**6. Appendix**

3HAA3-hydroxyanthranilic acid 4-HNE4-hydroxynonenal Aβ Beta amyloid ADAlzheimer's disease ALSAmyotrophic lateral sclerosis BBBBlood-brain barrier

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is a quinoline metal chelator that binds selectively to zinc and copper ions (Cherny *et al.* 2001). Having a hydrophobic nature, it crosses the BBB easily. Recent research with clioquinol in neurological disorders contributed by an imbalance in metal ions has led to promising results, presenting the possibility of a new therapeutic strategy. In AD transgenic mice, treatment with clioquinol resulted in the dissolution of aberrant neocortex beta amyloid (Aβ) aggregates, which are enriched with copper and zinc ions (Cherny *et al.* 2001). In a pilot phase II clinical trial, the drug was well tolerated and led to a significant decrease in Aβ plasma levels in AD patients, providing support for future trials (Ritchie *et al.* 2003). In PD, elevated levels of iron in the substantia nigra, the brain region affected in PD, has been reported. In mice, oral administration of clioquinol antagonized the action of the Parkinson's inducing agent 1-methyl-4-phenyl-1,2,3,6-tetra-pyridine (MPTP) (Kaur *et al.* 2003). In HD, where iron, copper and zinc have been implicated, clioquinol improved the symptoms and lifespan of transgenic HD mice

A second generation 8-hydroxyquinoline, PBT2, has been developed to improve the safety and efficacy of clioquinol and also its pharmaceutical properties, such as solubility and bioavailability. In preclinical *in vivo* and *in vitro* trials on transgenic AD mice, PBT2 was more effective in lowering plaque formation and reducing plaque toxicity. More

The current consensus is that ALS is a multifactorial disease. However, an explanation for the initiation of the putative causative mechanism of ALS remains elusive, and there lacks a hypothesis that can link all the mechanisms together. In recent years, the implication of the kynurenine pathway in multiple diseases, particularly neurodegenerative diseases, has led to an increase in assessing the efficacy of drugs targeting the kynurenine pathway in

The kynurenine pathway has been demonstrated to be involved in ALS and this provides an important link that ties together some of the major hypotheses underlying the pathogenesis of ALS, namely glutamate excitotoxicity, oxidative stress, non-cell-autonomous mechanism and apoptosis, which are also the major mechanisms via which QUIN exerts its neurotoxicity effects. Due to the multiple pathways involved in the pathogenesis and progression of ALS, it may be speculated that a combination therapy could be more efficacious. Hence, by targeting the kynurenine pathway, it is hoped that more effective therapeutic agents, acting in synergy with other agents, may uncover a better treatment for

ameliorating disease symptoms and/or retarding disease progression.

**4.8 Clioquinol** 

(Nguyen *et al.* 2005).

**5. Conclusion** 

ALS.

**6. Appendix** 

Aβ Beta amyloid ADAlzheimer's disease

BBBBlood-brain barrier

3HAA3-hydroxyanthranilic acid 4-HNE4-hydroxynonenal

ALSAmyotrophic lateral sclerosis

importantly, it may also improve cognition.

CNSCentral nervous system CSFCerebrospinal fluid D-1-MTD-1-methyl-tryptophan EAEExperimental autoimmune encephalomyelitis GCN2General control non-derepressible-2 kinase GTPGuanosine triphosphate HDHuntington's disease HIVHuman immunodeficiency virus IDOIndoleamine 2,3-dioxygenase IFN-γInterferon gamma ILInterleukin KMOKynurenine 3-monooxygenase KYNKynurenine KYNAKynurenic acid MCPMonocyte chemoattractant protein MIPMacrophage inflammatory protein MPTPMethyl-4-phenyl-1,2,3,6-tetra-pyridine mRNAMessenger ribonucleic acid NF-κBNuclear factor *kappa*-light-chain-enhancer of activated *B* cells NMDA*N*-methyl *D*-aspartate NRNMDA receptor PICPicolinic acid QUINQuinolinic acid ROSReactive oxygen species SOD1Superoxide dismutase 1 TDOTryptophan 2,3-dioxygenase TGF-βtransforming growth factor β TRPTryptophan

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**Part 3** 

**Cellular Pathophysiology,** 

**the Immune System and Stem Cell Strategies** 

