Chelation and Neurodegenerative Diseases: Nanoparticles as Proof of Concept
The notion that iron dyshomeostasis contributes to the pathogenesis of a number of neurodegenerative disorders, now including amyotrophic lateral sclerosis (Jeong et al., 2009), is well established (Castellani et al., 1995; Smith et al., 1997; Castellani et al., 2000; Sayre et al., 2000; Petersen et al., 2005; Smith, 2006). In parallel, changes in a number of iron homeostasis proteins are also altered, including heme oxygenase-1 (Smith et al., 1994; Schipper et al., 1995), ferritin (Connor et al., 1992), and iron regulatory proteins (Connor et al., 1992; Smith et al., 1998).

While clinical trials in neurodegenerative diseases using chelation therapy have been limited, such an approach has shown promise (McLachlan et al., 1993). Unfortunately, limited blood-brain barrier permeability and/or cytotoxicity with resultant side effects have limited the interpretation of...  Read more

Chelation and Neurodegenerative Diseases: Nanoparticles as Proof of Concept
The notion that iron dyshomeostasis contributes to the pathogenesis of a number of neurodegenerative disorders, now including amyotrophic lateral sclerosis (Jeong et al., 2009), is well established (Castellani et al., 1995; Smith et al., 1997; Castellani et al., 2000; Sayre et al., 2000; Petersen et al., 2005; Smith, 2006). In parallel, changes in a number of iron homeostasis proteins are also altered, including heme oxygenase-1 (Smith et al., 1994; Schipper et al., 1995), ferritin (Connor et al., 1992), and iron regulatory proteins (Connor et al., 1992; Smith et al., 1998).

While clinical trials in neurodegenerative diseases using chelation therapy have been limited, such an approach has shown promise (McLachlan et al., 1993). Unfortunately, limited blood-brain barrier permeability and/or cytotoxicity with resultant side effects have limited the interpretation of such trials. In contrast to existing chelators, we recently developed a novel nanoparticle-chelator conjugate that shows potential for allowing free passage into and out of the brain without changing chelation properties (Liu et al., 2005; Liu et al., 2006; Liu et al., 2009). While still at a preclinical stage of development, the utility of such nanoparticle conjugates obviously merits serious consideration for future clinical trials to evaluate the potential of this strategy for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis.

References:
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Castellani RJ, Siedlak SL, Perry G, Smith MA (2000) Sequestration of iron by Lewy bodies in Parkinson's disease. Acta Neuropathol (Berl) 100(2): 111-4. Abstract

Connor JR, Menzies SL, St Martin SM, Mufson EJ (1992) A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains. J Neurosci Res 31(1): 75-83. Abstract

Connor JR, Snyder BS, Beard JL, Fine RE, Mufson EJ (1992) Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer's disease. J Neurosci Res 31(2): 327-35. Abstract

Jeong SY, Rathore KI, Schulz K, Ponka P, Arosio P, David S (2009) Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci 29(3): 610-9. Abstract

Liu G, Garrett MR, Men P, Zhu X, Perry G, Smith MA (2005) Nanoparticle and other metal chelation therapeutics in Alzheimer disease. Biochim Biophys Acta 1741(3): 246-52. Abstract

Liu G, Men P, Harris PL, Rolston RK, Perry G, Smith MA (2006) Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance. Neurosci Lett 406(3): 189-93. Abstract

Liu G, Men P, Perry G, Smith MA (2009) Metal chelators coupled with nanoparticles as potential therapeutic agents for Alzheimer’s disease. J Nanoneurosci 1: 42-55.

McLachlan DR, Smith WL, Kruck TP (1993) Desferrioxamine and Alzheimer's disease: video home behavior assessment of clinical course and measures of brain aluminum. Ther Drug Monit 15(6): 602-7. Abstract

Petersen RB, Siedlak SL, Lee HG, Kim YS, Nunomura A, Tagliavini F, Ghetti B, Cras P, Moreira PI, Castellani RJ, Guentchev M, Budka H, Ironside JW, Gambetti P, Smith MA, Perry G (2005) Redox metals and oxidative abnormalities in human prion diseases. Acta Neuropathol 110(3): 232-8. Abstract

Sayre LM, Perry G, Harris PL, Liu Y, Schubert KA, Smith MA (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. J Neurochem 74(1): 270-9. Abstract

Schipper HM, Cisse S, Stopa EG (1995) Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain. Ann Neurol 37(6): 758-68. Abstract

Smith MA (2006) Oxidative stress and iron imbalance in Alzheimer disease: how rust became the fuss! J Alzheimers Dis 9(3 Suppl): 305-8. Abstract

Smith MA, Harris PL, Sayre LM, Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A 94(18): 9866-8. Abstract

Smith MA, Kutty RK, Richey PL, Yan SD, Stern D, Chader GJ, Wiggert B, Petersen RB, Perry G (1994) Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease. Am J Pathol 145(1): 42-7. Abstract

Smith MA, Wehr K, Harris PL, Siedlak SL, Connor JR, Perry G (1998) Abnormal localization of iron regulatory protein in Alzheimer's disease. Brain Res 788(1-2): 232-6. Abstract

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