As discussed previously, it has been shown that dyshomeostasis of the redox-active metals and oxidative stress are intimately associated, contributing to the neuropathology of AD. Using an in situ detection system, we showed that NFT and senile plaques are major sites for catalytic redox reactivity. Pretreatment with DFO or diethylenetriaminepentaacetic acid abolished the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions (Smith et al., 1997; Sayre et al., 2000). Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Our findings suggest that NFT and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment. Savory and others performed a study aimed to determine an optimal DFO treatment protocol in an animal model exhibiting Alzheimer's-like intraneuronal protein aggregates (Savory, Huang, Wills, & Herman, 1998). New Zealand white rabbits were injected intracisternally with either aluminum maltolate or with saline on day 0. Intramuscular injections of DFO were given to selected rabbits for 2 days before sacrifice on days 4, 6, or 8. Bielschowsky's silver impregnation demonstrated widespread neurofibrillary degeneration (NFD) in neuronal cell bodies and neurites of brain and spinal cord from aluminum-treated rabbits. The authors observed that DFO treatment was capable to reverse tau aggregation after 2 days of treatment. McLachlan and collaborators performed a 2-year, single-blind study aimed to investigate whether the progression of dementia could be slowed by DFO (McLachlan, Smith, & Kruck, 1993). In this study, 48 patients with probable AD were randomly assigned to receive DFO (125 mg intramuscularly twice daily, 5 days per week, for 24 months), oral placebo (lecithin), or no treatment. Analysis showed that the treatment and no-treatment groups were closely matched at entry into the trial but that the rate of decline, as measured over 2 years of observation, was twice as rapid in the no-treatment group compared with the DFO-treated group. Furthermore, trace-metal analysis of autopsied brain confirmed that extended treatment with DFO lowered neocortical brain aluminum concentrations to near control concentrations. The authors concluded that the administration of DFO may slow the clinical progression of dementia associated with AD. However, it must be noted that this drug has high affinity also for zinc, copper, and iron and the levels of these metals were not evaluated. The administration of DFO is associated with several difficulties including systemic metal-ion depletion and the fact that DFO is a charged molecule that does not easily penetrate the blood-brain barrier and is rapidly metabolized (May & Bulman, 1983).
Clioquinol, a 8-hydroxyquinoline derivative, is producing very encouraging results in the treatment of AD. Its biological effects are most likely ascribed to complexation of specific metal ions, such as Cu(II) and Zn(II), critically associated with protein aggregation and degeneration processes in the brain. Cherny et al. (2001) reported a 49% decrease in brain Ap deposition in a blinded study of APPP2576 transgenic mice treated orally for 9 weeks with clioquinol. This was accompanied by a modest increase in soluble Ap and ApPP while synaptophysin and GFAP levels remained unaffected. Recently, Ritchie et al. (2003) developed a pilot phase II clinical trial where 36 patients with moderately severe AD were treated with clioquinol. The effect of treatment was significant in the more severely affected group due to a substantial worsening of scores in those taking placebo compared with minimal deterioration for the clioquinol group. Plasma Ap42 levels declined in the clioquinol group and increased in the placebo group. Plasma zinc levels rose in the clioquinol-treated group.
Recently, a novel system of chelation therapy through the use of nanoparticles has been proposed (Liu et al., 2005). Nanoparticles conjugated to chelators show the ability to cross the blood-brain barrier, chelate metals, and exit through the blood-brain barrier with their corresponding complexed metal ions. The authors suggest that this method may prove to be a safe and effective means of reducing the metal load in neural tissue thus staving off the harmful effects of oxidative damage and its sequelae (Liu et al., 2005). However, clinical studies based in larger sample sizes and longer study periods should be performed.
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