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Parkinsons disease is a neurodegenerative movement disorder with an age-adjusted prevalence of 1 worldwide. Moore It is the second most common neurodegenerative disease and affects 1 in 500 of the general population, and is increasing as we have an ever ageing population. This is one of the reasons why it is vital that extensive research in this area has become high priority amongst researchers.
The disease was named after James Parkinson who first described the disease in 1817 in his work, "An Essay on Shaking Palsy." The four main symptoms that characterise the disease, which is also known as primary parkinsonism, include resting tremor (shaking forwards and backwards when the limb is relaxed), bradykinesia (slowness of movement), rigidity (stiffness to passive movement) and postural instability (intrinsic muscle stiffness), along with associated mental changes.(Hauser R., 2000)
A substantial amount of our current knowledge regarding Parkinson's disease has been derived from our use of the animal model. It was discovered accidentally when a number of young patients were admitted to hospital with symptoms very similar to those we ascribe to Parkinson's disease. Upon further investigation it was discovered that an artificial drug called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyradine) was the actual cause and that each of these patients was an addict. (Langston JW, 1983) The chemical destroys the dopaminergic neurons in the substantia nigra, thus reducing dopamine supply, mimicking old age Parkinson's disease.
As well as the histological hallmark of Lewy bodies, the disease is characterised by a loss of dopaminergic neurons in the basal ganglia, particularly in the substantia nigra pars compacta and striatum. Symtpoms begin to appear when 60-80 of the substantia nigra cells are lost, correlating to a 60 reduction in dopamine. (Duty, 2010) The anatomical structures most relevant to understanding the mechanism by which Parkisons disease operates, and how it produces the clinical symptoms associated with it, are the basal ganglia Hence, in order to understand the pathophysiology, an understanding of the basal ganglia is required. The basal ganglia are a group of interconnected nuclei structures in the subcortical region of the brain, that span the telecephalon, diencephalon, and the midbrain(Albin RL, 1989). There is no strict anatomical definition, but the main structures of the basal ganglia are the striatum, pallidum, substantia nigra, and subthalamic nucleus.
First thought to be merely motor structures (MacLean PD, 1978) (Teuber HL, 1976) due to their obvious influence on motor activities of the body, the basal ganglia are now known to be modulators that mediate a whole range of goal directed behaviours (Haber S N, 2005), and have a direct impact on the descending pathways from the brain and can manipulate information sent to them from different areas of the cerebral cortex. The basal ganglia in themselves are very complex and damage to different parts of the one structure will produce differing symptoms.
Figure 1 Diagram showing the different intrinsic pathways interconnecting basal ganglia structures, (Knierim J, 1997)
The two main pathways are the direct and the indirect pathways. They both consist of a series of inhibitory and excitatory steps. In fig.1, the different intrinsic pathways connecting the various nuclei in the basal ganglia are shown. The solid lines represent the direct pathway, whereas the dashed lines represent the indirect pathway. The red lines represent inhibitory connections and the green lines represent excitatory connections.
There are 3 main transmitter systems involved; glutamate, gamma-aminobutyric acid (GABA) and dopamine. Therefore the loss of dopamine neurons affects the modulation of voluntary movements, causing overactive and underactive systems, as well as involuntary movements.
One of the most important aspects that need to be understood before adequate neuroprotective treatment can be developed is the mechanism of cell death in Parkinson's disease. Currently our thoughts on the mechanisms of cell death in PD are based on experimental data from the substantia nigra of deceased patients, and from the range of neurological experiment carried out in primates and rodents. There are a few principal mechanisms that contribute to cell death in PD.
Oxidative Stress - There is evidence from a human tissue source suggesting the involvement of free radical in the pathological process of PD, as increased levels of malondialdehyde and lipid hydroperoxides were recorded. The oxidative stress implicates an increased basal lipid peroxidation, superoxide dismutase activity and zinc levels in the substantia nigra, investigated in dead brain tissue. (Jenner P, 1992) The high basal lipid production could be as a result of auto-oxidation of dopamine to form neuromelanin. Elevated levels of Fe2+ in the substantia nigra help drive the Fenton reaction that adds to the free radical production, and the impairment of mitochondrial complex I activity also contributes to the production of free radicals.
Excitotoxicity - This is neuronal cell death caused by activation of excitatory amino acid receptors (Beal MF). The impairment of mitochondrial complex I, of the electron transport chain, activity in the subtantia nigra cells lead to reduced production of ATP. As a result the membrane depolarises, caused by a loss of transfer in the sodium-potassium ATP-ase. As the neurones have been found to have low calbidin levels, they are already very sensitive to high calcium excitation, and this is one of the ways cell death is believed to occur. (Duty S, 2010) This was first investigated in the drugs-induced Californian case of 1983 (Langston JW, 1983) which suggested the MPP+ is a complex I inhibitor and a substrate for dopamine transporter.
Protein dysfunction - The Ubiquitin Proteasome System (UPS) normally labels abnormally folded proteins by conjugation of a polyubiquitin tag through an enzymatic cascade, for 20S or 26S proteasomal degradation. Pathologically, it is believed to be dysfunctional as it inappropriately labels cells by binding, causes excess cell death.
Genetic causes - PD can result from genetic defects, and this can vary from various different known genes. The most common gene mutations are the Parkin, LRRK2 and GBA. (Jenner P. , 2010). This is an area where a great deal of research is taking place, and a hopeful basis for future treatment.
The clinical diagnosis of PD lies on the identification of the effects of dopamine deficiency. The diagnosis is still primarily based on the recognition of external symptoms of PD such as a slowness of movement (bradykinesia), poverty of movement (hypokinesia), rigidity and resting tremor. (NICE) Microgaphia is another symptoms of PD, where the patients writing gets continually smaller as they write.
Tremor is the most apparent symptom, that can actually however be mistaken for the more common condition of essential tremor. A way of differentiation between the two conditions is by looking at whether the tremor is at resting or during action. Resting tremor is generally associated with Parkinson's disease whereas tremor in action is associated with essential tremor. In addition, patients with PD usually have a unilateral tremor to begin with, whereas essential tremor in present in both limbs. (Mark Guttman, 2003)
Rigidity of the muscles during passive movement can be confused with rigidity due to upper motor neuron lesions. The rigidity caused by upper motor neuron lesions, however, the muscles suddenly relax after a period of rigidity and resistance. In PD there is continuous resistance throughout the entire range of the motion, and some patients show cogwheel rigidity.
In the UK, the Levodopa challenge test is used to diagnose Parkinson's disease. Levodopa, the benchmark motor symptom treatment, is given to the patient and if a marked improvement in the tremor is observed, then PD is diagnosed.
Causes of Parkinson's disease
There is no one single cause of PD, rather it is a syndrome that can be caused for many reasons but most cases are idiopathic and their aetiology is unknown. About 10 of cases are genetic, hence they are caused by a genetic mutation that leads to dopaminergic cell loss. (Jenner P. , 2010)
Current Symptomatic Treatment
Anticholinergics/muscarinic receptor antagonists
These were the first drugs available for the treatment of PD and are still used both as monotherapy and as adjuncts. Drugs such as benzhexol and benzatropine activate the muscarinic Ach receptors in the striatum. This further increases the overactivity of the indirect pathway, and adds to the overactivity of the indirect pathway hence contributing to the symptoms of tremor and rigidity. In around 30 of patients, muscarinic antagonists reduce resting tremor. (Duty, 2010) The side effects of these drugs are vast, including peripheral effects such as dry mouth as a result of the blockade of muscarinic ACH receptors in the salivary glands. However this effect can be useful in treating sialorrhea experienced by some PD patients. Constipation may also be a side effect due to the effect on the smooth muscle of the GI tract, and another effect of blockade is urinary retention. The central side effects are predominantly confusion and memory loss, with some patients even experiencing hallucinations. (Stewart A. Factor, 2008)
L-3,4-dihydroxyphenylalanine otherwise known as L-dopa or Levodopa is an intermediate in dopamine synthesis. It is currently the best symptomatic treatment avaible, and used as the standard treatment in the UK. It is a natural dopamine precursor, and unlike dopamine it can cross the blood-brain barrier. L-dopa is broken down into dopamine through the action of the enzyme dopadecarboxylase (DDC). DDC however is also present in the intestinal walls, so around 90 of orally administered L-dopa is converted in the intestines. For this reason, it is administered with peripherally acting DDC inhibitors, such as benserazide, carbidopa and methyldopa. In addition, around 5 of L-dopa is metabolised by plasma Catechol O-Methyl Transferase, and so a COMT inhibitor such as entacopone can be used as adjunct.
The main therapeutic effects of L-dopa include, when administered with a DDC inhibitor, a rise in striatal DA levels. As a result activity in both the direct and indirect pathways is normalised, improving rigidity, bradykinesia, facial expression, speech and handwriting ina round 80 of patients. (Duty, 2010)
The side-effects of L-dopa are another hot issue in PD research, as much of the concerns of patients are related to the adverse effects of L-dopa. The acute side-effects of L-dopa include nausea, as a result of the remaining peripheral dopamine receptor activation. To reduce this, peripheral DA receptor antagonist, domperidone, can be given as adjunct. Some patients experience postural hypotension, especially those taking anti-hypertensive drugs. Other acute side-effects include hallucinations, confusion and insomnia.
The chronic effects of L-dopa are experienced by most patients, generally within 2 years of starting L-dopa therapy, such as abnormal involuntary movements (AIM), disease fluctuations and severe confusion. (Marsden CD, 1977:ii). The 'on-off' effect and the wearing off of the drug is arguably the most aggravating side-effect of L-dopa. This consists of on dyskinesias, diphasic dyskinesias (DD), and off periods. (Luquin M R, 1992) These periods mean quick disease fluctuations and sometimes the patient goes into a frozen state where they experience muscle inactivity that could last minutes or even hours. There have been many possible suggestions explaining the freeze effect. This could be linked to plasma fluctuations of L-dopa. Another chronic side-effect is L-dopa induced Dyskinesias (LIDs), where the limbs and face are mostly affected. Research suggests that these dyskinesias may be link with peak plasma levels of dopamine. (Mouradian M.M, 1989)
Dopamine receptor agonists, like bromocriptine, lysuride, pramipexole and ropinirole, can be used alone or in adjunction to L-Dopa. Their effects are produced mainly by the stimulation of D2 receptors although selective D1 receptor agonists are currently been tested; neither are affected by progressive neurodegeneration. Although dopamine agonists are less effective at relieving PD symptoms than L-dopa, as they have a longer half-life there is less fluctuation in plasma levels, hence less experience of the "on-off" effect. The acute side-effects for dopamine agonists are similar to those for L-dopa, whereas there is a lesser incidence of chronic side effects. Research suggests that there is a less incidence of dyskinesia when using dopamine agonists perhaps due to the pharmacokinetic profile. (Jenner, 2003)
Monoamine Oxidase-B Inhibitors
Monoamine oxidase B (MAO-B) is a major breakdown enzyme in DA metabolism, in DA rich brain regions. Therefore MAO-B inhibitors stop DA metabolism, and as often used as an adjunct to L-dopa. The most common example is selegiline, which was also claimed to be neuroprotective. In addition, as they are selective MAO inhibitors towards MAO-B, they do not have the cheese reaction side effect that occurs with use of non-selective MAO inhibitors. However the metabolic breakdown of selegiline leads to the production of methamphetamine derivatives that have been associated with cardiac and psychiatric effects in some patients.
Catechol-O-methyltransferase (COMT) inhibitors
COMT is an enzyme involved in the breakdown of levadopa, and so COMT inhibitors are administered with levodopa to prolong its effects. There are two main types of COMT inhibitor. Encaptone, which inhibits COMT peripherally, is a short-acting COMT inhibitor but it is not toxic. Tolcapone is a peripheral and centrally inhibiting drug which is longer acting but is hepatotoxic. (Waters & Constantino, 2001)
Deep Brain Stimulation
Deep Brain Stimulation is an invasive surgical procedure that stimulates the subthalamic nucleus and reduces motor complications patients suffer as a result of long term levodopa therapy in advanced Parkinson's disease. (Deuschl et al, 2006)
Need for better symptomatic treatment
Levodopa is currently the gold standard drug, and whilst it works very effectively to produce dopamine, its long term side effects cause huge distress for many PD sufferers. Therefore this needs to be addressed for patients in advanced stages of PD. Also, there needs to be further consideration of the non-motor symptoms associated with PD such as sleep disturbance, fatigue, depression, constipation and sexual dysfunction amongst many more. (Chaudhuri, 2006)
Importance of neuroprotective treatment
As PD is a progressive disorder with a wide range of symptoms that severely reduce the quality of life, an effective way of improving the condition is to stop it from progressing or at least slow the process down.
Current neuroprotective treatment
Currently there is no proven neuroprotective treatment in the UK, however there are claims of neuroprotection by drug companies. Selegiline is a monoamine oxidase-B (MAO-B) inhibitor, and has been used as an adjunct therapy in PD for many years now. A number of studies, (Parkinson Study Group, 1989) (Parkinsons Study Group, 1993) (Myllyla V.V., 1993) have claimed that Selegiline has a neuroprotective effect. However as the patent for Selegine expired, newer studies re-evaluating these studies and claimed that the lesser need for L-dopa at an early stage was probably due to a sympomatic effect rather than a neuroprotective effect. (Calne DB, 1995) (Ward C D, 1994)
Problems with findings effective neuroprotective treatment
Some of the major issues encountered when trying to discover new treatments that are neuroproective include the fact that the causes of idiopathic are unknown. A major problem in the extrapolation from investigation to clinical trials could be the selection of patients. If different patients have PD for different reasons, then how can we see conclusive results for one particular mechanism?
The lack of a definitive measure of neuroprotection also makes it difficult to assess the effectiveness of a neuroproctective treatment. Do we measure the levels of movement? And would we do this with the influence or without the influence of treatment? All these questions need to be solved to make the process of finding good neuroprotective treatment. (Jenner P. , 2010)
Future neuroprotective treatment
Rasagiline is a selective, irreversible MAO-B inhibitor produced by Teva Pharmaceuticals. It is closely related to selegiline but does not have amphetamine metabolites. Both of these compounds are propargylamines, and are useful in releiving the motor symptoms of PD. Rasagiline is currently in late stages of clinically trials under the brand name Azilect. The mechanism for neuroprotection in Rasagiline is beleived to not be the actual MAO-B inhibiton but a range of other mechanisms.
Figure 2 - Research that shows an increased levels of superoxide dismutase and catalase activity in rodents under the influence of 0.5 mg/kg/day Rasagiline, (Maruyama et al., 2000)
There has been some evidence suggesting that rasagiline has an anti-apoptotic effect and Fig.1 demonstrates an increased activity especially in the substancia nigra and striatum, where dopamine neurons are present. PD patients who have taken rasagiline have experienced similar symtomatic effects to selegiline, a similar drug that have been criticised for its neuroprotectuve claims, but there is still a fair case for rasagiline and further clinical trials will need to find the mechanisms the stop apoptosis in PD patients.
One of the main problems we experience with finding neuroprotective methods is that we have no definitive way of measuring neuroprotective. However, a recent study has shown a link between serum urate and progression of PD. (Schwarzschild, et al., 2008) This study shows an inverse relationship between the level of serum urate and rate at which PD progresses. Therefore if someone has a high serum urate they are likely to have a slower progression than someone with a lower serum urate level. It is thought that urate may protect cells from free radicals, and so inosine, a precursor to urate, is now being examined as neuroprotective treatment for PD.
A neuroprotective solution could lie within a class of drugs that have already been trialled and tested and are being used currently in the treatment of other conditions, Calcium-channel blockers. SNc dopamine neurons are autonomously active like cardiac cells, which means that they in activity of around 2 - 4Hz even without any synaptic trigger. These L-type calcium channels have a pore-forming Cav1.3 as oppose to Cav1.2 subunit in cardiac cells. Therefore traditional pharmacological calcium channel blockers used to treat hypertension need to be rendered before being suitable for PD. (A Bonci, 1998)
Figure 3 Schematic summarising the key events in the ageing model of Parkinson's disease (Surmeier, 2007)
The pathological mechanism suggested is illustrated above on the left whereby calcium influx in the pacemaking increases demand for oxidative phosphorylation, which leads to an increased production of reactive oxygen species, hence causing cellular damage and death over time. The red circles show the damage by ageing. On the right hand side of fig. 2 is a flow diagram illustrating the same mechanism, emphasizing the additive effect on cell death due to ageing by genetic mutations, polymorphisms and environmental toxins.
Research has shown that systemic administration of isradipine makes dopaminergic neurons in rodents follow a Ca2+-independent mechanism to generate autonomous activity. This also allows protection against toxins caused by experimental parkinsonism, allowing this to be an effective possible future neuroprotective treatment. (Surmeier, 2007)
Cell Based therapies
Studies have shown that L1, a neural cell adhesion molecule, over-expressing substrate-adherent embryonic stem cell-derived neural aggregates (SENA) grafts improved the functional recovery on an MPTP-lesioned mouse after they were transplanted into the striatum. The L1 influences not only the survival of these grafted cells but also their neuronal differentiation in the substantia nigra. In addition, the transplantation adjacent to the substantia nigra increased the density of tyrosine hydroxylase-positive neurons. (Cui et al, 2010)
The main benefits of L1 overexpression are neuronal migration and neurite outgrowth, differentiation, myelination, and importantly survival. Substrate-adherent embryonic stem cell-derived neural aggregates neural cell adhesion molecule L1 has promising prospects, but further research and trials will be required before patients of PD can benefit from this treatment on a large scale. (Cui et al, 2010)
One of the limitations of gene therapy is the lack of transduction of all the required cells to the target organ. This is especially important in the case of the brain and in particular the dopamine receptor rich areas of the basal ganglia, and another major problem lies within the differences in scale and system, from animal models to clinical use such that results from the animal cannot be extrapolated to humans.
Viral vectors can be used to insert DNA for dopamine production, glutamic acid de-carboxylase in order to generate GABA, and trophic factors that stimulate dopamine production. Different viral vectors are being experimented with. In the past some adenosine vectors (AV) have been tested however in these types of the vector, some wild-type adenosine genes led to an inflammatory response in the host, which deems it unsuitable for clinical use in this context. (Ronald J. Mandel, 2008)
There are various types of viral vectors currently being studied that seem to have a future in the treatment of Parkinson's disease:
Adeno-associated virus (AAV)
A number of adeno-associated virus serotypes have been found to infect cells of the brain (Passini, 2005) (Cearley, 2006). As this virus is non-pathogenic, incapable of replication on its own and has an inclination for latency, it is a good prospective for use in future therapy. It is a small, non-pathological parvovirus known as wild-type adeno-associated virus (wt-AAV), It was studied and was found to integrate into the host cell genome after infecting the cell, and then going latent at a site on chromosome 19. (N. Muzyczka and K.I. Berns, 2001)
Herpes simplex virus (HSV)
Herpes simplex virus type 1 is a neurotropic viral gene vector, and so it can spread across the nervous system, unlike adenvirus, AAV and lentivirus which do not generally spread very far from their site of injection. Normally the wild type herpes simplex virus, which is a large double-stranded DNA virus is a pathogen associated with corneal blindness and other ailments such cold sores. (D.J. Carr and L. Tomanek, 2006).
HSV's neural effectivity and transgene capacity put it in good stead when considered viable viral vectors of the futures, and so it is possible that it may well be used as a vector for PD treatment of the future.
Lentiviruses such as HIV, SIV and FIV are part of the retroviridae family of RNA type, and are known to have a long incubation period. Their efficiency lies within their capacity to deliver significant amounts of genetic information into the host DNA, and their ability to infect both mitotic and post-mitotic cells. (Gene Therapy Net., 2010)
ProSavin is a novel treatment being developed by a small biotech firm, Oxford Biomedica. It is a viral vector gene therapy based treatment using a lentivirus system developed by the company called the LentiVector system. The treatment is administered locally to the striatum, and contains...................................................................... causing........................
But Neurturin also worked really well in primates, but was not successful in PD patients.
Cogane (PYM50028) is a small non-peptide neurotrophic factor inducer molecule that is able to cross the blood brain barrier. It increases GDNF and BDNF levels in the striatum and can reverse the loss of neutrotrophic factors and dopaminergic neurones, and there has been in vitro research suggesting this effect. This small molecule is orally bioavailable and so reduces the risks associated with surgical intervention to increase these factors. (Phytopharm Plc, 2010)
Fig. 3 explains
GO THROUGH EACH SECTION AND EXPLAIN WHAT THIS MEANS FOR PD SUFFERERS!