7. Therapeutic strategies

At the present time, the treatment of each of these neurological diseases relies almost exclusively on therapeutic agents that merely treat the pathology of each of the diseases rather than their etiology. Apart from drugs to increase or diminish abnormal levels of neurotransmitters, there is an overwhelming requirements for better therapeutic approaches. However until the exact etiology of each of these pathologies is identified, such therapeutic approaches will remain the only option.

One of the main features of PD is the increase of iron in the substantia nigra and corpus pallidium. Its removal may therefore be of importance in preventing the toxicity of such iron. The use of desferrioxamine in the treatment of PD patients has not been advocated, since subcutaneous administration is required, and chelation therapy is not usually given in patients with reputed normal iron status. Therefore at this time there is an urgent requirement for the development of new orally bioactive chelating agents. The new orally active tridendate iron chelator, ICL670, which is used in the treatment of thalassaemia patients, may be a potential therapeutic agent for PD patients. Extensive studies will be needed to ensure that iron is removed from specific brain areas and that the iron-chelated complex is not redistributed to other brain regions. Molecules which have iron chelating properties as well as other beneficial effects include R-apomorphine, VK-28, (5-[4-hydroxyethyl) piperazine-1-ylmethyl]-quiniline-8-ol) and the flavenoid polyphenols, e.g. (-)-epigallocatechin-3-gallate, in green tea, Figure 14. As yet, no clinical studies have commenced on the ability of these compounds to remove iron specifically from the SN in the brains of PD patients.

Oxidative stress has been put forward as one of the major causes of the nigral degeneration, such that its amelioration may retard the progression of the disease.  An active inflammatory process will occur, with the induction of the transcription factor NFκappaB and of iNOS in brain glial cells. Increased CSF nitrite content was assayed in both untreated and treated PD patients by comparison to controls, while an increased NO signal in SN of PD patients was detectable by ESR in post mortem samples.. Such increases in NO may have detrimental effects on a number of mitochondrial and cytosolic enzymes. Drugs which inhibit nNOS (7-nitroindazole) and iNOS (ginsenoside, one of the biological active ingredients of ginseng) may help to prevent the destruction of dopaminergic neurons.

Non steroidal drugs, such as ibuprofen and aspirin, will primarily inhibit COX-1 (which is present in activated microglia) and COX-2, the rate limiting enzymes in prostaglandin synthesis and thereby inflammation. Whereas COX1 is constitutively expressed in most mammalian tissues, COX-2 is only expressed in certain tissues in response to inflammatory stimuli and is hence responsible for the elevated levels of prostaglandins found in inflammation. It therefore plays a role in the pathogenesis and selectivity of the PD neurodegenerative process. COX-2 inhibitors may be a useful adjunct therapy since they rapidly traverse the BBB. However, recent concern about their toxicity, via raised blood pressure and cardiovascular risks as well as changes in fatty acid synthesis, may preclude their use.

A range of cytoprotective enzymes are altered in the brains of PD patients. Our earlier studies failed to detect a reduction of α-tocopherol content in SN of PD thereby indicating that vitamin E supplementation may not yield any therapeutic advantages. Glutathione content is depleted within the SN dopaminergic neurons, such that its replenishment might be of therapeutic advantage, either by increasing the synthesis of this tripeptide or by slowing its degradation. Administration of precursors of GSH metabolism, such as γ-glutamyl cysteine, or cysteine precursors, or GSH analogues, e.g. YM737, able to traverse the blood brain barrier may be of potential interest for further studies in PD. The selegiline metabolite, (a monoamine oxidase inhibitor), desmethylselegiline, reduces apoptosis by altering gene expression of SOD, Bcl-1, Bcl-xl, NOS and cJun, thereby preventing the progressive reduction of mitochondrial membrane potential in preapoptopic neurons.

The removal of iron, copper and zinc from specific brain regions may prevent brain Aβ accumulation as well as disrupting preformed aggregates. In pre- and clinical trials, clioquinol, (an antibiotic and Zn/Cu chelator) induced a marked reduction of Aβ deposition in APP transgenic mice after several months of treatment, and a reduction of Aβ₄₂ concentration in a placebo controlled trial of AD patients with moderate to severe dementia. Recently, clioquinol was withdrawn from use in Japan because of concerns of its association with myelo-optic neuropathy. There have been no reports of the use of specific iron chelating compounds in the treatment of AD which might reduce both inflammation and Aβ formation.

Non-steroidal anti-inflammatory drugs, NSAIDs, such as indomethacin, attenuate inflammatory reactions and protect against nerve cell death that results from the generation of free radicals. Many different NSAIDs have Alzheimer's-protective effects and will reduce the generation of free radicals from activated microglial cells. Some NSAIDs, ibuprofen, indomethacin, and sulindac sulphide, can lower toxic Aβ levels by as much as 80%, independently of the inhibition of cyclooxygenase (COX) activity with a preferential increase of Aβ₃₈. The latter effect is possibly due to alterations in the activity of α and β secretase.

Chloroquine, the anti-malarial drug reduces the inflammatory stimuli by decreasing both tissue iron content and down-regulating NFκappaB activation in rat macrophages. However, a double blind parallel group multicentre trial of hydroxychloroquine for 18 months, did not slow the rate of decline in minimal or mild AD and showed no advantage, by comparison to placebo, with respect to quality of life and cognitive assessment.

We hope that in this brief review we have substantiated the hypothesis that certain metals play an important role in a number of neurodegenerative diseases, a) by generating metal-based oxidative stress, b) inducing oxidative damage c) particularly to specific proteins which d) lead to their misfolding and aggregation which e) prevents their removal by the cytosolic proteosomal system such that f) protein aggregates which are rich in β-pleated sheets are deposited. These  are the hallmarks of different neurodegenerative diseases Figure 15.  It is of vital importance that progress can be made in our understanding of the molecular basis of these neurodegenerative disease such that treatments may become available to both treat and ultimately prevent the progress of neurodegeneration. The increasing longevity of the population, particularly in the Western World, in part due to the  major advances that have been made in preventing and treating many maladies including cardiovascular disease and cancer, means that we are all at risk of this advancing, unseen and undetectable changes in our brain physiology and function.