator approach to therapeutics. In contrast to the direct chelation approach in metal ion overload disorders, in neurodegeneration the goal seems to be a better and subtle modulation of metal ion homeostasis, aimed at restoring ionic balance. Thus, moderate chelators able to coordinate deleterious metals without disturbing metal homeostasis are needed. To date, several chelating agents have been investigated for their potential to treat neurodegeneration, and a series of 8-hydroxyquinoline analogues showed the greatest potential for the treatment of neurodegenerative diseases.

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…Chelators are widely investigated because of their therapeutic potential in the treatment of metal overload and diseases related to imbalanced metal homeostasis including hemochromatosis, β-thalassemia, Alzheimer's or Parkinson's diseases and cancer [8,9,12,70].…”

Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease

“…Rats were given general anaesthesia (chloral hydrate 300 mg/kg, ip), followed by injection of streptozotocin 1 mg /kg (single dose) or 3 mg/kg (split in two doses on day 1 and 3) administered bilaterally into the left and right lateral ventricle as previously described (Grünblatt et al 2007;Salkovic-Petrisic et al 2006, 2011. Drug concentration and solution volume were adjusted according to the animal body weight, and a volume of 4 μL per 300 g body weight was administered (2 μL/ventricle).…”

“…Considering the involvement of iron accumulation in AD pathophysiology (Grünblatt et al 2010;Honda et al 2004), metal chelation has become one of the therapeutic strategies for the treatment of AD (Budimir 2011). Deferoxamine (DFO), the natural prototype iron chelator/radical scavenger slowed the clinical progression of AD dementia (Crapper et al 1991) and inhibited amyloidogenic processing of amyloid precursor protein (APP) and reversed iron-induced memory deficits and tau phosphorylation in mice model of AD (Guo et al 2013a,b).…”

“…Animal model which develops insulin resistant brain state and glucose hypometabolism following the intracerebroventricular application of a betacytotoxic drug streptozotocin in small rodents and cynomolgus monkey (STZ-icv model), (Agrawal et al 2011;Grünblatt et al 2007;Lannert and Hoyer 1998;Lee et al 2014;Lester-Coll et al 2006;Plaschke and Hoyer 1993;Salkovic-Petrisic et al 2006), shares similarities with the human sAD condition (Lannert and Hoyer 1998) since insulin resistant brain state was found postmortem in sAD patients (Correia et al 2011;de la Monte and Wands 2005;Frölich et al 1998). Additionally, STZ-icv model demonstrates also cognitive deficits (Mayer et al 1990;Lannert and Hoyer 1998) and decrement in cerebral cholinergic transmission (Blokland and Jolles 1993;Hellweg et al 1992), as well as other features of chronic neurodegeneration like oxidative stress and neuroinflammation (Saxena et al 2011;Sharma and Gupta 2001) and in particular tau protein hyperphosphorylation (Grünblatt et al 2007;Deng et al 2009;Liu et al 2014;Peng et al 2013), pathological Aβ accumulation (Shingo et al 2013) and cerebral amyloid angiopathy (Salkovic-Petrisic et al 2006, 2011.…”

Calculation of Solubility of Oxyquinolinates

“…In conclusion, metal ions play a very important role in biological processes, and metal homeostasis is required for the maintenance of metal balance [20] [21]. Many diseases arise from the loss of homeostasis including metal overload and deficiency, which are caused by abnormal metal metabolism or metal absorption.…”