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Timothy Woodward

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Discuss the drug treatment of the neurodegenerative disorders
The three major neurodegenerative diseases that will be discussed in this essay are Alzheimer’s, Parkinson’s and Huntington’s. Since all three diseases cause neuronal death, and neurons are unable to regenerate, one would imagine that drugs are of limited usefulness, at least until the underlying pathological processes are understood better. This is true to an extent: the only one of these diseases for which we currently possess useful drugs is Parkinson’s, and even then drugs such as L-DOPA are far from perfect. The initial pathogenesis for each of the diseases is distinct, and will be discussed separately. In all three cases, however, there are common mechanisms for neuronal death, some of which were discussed in the earlier essay on glutamate. For example, necrosis, and to some extent apoptosis are important mechanisms. Excitotoxicity, caused by glutamate, plays an important role, as does oxidative stress. Genetics has thrown new light onto these three diseases (Huntington’s is an autosomal dominant disorder, and single gene mutations can alter susceptibility to the other two diseases), and has allowed us to elucidate some of the pathways responsible for these diseases. 90% of the neurodegenerative disorders are linked to abnormalities in tau protein, alpha synuclein and beta amyloid protein (Cummings 2003). For example, patients with abnormalities in tau are prone to disinhibition and apathy, and may exhibit compulsion, while those with alpha synuclein abnormalities may exhibit delusional disorders, and for example disorders with REM sleep. Alzheimer’s is unusual in that it involves all three, although the roles of tau and beta amyloid have been more traditionally recognised and researched. Alzheimer’s is associated with progressive memory loss, and refers to dementia that does not have an antecedent cause1, such as stroke, brain trauma or alcohol (Rang and Dale). There is loss of factual memory (oddly enough implicit memory is spared), decision making, judgement, future planning, and language. The brain shrinks (although there is some overlap between controls and Alzheimer’s patients), with great loss of cortex (can be beyond 40% of cells), with enlarged sulci and ventricles. There is thinning of the medial temporal lobe (A David Smith OPTIMA), probably due to neuronal cell death here. The cells most affected are the cholinergic neurons from the nucleus of Meynert, medial septum and diagonal band of Broca. There is also loss of glutamatergic neurons from entorhinal cortex and hippocampus. There are also a number of histological changes seen at post mortem. Unfortunately, current imaging techniques are insufficient to detect these before death, and so a diagnosis of Alzheimer’s can only be confirmed after death. There are two major histological abnormalities. Amyloid plaques are made up of 42nm amyloid β (Aβ) fibrils. These are extracellular deposition of insoluble amyloid proteins, surrounded by microglia, which seem to mount an ineffective inflammatory response. Neurofibrillary tangles are intracellular, made up of tau protein, a microtubule associated protein. These spread during the pathogenesis of Alzheimer’s (Braak and Braak).
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The link between Alzheimer’s disease and aluminium ions is very widely known, but I am not sure that the mechanism is well understood.

Timothy Woodward

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For a long time, the relation of these histological abnormalities to the pathogenesis of Alzheimer’s was a mystery. Now, however, there are some hypotheses. The Amyloid cascade hypothesis puts the amyloid plaques, and their β amyloid component, centre stage. There is an Amyloid precursor protein (APP) gene on chromosome 21, and this exists in a number of different isoforms. It is also variably spliced. Isoforms of this gene are linked with Alzheimer’s, suggesting an unusual form of APP could contribute to Alzheimer’s. APP is broken down by various secretases, in particular the α, β, and γ secretases. The α secretase cleaves within the region of the Aβ, thus preventing its formation. This is the “physiological” cleavage2. The product is then cleaved by the γ secretase, which tends to result in soluble 40nm fibrils. On the other hand, cleavage by the β secretase, followed by cleavage by the γ secretase, forms the insoluble 42 nm fibrils, linked to formation of the amyloid plaques. The diagram below shows some of the mutations in APP. Note that they tend to cluster near the cleavage sites, and so it is not inconceivable that they are serving to either inhibit cleavage by α secretase, or promoting cleavage by β or γ secretases. In addition to this, people with trisomy 21 (the major cause of Down’s syndrome) also succumb to early onset Alzheimer’s. In this case, there is a surplus of APP, rather than any abnormalities in its structure. It is worth pointing out that while diagrams such as the one below might seem to show causes of Alzheimer’s, but these mutations have been identified in maybe around 20 families worldwide. If there is a genetic basis for Alzheimer’s, then it is polygenic in most cases. What a diagram like the one below is useful for, however, is indicating which protein products we should be looking at to better understand the pathogenesis.

The next diagram shows some of the other genes that have been linked with Alzheimer’s. Directly related to the APP “story” are the presenilin 1 and 2 genes, on chromosomes 14 and 1 respectively. These two genes seem to increase the activity of
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Although our knowledge of this is so limited that one has to be careful of using such terms. It could well be that β secretase action is also physiological, but we just don’t understand its function very well.

Timothy Woodward

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γ secretases. Apoε4 is a gene linked to chromosome 19, which enhances the risk of Alzheimer’s3, possibly by enhancing the aggregation of Aβ into plaques. Of the other alleles, Apoε2 decreases the risk of Alzheimer’s disease, whilst Apoε3 gives the normal risk of Alzheimer’s. I am not entirely sure about the completeness of this hypothesis of the mechanism of Apoε4, however. It is a general risk factor for a number of neurodegenerative diseases, and there is therefore a question of how specific, or otherwise, its effect might be. For example, Tsuang et al., 2005, found that Apoε4 increased the probability of Alzheimer’s patients presenting with Lewy bodies (post mortem), even though these are more commonly associated with Parkinson’s disease. Perhaps the Apoε4 gene is involved with a less effective cellular response to inflammation or oxidative insult, making necrosis more insult. In keeping with this idea, alpha 2 macroglobulin, shown on the diagram below, is an inflammatory protein. Other genes shown on the diagram include the gene for insulin degrading enzyme (at AD6), which can degrade beta amyloid amongst other things, and an inhibitor of cysteine proteases, which is found with APP in the brains of patients who have died of Alzheimer’s disease.

The exact mechanism by which the amyloid plaques cause the neuronal death is also disputed. There is some evidence that the cells die by apoptosis, although there is also an inflammatory response (Rang and Dale). In mouse models (although in general mice do not get Alzheimer’s, and the models are difficult to generate and therefore limited in their usefulness), deposition of plaques has suggested reduced tolerance to neuroexcitotoxicity and oxidative stress. Walsh et al. suggested that the plaque proteins themselves are inherently neurotoxic. This may be so, but experiments have shown that the severity of Alzheimer’s is not linked to the number of plaques, but rather to the total amount of soluble and insoluble amyloid protein. This tends to inhibit long term potentiation, thus explaining the memory loss.

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A recent, 2006, survey, Martins et al., also suggests that those with this allele develop Alzheimer’s at a younger age, and in them the disease develops more rapidly.

Timothy Woodward

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This amyloid-centric discussion may appear to be ignoring tau and the neural fibrillary tangles, and indeed for a time the field suffered from debate between the “βaptists” and the “tau-ists”! It now seems, however, that the amyloid hypothesis can be used to explain the deposition of tau. This a normal protein, associated with microtubules, since it initiates the polymerisation of tubulin to give microtubules. It disassociated and is deposited in many different neurodegenerative disorders, leading to microtubule instability. The free tau can be hyperphosphorylated, and Busciglio demonstrated that this process is induced by β amyloid fibrils, thus providing a causative link between the two4. They then aggregate to form paired helical filaments, which lead to tangles. Given the central role of this pathogenic process, the failure of drugs acting on it is rather surprising. An example are the secretase inhibitors. Inhibition of β or γ secretases would in theory be a good idea. Alternatively, increasing the activity of the α secretase is a theoretical idea, as is giving something to break down the amyloid plaques once they have formed. But these drugs either aren’t being developed (alpha secretase inhibitors) or don’t seem to work (beta and gamma secretase inhibitors). Indeed, beta secretase is also found in the pancreas, while gamma secretase might have other functions since it is not a very selective enzyme, and so these methods could have side effects5. Vaccination against Aβ protein was tried by Schenk, 1999. It works in mice, but clinical trials were halted when a few patients developed CNS inflammation. One recent experiment in mice (Singer et al. 2005) has used RNAi (injection of dsRNA seems to inhibit expression of the normal RNA: an effect first identified in petunias but slowly being applied to mammals as well) to inhibit expression of the beta secretase gene. They used a lentivirus to deliver the RNAi. And inhibition of this enzyme caused a reversal of the pathogenesis. Thus, in spite of amyloidosis already occurring, the pathogenesis actually reversed, which has exciting implications for curing (i.e. undoing damage already done) the disease, at least in the distant future. One realisation that tempers this optimism is that mouse models are not always very accurate (cf. the vaccination). The direct inhibition of this axis has so far failed to yield results, but other approaches that seek to counter the neurodegeneration have also received attention. There is an increasing body of evidence that Alzheimer’s disease is due in part to inflammation, for example the increase in concentration of acute phase proteins in the blood of these patients, along with IL1, IL6 and TNFα6. The activity of COX2 is increased in the brains of those with Alzheimer’s disease. There is also increased expression of IL6 mRNA in the hippocampus, which correlates with the severity of the disease. Perhaps the inflammation is a response to the formation of the abnormal plaques, but still contributes to the pathogenesis, with the inflammation increasing the vulnerability of the cells to calcium entry and neuroexcitotoxicity? Some NSAID’s, when given to treat arthritis, seem to lower the risk of Alzheimer’s, although the picture is complicated by the fact that others do not. Celecoxib, a COX2 inhibitor, actually increases amyloid plaque number (Kukar et al., 2005)! It has been suggested that some of the NSAID’s have their anti-Alzheimer’s effects by inhibiting gamma
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This however cannot be the whole story since tau tangles can also occur independently of beta amyloid plaques. Indeed, instead of being phosphorylated, they can also bind to GAGs, aggregate, and form the same paired helical filaments. 5 Gamma secretase inhibitors also inhibit Notch receptors, which can have potentially lethal consequences. 6 Which actually has direct neurotoxic effects.

Timothy Woodward

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secretase, independently of their effects on COX2. Statins, on the other hand, also have an effect on lowering the probability of developing Alzheimer’s. Strangely enough, this probably occurs by their anti-inflammatory actions, in addition to their cholesterol lowering effect7. Several other agents also decrease the effects of neuroexcitotoxicity and oxidative stress on the neurons. For example, vitamin E, an antioxidant, combined with selegiline (a MAOB inhibitor typically associated with Parkinson’s, see below) has been shown to decrease neuronal degeneration. Unfortunately, vitamin E in high doses also causes disorders in blood coagulation. Second, the amyloid plaques can chelate metals such as zinc and copper, which causes them to release hydrogen peroxide, which can damage the neurons. Clioquinol is a metal chelating agent that inhibits this, and seems to cause regression of amyloid deposits. It is in clinical trials (Rang and Dale). Finally, memantine is an NMDA antagonist, which decreases the neuroexcitotoxicity via the NMDA receptor, and thus could have some usefulness in Alzheimer’s, particularly later on8. The therapies described above all to a greater or lesser extent attempt to treat the underlying pathology. Some seem more promising than others, but none is a standard treatment for Alzheimer’s. The standard clinical approach concentrates much more on treating the symptoms. As already mentioned, Alzheimer’s causes a relatively selective loss of cholinergic neurons in the basal forebrain, with a significant reduction in ChAT (choline acetyltransferase) activity here being seemingly symptomatic of the disease. Cholinesterase inhibitors are currently the only drugs clinically approved for the treatment of Alzheimer’s. The cholinesterase inhibitors include drugs such as tacrine, donepezil, rivastigmine and galanthamine. The use of tacrine in this country, however, has been abandoned since it was felt to have unacceptable hepatotoxic effects. Rivastigmine is claimed to be CNS selective, and thus have fewer side effects. Galanthamine, in addition to its anti-cholinesterase activity, also has nicotinic agonist effects, which might be helpful. There are however side effects with these drugs, including nausea, vomiting, diarrhoea, anorexia, dizziness and headache. There is a real question as to whether the quality of life is actually improved much by these drugs: with this in mind, NICE recently recommended not using these drugs in early stage Alzheimer’s. Since end stage Alzheimer’s will not be much affected by them either, this means that the current guidelines state that they are only to be used for middle stage disease. In the previous essay I commented on how attention on anti-depressant drugs has shifted from modulating NA and 5HT metabolism, to affecting the receptors directly.
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Cholesterol can increase formation of Aβ plaques. Thus, the polypill proposed as a prophylactic for heart disease (aspirin, statin, folic acid (also has anti-Alzheimer’s effects) and four anti-hypertensives), might have effects on Alzheimer’s, although I am not sure if anyone has done the study. There do seem to be links between lowering heart disease and lowering Alzheimer’s. For example, regular exercise decreases risk of both, while type II diabetes and increased blood homocysteine levels increase risk of both. Does this suggest that there might be any common mechanisms for the two diseases? Smoking also doubles the risk of Alzheimer’s for most people, except that it oddly has seems to have a protective effect in those who also have the Apoε4 gene. 8 Alzheimer’s patients show abnormality in glutamate synapses. One hypothesis is that this causes the rest of the neurodegeneration by causing neuroexcitotoxic effects on the cholinergic cells. But this would seem to ignore the genetic evidence of mutations in the plaque proteins contributing to Alzheimer’s.

Timothy Woodward

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This stage has not yet been achieved for treatment of the neurodegenerative disorders, however. The second generation neuro selective muscarinic agonists include milameline and xalomeline, and seem moderately effective9. The peripheral side effects have still, however, not been completely eliminated. There are no nicotinic agonists in clinical trials, apparently (Leonard, 2003), although these could presumably be quite useful. Parkinson’s disease is the second most common neurodegenerative disorder, after Alzheimer’s. It has the histological hallmark of the Lewy bodies, made up of alpha synuclein, and mentioned earlier. These occur in the substantia nigra, hypothalamus, hippocampus, autonomic ganglia and olfactory tracts. There is loss of dopaminergic neurons, particularly in the nigrostriatal pathway. This can probably be attributed to the usual mechanisms of excitotoxicity, oxidative stress, necrosis and apoptosis. Possibly the depositions, by mechanisms unknown, make dopaminergic neurons more susceptible to damage by these mechanisms, secondary to some environmental insult. The loss of dopamine was first identified by Hornykiewicz, and takes years to become apparent: there is upregulation and increased sensitivity of dopamine receptors in response to dopamine depletion, and symptoms only occur when dopamine levels have fallen by 40 to 50%. The indirect pathway (inhibitory) in the basal ganglia is particularly affected, leading to hypokinesia, suppression of voluntary movements, and postural ataxia. These are all motor defects: later on in the disease cognitive defects become apparent in about 30% of patients. Unsurprisingly, given this involvement of dopamine, the neuroleptics – dopamine2 receptor antagonists used to treat schizophrenia such as chlorpromazine – can cause parkinsonisms via D2 receptor blockade: there can be acute dystonias (involuntary movements, onset in first few weeks, decrease after that, in any case stop when treatment stopped, if not long before that). Interestingly, though unfortunately, tardive dyskinesia develops after years of therapy in 20 to 40% of all patients treated with classical neuroleptic drugs. This is a disabling and often irreversible condition involving involuntary movements of face, tongue, trunk and limbs, and persists even after treatment is stopped (Rang and Dale). This is oddly enough rather similar to the effects of L dopa therapy for Parkinson’s itself. Perhaps there is upregulation of the expression of D2 receptors, leading to increased inhibition of the indirect pathway, and thus involuntary movements? Neuroleptics should never be given at the same time as L DOPA. There seems to be little genetic basis for the disease, at least clinically, and Parkinson’s is normally thought of as an environmental disease. Viral infections can also contribute to the disease, as can ischaemia and trauma. MPTP, a recreational drug, causes very similar effects to Parkinson’s, and is used in animal models. It is taken up into the dopaminergic neurons by the dopamine uptake system, and is converted into the toxic metabolite MPP+ by MAOB (inhibited by selegiline). MPTP thus causes irreversible destruction of the dopaminergic neurons. This has thrown some light on the pathogenesis. Since the NMDA antagonist MK-801 inhibits the toxic effects of MPTP, this implies a role for excitotoxicity, certainly for the pathogenesis of MPTP and possibly for Parkinson’s more generally. Selegiline is used as a therapy for Parkinson’s disease. Another toxin that can lead to a Parkinson’s like
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The first generation being drugs such as muscarine, which had enormous peripheral side effects since they were never designed with Alzheimer’s disease in mind.

Timothy Woodward

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syndrome is the herbicide rotenone, which inhibits mitochondrial function. This implies a possible role for mitochondrial dysfunction in the pathogenesis of Parkinson’s. There is the possibility that environmental toxins, as yet unknown, induce Parkinson’s by some of mechanisms10. Just as for Alzheimer’s, there are rare forms of familial Parkinson’s disease. One genetic link has been mapped to chromosome 4, and the gene for alpha synuclein. Peptide fragments of this protein, which is normally found at synapses, can adopt extended, non-globular structures, called non-random coils. This promotes formation of amyloid, at least in vitro. By comparison with Alzheimer’s then, one might expect this to play an important role in the disease. Oddly enough though, Parkinnen et al. 2005 concluded that alpha synuclein pathology involvement in clinical symptoms is not clear: they went back over all the autopsy cases they could find which had alpha synuclein inclusions: only 30% had any neurodegenerative symptoms at all. Other genes that have been identified include Parkin and PINK1, and seem to be involved in proteasome function: possible mishandling of proteins. In Parkinson’s disease, there is also an increase in cholinergic activity, leading to the so-called positive effects of Parkinson’s: tremor and pill rolling rigidity. The motor effects mentioned in respect to loss of dopamine are the “negative” effects: those probably attributable to cholinergic activity are the positive effects. ACh release by the cholinergic neurons of the corpus striatum is inhibited by dopamine, and its loss causes a great increase in their activity. Huntington’s disease, on the other hand, where there is degeneration of the GABAergic neurons, causes an increase in dopamine activity and hypoactivity of these neurons. Instead of rigidity and hypokinesia, we now have hypotonia and hyperkinesia. This gives us hope for clinical intervention in both these diseases, to redress the balance of hormones11. In Parkinson’s, just as for Alzheimer’s, the drugs currently in use merely treat the symptoms and do not seem to have any effect on the underlying pathology. Another disadvantage they all share is that their effects are limited. Although this is the subject of some debate, current mainstream thinking is that there is little point in treating Parkinson’s until the symptoms become unmanageable: this gives the drugs the longest time to be useful. There are some parallels here with recommendations on Alzheimer’s treatment. The drugs divide into those increasing dopamine levels, and those decreasing cholinergic activity. The best known, and most important, is L DOPA, which is the frontline treatment for Parkinon’s. It was a treatment founded on rational basis, after the observations of Hornykiewicz. It is a dopamine precursor (dopamine itself cannot cross the blood brain barrier), is taken up by dopaminergic neurons, and converted to dopamine by the DOPA decarboxylase enzyme. It is given with the DOPA decarboxylase enzyme inhibitor carbidopa: this cannot cross the blood brain barrier, and so inhibits the surge in peripheral dopamine levels that would eventually result. One would imagine that one downside of this drug would be that it requires neurons:
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Although all these various experimental techniques seem to be doing is identifying different ways to kill a specific cell type. There is more than one way to skin a cat, and no-one seems to have come up with hard evidence as to what exactly is killing the cells in Parkinson’s. 11 These are the two major hormonal changes. There are also more minor effects of 5HT, NA and GABA levels, at least in Parkinson’s.

Timothy Woodward

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indeed there is some reduction in L DOPA’s efficacy as neurons degenerate and Parkinson’s progresses. That there is any effect at all, however, tells us that the L DOPA itself must be having some effect in solution. About 80% of patients show initial improvement with L DOPA, and 20% reach virtually normal motor function. The beneficial effects of L DOPA do not last for ever, as already mentioned. There are also two very serious side effects. Dyskinesias develop in the majority of patients within 2 years of starting L DOPA therapy, where there are involuntary movements of face and limbs on application of L DOPA (cf. tardive dyskinesia brought about by the neuroleptic drugs in the treatment of schizophrenia). The dose has to be reduced in order not to cause this, but then there is a progressively narrowing window of drug dose between no effect on the one side, and dyskinesia on the other. Second are the so-called on-off effects, where rigidity and hypokinesia can suddenly worsen, for anything from a few minutes to a few hours, before returning to normal. The patient may suddenly find himself rooted to a chair (Rang and Dale). It is thought that abnormal fluctuations in dopamine levels are in fact responsible for these serious motor side effects, which is particularly believable for the on-off effects, and research has thus focussed on finding ways to control this. There has been a recent (small) trial, Emre et al. 2005, which worked on the basis that serotonin receptors have a role to play in all this. They found that the 5HT1A agonist sarizotan causes a 40% reduction in L DOPA induced dyskinesias, despite seemingly having no effect on the underlying disease. The idea is that in the absence of dopaminergic nerve terminals, the L DOPA is decarboxylated in serotonergic nerve terminals. So the serotonergic nerve terminals release dopamine in addition to serotonin. As discussed in the last essay, 5HT1A receptors are inhibitory receptors for this release. So less L DOPA is released, and seemingly more importantly some control is exerted over the pattern of this release. Given that there are probably more than 50 different neurotransmitters in the basal ganglia, it is not inconceivable that some of these will also be found to alter the pattern of dopamine release: NMDA receptors have also been implicated, with NMDA antagonists helping to alleviate these adverse effects (Chase et al. 2000). At a more macroscopic level, involvement of the GABAergic direct pathway could also play a role. There is increasing evidence that other transmitter systems are involved in Parkinson’s, and one of the key reasons for understanding this is seemingly to develop a better understanding of these side effects, and how to avoid them. In addition to these two very severe effects, there are a series of more minor side effects. L DOPA does cause some build up of dopamine in the sympathetic ganglia, where it is an inhibitory transmitter. There is therefore postural hypotension. While the effects of L DOPA are to an extent specific to the basal ganglia, there are some side effects which are akin to the positive effects of schizophrenia, particularly in patients who are suffering from the demential effects of Parkinson’s. These include hallucinations, paranoia, mania, insomnia, anxiety and nightmares (Leonard 2003). There is often nausea, for which the peripherally acting dopamine antagonist domperidone might be useful. Selegiline is a MAOB inhibitor, which is the form of MAO that is selective for dopamine. It is only found in the dopamine neurons of the brain, and thus there is not the cheese effect seen with the MAOI’s discussed in the depression essay. It is used as an adjunct to L DOPA therapy.

Timothy Woodward

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A number of dopamine receptor agonists have been developed, in an attempt to bypass the non-specific, somewhat neuron reliant, effects of L DOPA. Turnover of dopamine in the synaptic clefts can itself generate potentially damaging reactive oxygen species – perhaps another explanation for the deleterious effects of L DOPA, but certainly something that is worth avoiding12. Apomorphine was one of the first drugs to be tried, but its action was too short, and its side effects too severe, for it to enter mainstream therapy. Bromocriptine, originally used in the treatment of galactorrhea and gynaecomastia (dopamine inhibits release of prolactin from the anterior pituitary), can also be used. It however has side effects (it is also a partial agonist at D1 receptors, which might have something to do with this) and oddly enough has limited therapeutic effects: patients cease to respond to it, but continue to respond to L DOPA. Rang and Dale suggest that the recently induced pramipexole might have anti-oxidant effects and a protective effect on mitochondria as well as dopamine agonist activity. The antiviral drug amantadine was discovered by accident to be of some use in the treatment of Parkinson’s in 1969. Although its mode of action is uncertain, it increases release and synthesis of dopamine, and inhibits its reuptake. This of course relies on the dopaminergic neurons still being in place, and so its long term use is limited. The other category of drugs is the acetylcholine muscarinic antagonists. These have been used for a lot longer, and for more than a century atropine was the drug treatment for Parkinson’s. This would have had the usual side effects, such as dry mouth, tachycardia, loss of visual accommodation and constipation. More selective drugs have now been developed, which include benztropine and bipiriden. Benzhexol is also a dopamine reuptake inhibitor. Above, the effects of Parkinson’s were divided into the positive, cholinergic, effects and the negative, adopaminergic effects. Although this is rather crude, it is supported by the observation that these drugs tend to preferentially alleviate the tremor and rigidity, with less effect on the hypokinesia. This is unfortunate, since the hypokinesia is probably more disabling than the tremor. The main use for these drugs, therefore, is in Parkinson’s patients who are already receiving neuroleptics for dementia, and therefore cannot take L DOPA. Huntington’s disease is an autosomal dominant disorder, where there is progressive brain degeneration, starting after the reproductive age in adulthood. It is invariably fatal. It is a triplet repeat (CAG) disease, which codes for a polyglutamine stretch. The abnormal gene is on chromosome 4, and codes for an abnormal version of huntingtin. The main symptoms are dyskinesias starting in the fingers and spreading to the rest of the body (hence the name “chorea”), although there is also some akinesia. The GABAergic cells of the striatum seem to be the main victims of this neurodegeneration, in particular those of the indirect pathway projecting to the external globus pallidus (enkephalin and substance P-ergic as well). In contrast to Parkinson’s, where there is a loss of the dopamine that would have inhibited the indirect pathway, causing a gain in function of the indirect pathway, here there is a loss of function in the indirect pathway and the direct pathway dominates. The
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Some have even suggested that L DOPA ultimately causes further neurodegeneration compared to placebo, and there is apparently some support for this due to neuroimaging studies. At the same time though, it is best not to be too pessimistic about the effects of L DOPA: many trials, and decades of clinical experience, suggest that it improves both lifespan and quality of life.

Timothy Woodward

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symptoms are thus the inverse of Parkinson’s, even down to a decrease in cholinergic function. The loss of GABA removes an inhibition of dopamine neurons, and there is increased secretion of dopamine in Huntington’s. Huntingtin interacts with many proteins, and is found in every cell in the body. One of the proteins it reacts with is a caspase, and thus defects in huntingtin may be linked to the response to excitotoxicity. It is unclear why the toxic effects of the abnormal protein seem to affect the GABAergic cells of the striatum so exclusively. Unlike Parkinson’s and Alzheimer’s, direct GABA replacement has not proved successful. Treatment so far has relied on the dopamine antagonist chlorpromazine, and the GABA agonist baclofen, to alleviate symptoms, but the disease remains fatal. The well defined mutation has allowed for easy mouse modelling. RNAi therapy in mice, to inhibit translation of the mRNA coding for huntingtin, has alleviated symptoms in mice, and even caused a reverse in pathogenesis that has already occurred (Davidson et al. 2005). This is surprising, but provides long term hope that this may one day be a curable disease. One downside to this particular method of attack is that the RNAi inhibits expression of both the mutated and normal protein product. It is not yet known whether this will be a problem in humans. The mouse model and the human model are also not quite comparable. Creatine, monocycline, the glutamate antagonist remacemide and co-enzyme Q all seem effective in mice, but not in humans (Leonard 2003). On the other hand, involvement of the eicosapentaenoic acid, a polyunsaturated fatty acid, seems to ameliorate symptoms in both mice and humans (Leonard 2003). Another potential technique of use in several of the neurodegenerative disorders, particularly Parkinson’s and Huntington’s, is that of the transplant of brain tissue, using fetal tissue. This was first tried for Parkinson’s in 1982. In addition to the technical and ethical problems, some of the patients have gone on to develop dyskinesias due to overproduction of dopamine. That, however, the cells integrated and produced dopamine at all must be viewed as a scientific triumph. Our lecturer Kay Davies claimed that in a few years time there could be cures for both Parkinson’s and Huntington’s, such is the rate at which our knowledge is progressing. On the other hand, with such a wealth of neurotransmitters and interactions, there does seem to be an awful lot of research to be done before these diseases are well understood. A cure for Alzheimer’s in particular also seems rather distant.