Neurodegenerative diseases onset observes a frequency more and more important in elderly, in developed as well in developing countries. These diseases are very complex in a psychiatric or clinical point view. In fact, most of patients need specific psychiatric cares and on the other hand, neurodegenerative diseases diagnosis is very delicate as the diseases are specific to each individual and moreover symptoms can be sometimes confused with other neuronal disorders (Fratiglioni and Qiu, 2008). These diseases are associated with many factors of risks, mainly genetic or environmental, knowing that at the moment it is impossible to determinate which one has the greatest part (Bertram and Tanzi, 2005; Fratiglioni and Qiu, 2008). But all these diseases are resulting from neurodegeneration process and have shown some similarity in the way of occurrence and progressing. One of the most important similarity found is foremost the loss of cell which can be then identified as a result of dopamine activity, and more especially of dopamine dysfunction (Hastings et al., 1996). Dopamine main functions have been identified in 1958 by Arvid Carlsson and Nils-Åke Hillarp from Sweden. After approximately 50 years of research, the link between this neurotransmitter and neurodegenerative disease is becoming more and more precisely explained even if dopamine all alone does not explain enough the neurodegeneration process (Chen et al., 2008). This link was the topic of several studies which sometimes provides some different results because the way of approaching the direct or indirect role of dopamine in neurogeneration can be differently interpreted.
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Dopamine and dopaminergic system
Dopamine which chemical name is 4-(2-aminoethyl)benzene-1,2-diol, is a catecholamine neurotransmitter biosynthesised in dopaminergic neurons into two steps. First, the amino acid tyrosine is transformed in L-3,4-dihydroxyphenilalanine (L-dopa) via the tyrosine hydroxylase then L-dopa is converted in dopamine via the aromatic amino acid decarboxylase (Eisenhofer et al., 2004; Elsworth and Roth, 1997). Dopamine is a precursor for both neurotransmitters norepinephrine (or noradrenaline) and epinephrine (or adrenaline). After synthesis, dopamine can be stored in specialized storage vesicles in the cytosol of the neuron, where it can be released by exocytose into the synapse upon arrival of a pre-synaptic action potential (Elsworth and Roth, 1997).
According to Lindvall and Bjorklund (1978), the dopaminergic system is divided in four anatomically different groups of dopamine-containing neurons: the nigrostriatal, the mesolimbic, the mesocortical and the tuberoinfundibular pathways. These four pathways correspond to specific neuronal functions each via the action of pre-synaptic and post-synaptic dopamine receptors. All the group of receptors can be classified in two categories: the D1-like subfamily with the D1R and D5R receptors, and the D2-like subfamily with the D2R, D3R and D4R receptors (Holmes et al., 2004).
Dopamine functions in the brain
Dopamine is involved via its receptors in several functions in the brain and more precisely in mediating responses to the environment. In fact, Cools in 2008 highlighted that dopamine has a very complex role in the control of motivation, reward and punishment and the control of cognitive functions. His study also permitted to associate this controls respectively to the mesolimbic pathway and to the mesocortical and nigrostriatal pathways. Indeed, dopamine activates the appetitive and aversive sensations via the stimulation of the mesolimbic pathway whereas the capacity of working memory is associated to stimulation of the mesocortical and nigrostriatal pathways. Moreover, the dopamine's role in human brain is specific to each individual. That is why understanding the functions of dopamine is very complex. In practice, and more precisely in neuropsychiatry which uses dopamine therapy, these variations involve specific treatments with specific doses to each individual. In 2007, Volkow et al. has also demonstrated the role of dopamine in the reinforcement of drug actions and so of drug addiction and especially for cocaine, methylphenidate and amphetamine drugs. In fact these drugs increase dopamine synthesis and thus, as we have seen earlier, increase reward manifestations such as euphoria. This work also adds that the D2 receptor is the one that is implicated in drug addiction.
Neurodegeneration is described as nervous system disorders initiated by degradation of neuronal cells. Although it remains partly unexplained, many studies have permitted to conclude that this process results mainly of aging as well as familial aggregation or environmental risk factors (Bertram and Tanzi, 2005; Brown et al., 2005). Age is the main risk factor involved in neurodegeneration process because of the degradation of biological functions. Oxidative stress, which increases cell dysfunctions, is one of the most important neuronal consequence of aging and thus one of the most risky factors of neurodegeneration (Cantuti-Castelvetri et al., 2002). Familial aggregation is described as specific protein mutations which can be identified in several members of a same family. So, people with neurodegeneration history have more risks to develop a neurodegenerative disease as shown by Bertram and Tanzi in 2005. These scientists have also added that all these diseases can appear within a sporadic form (rare form) or an idiopathic form (unknown origin form) knowing as well that many other non-genetic factors can be associated with neurodegenerative disease onset. The environmental impact on neurodegenerative disease onset can be associated with environmental agents exposure. The latter is mainly chemical agent such as pesticides, herbicides or fungicides even if those categories are too large to be identified as a precise cause of neurodegenerative disease onset (Brown et al., 2005).
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Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by foremost dementia, corresponding to memory and cognitive dysfunctions, as well as behavioural and psychological disorders (McKhann et al., 1984). Although dementia has been related to neuronal degeneration and loss of synaptic connections, the mechanism of this process remains partly unexplained. Nevertheless, clinical manifestations such as memory impairment, apathy, depression and later confusion, behaviour change as well as trouble speaking, swallowing and walking have been identified (Alzheimer's Association, 2009).
Nevertheless, AD is difficulty diagnosed. A clinical diagnosis is currently based on criteria described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the International Classification of Diseases, Tenth Revision (ICD-10), or the National Institute of Neurological Disorders and Stroke-Alzheimer Disease and Related Disorders (NINCDS-ADRDA) (McKhann et al., 1984). The latter has been revised by Dubois et al. (2007) to finally identify core diagnostic criteria with supportive features as well as exclusion criteria. Thus, AD can be diagnosed, with more or less confident, in case of early and significant memory impairment and atrophy of medial temporal lobe among others.
The two most important risk factors for AD are the age (risks increase from 65 years old) and the genetics factors (Alzheimer's Association, 2009).
De Lau and Breteler (2006) have described Parkinson's disease (PD) as the second most common neurodegenerative disease induced by dopaminergic cells loss and whose onset appears the most often after 60 years old. Clinical manifestations of this disease are dementia, resting tremor, bradykinesia, rigidity or postural inequity among others. They also have demonstrated that, as the mechanism of this disease remains not well known, it is difficult to identify the main cause agent. However, Mattila et al. demonstrated in 2000 that dementia resulted from the presence of an abnormal accumulation of α-synuclein proteins which forms Lewy bodies inclusion. The presence of these Lewy bodies is the main pathological characteristic finding in PD. On the other hand, it is impossible to distinguish the major part between the genetic or the non-genetic origin. Indeed, several genetic and environmental risk factors have been identified by De Lau and Breteler, such as respectively, presence of causative or susceptibility genes and environmental toxins exposures or dietary factors, but, depending on each individual, none of them seems to be predominant. What is more, interactions between both genetic and non-genetic risk factors are considered to be more influent in PD onset.
In 2007, Walker has described Huntington's disease (HD) as a progressive genetic neurodegenerative disorder characterized by three phases: asymptomatic, prediagnostic and diagnostic. The asymptomatic phase can last within an individual from one to eighty years old. During this phase, individual presents no clinical signs of the disease. Then, the prediagnostic phase begins when individual starts to behave differently as they are becoming more irritable and have more difficulties to carry out daily tasks. Finally comes the diagnostic phase when individual presents chorea, incoordination and inability to sustain a movement, and slowed saccadic eye movements. Cognitive and executive functions also began to be impaired with long-term memory loss, incapacity to plan or organise actions, or speech and then comprehension decline. Walker adds moreover that latency period for this disease is estimated to be 20 years and patients often die because of the cognitive and motor dysfunctions (starvation, breathing stop).
HD diagnosis can be difficult as it can be confused with late diskynesia or chorea. Nevertheless, family history is an important marker in HD diagnosis. In fact, individual with HD gene carriers in family has 50% chance of inheriting the disease (Myers, 2004).
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a familial or sporadic neurodegenerative disease characterized by death of neuronal motor cells in spinal cord or cerebral cortex. This disease leads to motor dysfunctions, atrophy and then paralysis. Patients, usually aged between 50 and 60 years, die within 3 and 5 years after disease starting (Tandan and Bradley, 1985).
Main symptoms for clinical spectrum are motor speech as well as movements dysfunctions and clinical features permitting ALS diagnosis, are the absence of muscle twitching, sensorial deficiency or autonomic dysfunctions (Eisen, 2008).
EFFECT AND USING OF DOPAMINE IN NEURODEGENERATIVE DISEASE
Dopamine dysfunctions and neurodegeneration
The role of dopamine, and more precisely of unregulated cytosolic dopamine, in the neurodegeneration process has been demonstrated in many studies. Indeed, excess of dopamine level becomes a factor of neurotoxicity, and this leads to oxidative stress which leads itself to significant cell function impairment or apoptosis signal (cell programmed death). In fact, oxidative stress results from transformation of dopamine excess, which has not been reabsorbed, into its deaminated metabolite dihydroxyphenylacetic acid (DOPAC). When dopamine oxidative products, resulting from dopamine excess and DOPAC bind covalently to cysteinyl residues on striatal protein, this can induce protein impairment and finally cell dysfunctions or cell death. Moreover, this oxidative stress process occurs in mitochondria and leads to mitochondria damages, and more generally cell damages by the production of reactive oxygen species (ROS) which are very toxic for cells (Beal, 1998; Chen et al., 2008; Hastings et al., 1996).
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The role of dopamine in oxidative stress has been demonstrated several years earlier, in a study showing that unregulated cytosolic-dopamine involved many consequences. In fact, experimental injection of high level of dopamine in the striatum causes two responses. First and as shown earlier, surplus of dopamine in cell leads to oxidative stress. The second answer is the loss of selective dopaminergic regions by the fact that they are more vulnerable to oxidative stress. In conclusion, high levels of dopamine leads to oxidative stress generation which itself cause a dopamine depletion because of cells deterioration. The same study also shown that, this dopamine depletion could be one of the specific causes of Parkinson's disease onset (Hastings et al., 1996). However, about this point, Chen et al. demonstrated later that chronic exposure to dopamine's toxicity is much more a cause for neurodegeneration than dopamine deficiency (2008).
In fact, a chronic exposure to dopamine's toxicity can be a consequence of aging. The central nervous system is more vulnerable to dopamine's neurotoxicity in middle-aged people than young people. Actually, the age-related brain damages increase the oxidative stress process and dopamine's specific pathways such as the nigrostriatal one is very sensitive to it. That is the reason why most of the neurodegenerative diseases occur preferentially in elderly. However, some symptoms of neurodegenerative diseases such as motor impairments are more a consequence of exogenous dopamine excess than aging alone. Indeed, injection of dopamine in young or aged rat in this study caused motor impairments and inabilities to perform tasks in both groups. Moreover, removing extracellular dopamine supply in striatal neurons reduces the onset of motor dysfunctions (Cantuti-Castelvetri et al., 2002; Chen et al., 2008).
Dopamine dysfunction, alone or via oxidative stress and aggravating by aging can thus be significantly identified as a factor in neurodegeneration. In fact, mitochondria dysfunctions, resulting from dopamine neurotoxicity, have been identified as a marker of neurodegenerative diseases such as Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis. Moreover, in the case of Parkinson's disease, it was demonstrated that the main cause of the onset of the disease was the loss of neuronal cells. This loss of neuronal cells is, as shown earlier, one of the consequences of dopamine neurotoxicity (Beal, 1998; Hastings et al., 1996).
Effects of Levodopa treatment in Parkinson's disease
In the case of Parkinson's disease, Levodopa treatment is the principal allowed therapy. Levodopa is based on the utilisation of L-dopa. As cited in the paragraph 2.1, L-dopa is a precursor of dopamine. L-dopa is used as a pro-drug because of its capacity to cross the blood-brain barrier unlike dopamine, and thus is able to act directly on the central nervous system. The administration of L-dopa in parkinsonian patients has been first tested in the 1960s, by Barbeau among others (1969). In his study, Barbeau first reviewed his first trials of L-dopa administration realized between 1960 and 1968. These first trials permitted to conclude that chronic administration of L-dopa allowed improving parkinsonian symptoms such as rigidity and tremor. However, the usefulness of L-dopa treatment has not been immediate because some other trials have not been so concluding and because nobody dared at this period to increase the dose of L-dopa. Barbeau in 1969 finally realized these trials with doubled doses. He concluded that the more the dose is important, the more the parkinsonian symptoms are improved. Moreover, after two months of treatment with higher dose, Barbeau admitted that L-dopa could improve other parkinsonian symptoms such as akinesia, sialorrhea, gait and posture, memory, associated movements or speech.
These essays also highlighted that high dose of L-dopa injections could significantly increase the occurrence of side effects such as abnormal involuntary movements, nausea, hypotension or confusion, hallucinations and vivid dreams among others. Occurrence of other side effects has also been recently demonstrated. The use of dopaminergic medication within parkinsonian patients can involve different effects on movement, reward and cognition (Barbeau, 1969). This has been partly explained by Chen et al. who demonstrated that L-dopa treatment is also a cause of neurodegeneration. Indeed, a four-week exposure to L-dopa injections lead to extracellular dopamine supply and so increasing of oxidative stress and thus cell loss in the striatum as shown earlier. Moreover, it has been demonstrated that dopaminergic treatment induced a change in the relationship between the disease severity and the neural effects. Normally, there is a linear relationship between these both but the dopaminergic medication induces a non-linear relationship, meaning that neural damages onset becomes specific to each patient. The disease progression becomes thus less and less predictable. (Rowe et al, 2008). Finally, knowing that every individual shows specific responses to dopamine therapy, the balance between side effects and benefits of L-dopa therapy cannot be generalized (Chen et al., 2008).
Using of dopamine agonists
In order to reduced the L-dopa-induced side effects and in particular dyskinesia, Maratos et al. realized in 2002 trials to demonstrate the benefice of using dopamine agonists as a monotherapy. Pergolide and apomorphine respectively act with long-term and short-term on D1 and D2 dopamine receptors agonists. Maratos et al. first helped to prove that stimulation of dopamine receptors by L-dopa increased significantly the risk of developing dyskinesia and more especially in the case of long exposure. They also showed that, compared with L-dopa, both apomorphine and pergolide have the potentiality to decrease dyskinesia onset and that pergolide is more able to provide a quick improvement of locomotor activity and with a higher level. However, these findings also helped to show that L-dopa is not the only responsible in dyskinesia onset because both pergolide and apomorphine administrations induced as well dyskinesia. Thus, D1 and D2 dopamine receptors stimulation can't be associated with dyskinesia all alone.
The role of dopamine in neurodegenerative diseases is not yet totally understood. Dopamine function in central nervous system is very complex and this complexity is aggravated by the fact that scientists have to realize the most of their trials on animal models and observe results at the cellular and molecular levels. Moreover, as central nervous system via its cognitive, sensorial and motor functions is specific to each individual, dopamine function can give different results in different trials (Chen et al., 2008)
However, dopamine was definitely accepted as playing a major role in the neurodegeneration process in main neurodegenerative disease (Beal, 1998; Hastings et al., 1996). These major findings helped to provide therapies and medications, which do not cure these diseases yet, but at least relieve patients from their strongest symptoms even if dopamine therapy proved also to be aggressive with especially the manifestation of important side effects (Chen et al., 2008).
As the global world population is becoming to be more and more aging, involving more and more onset of neurodegenerative disease, deeply understanding the role of dopamine in neurodegeneration is to be a major aim of the next decades. Pharmaceutical industries and Research Center are concentrating more and more on this aim in order to prevent this aging and finally provide some eventual new medications or therapies to relieve patients as well as their family (Fratiglioni and Qiu, 2008).