Abstract

Parkinson’s disease is the 2nd most common neurodegenerative disease but its cause is still unknown. Parkinson's disease is characterized by the loss of dopamine by the time motor symptoms appear. It is progressive and worsens over time, but it is highly individual and affects people differently. In Parkinson's disease, the loss occurs at a much greater rate. Both biochemical measures and imaging studies suggest a significant decrease in the amount of protein that develops inside nerve cells in people with Parkinson's disease. The most common symptom of Parkinson's disease is the restless sensation of the lower extremities (also known as restless leg syndrome). The oxidative stressors in the tissue of the brain of both familial and sporadic Parkinson's disease patients are involved in the pathogenesis of the disease. Neurosurgical treatment for Parkinson's disease includes pallidotomy and thalamotomy. This procedure may be recommended for patients with aggressive Parkinson's disease or for those who do not respond to medication. This review aims to provide an overview of the pharmacological and neurological targets for Parkinson's Disease and allow modern clinicians to offer an array of therapies to improve function in this still incurable disease.

Keywords

Parkinson’s disease, dopamine, neurodegenerative disease, restless syndrome

Introduction

Neuronal Degeneration is a condition in which neurons continuously lose their function and structure, ultimately leading to the death of neurons within the body. It is a well-known fact that in the central nervous system (CNS) of adults, dead neurons are not replaced, nor are their terminals regenerated, nor is the interrupted axon. Therefore, the death of neurons is generally irreversible. Many neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyotrophic lateral sclerosis, are caused by neuronal degeneration ^{(Emily M. Rocha, 2018) (Dale, 2012)}.

Neurodegeneration occurs due to cell injury, which undergoes necrosis through cell swelling and lyses, resulting in Ca2+ overload and damage to the membrane. This process is associated with inflammatory responses due to the spilling of necrotic cell content. In neurodegenerative conditions, protein misfolding is another factor that leads to the death of neurons, as it results in the formation of large insoluble aggregates due to abnormal conformations of protein molecules. Excitotoxicity is another factor that contributes to neuronal degeneration, as small doses of glutamate, an excitatory neurotransmitter, can kill cells, leading to excitotoxicity. Additionally, oxidative stress, which results in mitochondrial dysfunction due to genetic, environmental, and aging factors, can cause damage to neurons. Oxidative stress is characterized by the accumulation of reactive oxygen species (ROS), which can cause damage to neurons ^{(Emily M. Rocha, 2018) (Shenyu Zhai, 2018)}. Parkinson's disease is the 2nd most common neurodegenerative disease but its cause is still unknown. It is said that in Parkinson's disease, there is a progressive loss of dopaminergic neurons. Dopamine (DA) is one of the most important catecholamine in the brain and also the precursor of other neurotransmitters ^{(Bottaro, 2007)}. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic dopamine are converted to neuromelanin in a stepwise process involving the melanisation of peptides and proteins. However, excessive cytosolic or extra neuronal dopamine can give rise to nonselective protein modifications. These reactions involve the oxidation of dopamine to quinone species and depend on the presence of redox-active transition metal ions such as iron (Fe) and copper (Cu) ^{(Emily M. Rocha, 2018) (Dale, 2012) (shenyu Zhai, 2018)}. Other oxidized dopamine metabolites likely participate in post-translational protein modification. Thus, the modification of protein–quinone is a heterogeneous process which involves multiple residues derived from dopamine that cause structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins ^{(Dale, 2012) (Bruvn, 1964)}.

In Parkinson’s disease (PD), there is the degeneration of the nigrostriatal neuron of substantia nigra pars compacta, whereas substantia nigra controls the movement. A progressive, degenerative neurological disease characterized by a Tremor that is maximal at rest, retropulsion, rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features may include the loss of neurons which contains melanin in the substantia nigra and other pigmented nuclei of the brainstem ^{(shenyu Zhai, 2018) (Bruvn, 1964)}. Lewy Bodies are present in the substantia nigra and locus coeruleus but may also be found in a related condition (Lewy body disease, Diffuses) characterized by dementia in combination with varying degrees of parkinsonism ^{(Jessika, 2018)}.

The first clear medical description of Parkinson’s disease was written by James Parkinson in 1817. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease ^{(JM, 1888) (Charcot, 1887)}. He distinguished Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes ^{(JM, La Medicine vibrato ire, 1892)}. Early treatments for Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa ^{(JM, La Medicine vibrato ire, 1892; JM, Vibratory therapies, 1892)}. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease (JM, Vibratory therapies, 1892) (Charcot, 1892)21Error! Bookmark not defined. In 1872 Charcot and his disciple, described the clinical spectrum of this disease, noting

two prototypes, the tremorous and the rigid/akinetic form (Charcot, 1887). They described in full detail the arthritic changes, dysautonomia, and pain that can accompany Parkinson's disease. Charcot was also the first who suggested the use of the term “Parkinson's disease” rejecting the earlier designation of paralysis agitans or shaking palsy because he recognized that Parkinson's disease patients are not markedly weak and do not necessarily have tremors ^{(JM, 1888) (JM, La Medicine vibratoire, 1892) (JM, Vibratory therapies, 1892)21}.

Epidemiology

Even though the specific causes of Parkinson’s disease (PD) are not known, its incidence increases with age, especially after 50 years. Both genders and all ethnic groups appear to be susceptible to Parkinson's disease; however, Parkinson's disease is approximately 2 times higher in men as compared with women. Environmental risk factors such as pesticide exposure, repeated loss of consciousness, and antidepressant drug use along with family history are all positively related to Parkinson's disease ^{(Emily M. Rocha, 2018) (Lonneke ML de Lau, 2006)}. It is found in one study, that first-degree relatives of Parkinson’s disease patients demonstrated a 3.5-fold increase in odds of developing Parkinson's disease. Recent evidence has shown the dysregulation of several genes to the Parkinson's disease’s development. It shows that Parkinson's disease may be, somehow, a heritable disease. Additional proposed causes of Parkinson's disease include mitochondrial dysfunction and/or reactive oxygen species formation. Fascinatingly, many of the dysregulated genes involved in the development of Parkinson's disease are also involved in mitochondrial regulation ^{(Lonneke ML de Lau, 2006)}.

There are 4 principal symptoms of Parkinson's disease resting tremor, bradykinesias, rigidity, and decreased postural reflexes. Secondary motor symptoms may include shuffling gait, festination, freezing, dystonia, hypomimia, dysarthria, dysphagia, sialorrhea, micrographic, and glabellar reflex ^{(Aams, 1964)}. There are some definitions associated with Parkinson's disease are listed below:

Akathisia- it is restless sensation of lower extremities (also known as restless leg syndrome).

Cachexia   - having extreme weight loss, especially of skeletal muscles.

Dysarthria - poor articulation.

Dyskinesis - it is irregular movement patterns due to difficulty performing voluntary muscle contractions.

Dysphagia - difficulty swallowing.

Dystonia-abnormal tonicity of muscle tissues resulting in unnatural positions on the head and/or limbs.

Festination- short rapid steps, usually in an attempt to maintain balance due to excess trunk flexion.

Freezing (motor block) - involuntary sudden loss of or inability to initiate movement.

Glabellar reflex - persistent blinking in response to repetitive tapping on the forehead.

Hypomimia - reduced or loss of facial expressions.

Micrographic- progressively smaller handwriting.

Sialorrhea - excessive salivation ^{(Lonneke ML de Lau, 2006)}.

Additionally, Patients of Parkinson's disease often suffer from non-motor symptoms such as neuropsychiatric, cognitive impairment, autonomic, sensory, and sleep disorders. Both of the motor and non-motor symptoms can present significant functional limitations that worsen with the disease stage. Common symptoms and related functional limitations of Parkinson's disease can be found. It should also be noted that Parkinson's disease may also accompanied by other age-associated conditions, such as hypertension, cardiovascular disease, and arthritis ^{(Babinski, 1921) (Bruvn, 1964)}.

Although Parkinson’s disease (PD) is progressive and worsens over time, it is highly individual and affects people differently. All the symptoms of Parkinson's disease are not shown in patients, and its symptoms may vary in severity

between patients. Progression is experienced by different people at different speeds, as well. However, physicians have established different stages varies with the severity of symptoms, that describe how the disease progresses. These five stages of Parkinson’s are known as the Hoehn and Yahr Scale used by physicians throughout the world to classify patients in research studies ^{(Jacopo Pasquini, 2018)}.

Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

Stage one of Parkinson’s disease

The earliest stage is stage one, the symptoms of Parkinson's disease are mild and only seen on one side of the body (unilateral involvement), and there is usually no functional or minimal impairment. The symptoms of Parkinson's disease at stage one are so mild that the patient doesn’t pursue any medical attention and the physician may be unable to make a diagnosis. Symptoms at stage one may include tremors, such as on one hand intermittent tremors, rigidity, or one hand or leg feeling clumsier than another, or it may affect one side of the face, impacting the expression. This is the stage, which is very difficult to diagnose and a physician can wait to notice if the symptoms get worsen over the time before making a formal diagnosis ^{(Jacopo Pasquini, 2018) (Calabresi, 2006)}.

Stage two of Parkinson’s disease

The second stage of Parkinson's disease is also considered an early disease in Parkinson's disease, and it is characterized by symptoms on both sides of the body (bilateral involvement) or at the midline without impairment to balance. Stage two may develop months or years after stage one. Parkinson's disease symptoms in stage two may include the loss of facial expression on both sides of the face, decreased blinking, speech abnormalities, soft voice, monotone voice, fading volume after starting to speak loudly, slurring speech, stiffness or rigidity of the muscles in the trunk which can cause pain in the neck or back, stooped posture, and general slowness in all activities of daily living. However, at this stage, the person may still be able to perform tasks of daily living. Diagnosis may be easy at this stage if the patient has a tremor; however, if stage one was missed and the only symptoms of stage two are slowness or lack of spontaneous movement, Parkinson's disease could be misunderstood as only advancing age effect ^{(Jacopo Pasquini, 2018) (Calabresi, 2006)}.

Stage three of Parkinson’s disease

Stage three is considered mid-stage and is characterized by loss of balance and slow movement. Balance is compromised by the inability to make the rapid, automatic, and involuntary adjustments necessary to prevent falling, and falls are common at this stage. All other symptoms of Parkinson's disease are also present at this stage, and generally, there is no doubt in the diagnosis at stage three. Frequently a physician will diagnose impairments in reflexes at this stage by standing beside the patient and gently pulling the shoulders to determine if the patient has trouble maintaining balance and falls backward (the physician of course will not let the patient fall). An important clarifying factor of stage three is that the patient is still fully independent in their daily living activities, such as dressing, hygiene, and eating ^{(Jacopo Pasquini, 2018) (Roberto, 2018)}.

Stage four of Parkinson’s disease

In stage four, Parkinson's Disease has progressed to a severely disabling disease. Patients with stage four Parkinson's Disease may be able to walk and stand unassisted, but they are noticeably incapacitated. Many use a walker to help them. At this stage, the patient is unable to live an independent life and needs assistance with some activities of daily living. The necessity for help with daily living defines this stage. If the patient is still able to live alone, it is still defined as stage three ^{(Jacopo Pasquini, 2018)}.

Stage five of Parkinson’s disease

Stage five is the most advanced and is characterized by an inability to rise from a chair or get out of bed without help, they may have a tendency to fall when standing or turning, and they may freeze or stumble when walking.

Around-the-clock assistance is required at this stage to reduce the risk of falling and help the patient with all daily activities. At stage five, the patient may also experience hallucinations or delusions.

While the symptoms worsen over time, it is worth noting that some patients with Parkinson's Disease never reach stage five. Also, the length of time to progress through the different stages varies from individual to individual. Not all the symptoms may occur in one individual either. For example, one person may have a tremor but the balance remains intact. In addition, there are treatments available that can help at every stage of the disease. However, the earlier the diagnosis, and the earlier the stage at which the disease is diagnosed, the more effective the treatment is at alleviating symptoms ^{(Jacopo Pasquini, 2018) (Calabresi, 2006) (Bottaro, 2007)}.

Prevalence and Incidence

It is estimated that 60,000 new cases of Parkinson’s disease are diagnosed each year, adding to the estimated one to 1.5 million Americans who currently have the disease. There were nearly 18,000 Parkinson’s disease-related deaths in the United States in 2003. While the condition usually develops after the age of 55, the disease may affect people in their 30s and 40s, such as actor Michael J. Fox, who was diagnosed at age 30. [Everyday Health] [Health Line] A partial list of famous people with Parkinson’s: Muhammad Ali, boxer (boxing include) Johnny Cash, singer 0 Michael J. Fox, and actor Estelle Getty.

Pathophysiology

Although Parkinson's Disease affects numerous areas of the central nervous system, the primary brain areas affected are the basal ganglia, thalamus, and reticular formation, all of which are involved in motor control. The substantia nigra, located within the basal ganglia, is particularly sensitive to the pathological processes involved in Parkinson's Disease. The balance between the neurotransmitters dopamine and acetylcholine is critical for coordinated motor control. In Parkinson's Disease, dopaminergic cells within the basal ganglia are targeted for degradation. This results in an altered balance of these neurotransmitters such that dopamine is decreased, causing a relative increase in acetylcholine. The altered neurotransmitter balance results in the abnormal motor control patterns observed in Parkinson's Disease (^{Emily M. Rocha, 2018) (Aams, 1964) (Jessika, 2018)}.

Role of Dopamine

Like other neurotransmitters, dopamine crosses the synapse—the gap that exists between the postsynaptic receptor and the presynaptic cell—to transfer chemical messages from one nerve cell to another. Membrane storage vesicles in the presynaptic membrane release dopamine into the synapses. It attaches to the postsynaptic membrane after crossing the synapse, activating dopamine receptors there. Remaining unspent dopamine in the synapse is taken up by the presynaptic cell, where it is repackaged into storage vesicles and released back into the synapse (Bertler,1959).
Two enzymes, catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO), can degrade dopamine as it moves between cells in the synapse and make it inactive.

One therapeutic strategy introduces an MAO inhibitor into the synapse, which interrupts the action of the MAO enzyme and prevents the breakdown of dopamine. This allows more dopamine to remain in the synapse and increases the likelihood that it will bind to the postsynaptic membrane ^{(Bertler, 1959) (Barbeau, 1969)}.

Progressive loss of Dopamine

Although dopamine cell loss cannot be measured directly, measurements in neurologically normal people and in nonhuman primates reveal a slow progressive loss of dopamine with age. In Parkinson’s disease the loss occurs at a much greater rate and both biochemical measures and imaging studies suggest there is a significant decrease in dopamine by the time motor symptoms appear. In this view, Parkinson’s disease is an accelerated version of the cell death seen with normal aging. This is illustrated in the graph below, which shows the decline of dopaminergic neurons during normal aging, in idiopathic Parkinson's Disease, in Parkinson's Disease caused by environmental or genetic factors, and in early-onset Parkinson's Disease ^{(Barbeau, 1969) (Bertler, 1959)}.

As the severity of Parkinson's Disease increases, the depletion of dopamine leads to further changes in the basal ganglia pathways, including altered function of other basal ganglia neurotransmitters such as glutamate, GABA, and serotonin. Although there is a relative vulnerability of dopamine-producing neurons in the substantia nigra, not all dopamine cells are affected in Parkinson’s disease; in some parts of the brain the dopamine-producing neurons are relatively spared ^{(Dale, 2012) (Bertler, 1959)}.

Inflammation and new immune response

The trigger of dopaminergic degeneration seems to be multifactorial—affected by both endogenous and environmental elements. Inflammation and immune responses are increasingly being considered as important mediators of dopaminergic degeneration. Large population studies have suggested that individuals taking nonsteroidal NSAIDs have less risk of developing idiopathic Parkinson's Disease, which suggests that anti-inflammatory drugs may be a promising disease-modifying treatment for Parkinsonian patients ^{(shenyu Zhai, 2018) (Calabresi, 2006)}.

New trial phases have involved anti-inflammatory treatments—specifically looking for an objective biomarker in treatments aimed at reducing

inflammatory changes in patients with Parkinson's Disease. Researchers are using neuroimaging tools to develop a relevant biomarker to test this in large clinical imaging trials. The outcome of these trials will provide data to test and monitor the progression of anti-inflammatory treatments for Parkinson's Disease and will help to identify the timely therapeutic window to stop, or at least slow, inflammatory-mediated dopaminergic degeneration ^{(Calabresi, 2006) (Bucy, 1939) (Spiegel, 1971)}

Genetic factor

There are a small number of genes that are known to be involved in up to 6% of total Parkinson's Disease cases, and there are probably other genes that increase the potential risk of Parkinson’s, without necessarily causing it. Up to 15% of Parkinson’s Disease patients have a direct family member who has also had Parkinson’s Disease ^{(Douglas, 2007)}.

Diagnoses

Presently, the diagnosis of Parkinson's is primarily based on the common symptoms outlined above. No X-ray or blood test can confirm the disease. However, noninvasive diagnostic imaging, such as positron emission tomography (PET) can support a doctor's diagnosis ^{(Aams, 1964)}. Conventional methods for diagnosis include:

The presence of two of the three primary symptoms. The absence of other neurological signs upon examination. No history of other possible causes of Parkinsonism, such as the use of tranquilizer medications, head trauma, or stroke Responsiveness to Parkinson's medications, such as levodopa 2.5.

Treatment

Pharmacological treatment of PD can relieve many of the motor symptoms. Typically, levodopa (L-DOPA) is prescribed to compensate for the decreased dopamine associated with PD. Levodopa is structurally similar to dopamine and stimulates the dopamine receptor to decrease symptoms. This has consistently proven to be the most effective treatment for PD. However, as tolerance for L-DOPA develops, symptoms can return during “off” periods. The most common time for this to occur is the period between doses. Additional treatments include anticholinergics, monoamine oxidase-B, and catechol-O-methyl transferase inhibitors.

The majority of Parkinson's patients are treated with medications to relieve the symptoms of the disease. These medications work by stimulating the remaining cells in the substantia nigra to produce more dopamine (levodopa medications) or by inhibiting some of the acetylcholine that is produced (anticholinergic medications), therefore restoring the balance between the chemicals in the brain. It is very important to work closely with the doctor to devise an individualized treatment plan. Side effects vary greatly by class of medication and patient ^{(Jacopo Pasquini, 2018) (Bernadette, 2018) (Calabresi, 2006)}.

Levodopa

Levodopa, which was created more than 30 years ago, is frequently considered the best treatment for Parkinson's disease. By navigating the complex network of tiny blood arteries and cells that filter blood before it reaches the brain and is transformed into dopamine, levodopa can penetrate the blood-brain barrier. These days, levodopa is coupled with an enzyme inhibitor called carbidopa because blood enzymes, also known as AADCs, break down the majority of levodopa before it reaches the brain. More levodopa can reach the brain because carbidopa inhibits it from being metabolized in the liver, gastrointestinal tract, and other tissues. As a result, levodopa dosages are reduced to alleviate symptoms. This development also lessens the acute nausea and vomiting that levodopa side effects frequently cause.

Levodopa typically lessens tremors, rigidity, and slowness in individuals. Patients experiencing a loss of spontaneous mobility and muscle rigidity benefit most from it.
However, the sickness does not stop or slow down as a result of this medicine ^{(shenyu Zhai, 2018; Barbeau, 1969; Berttler, 1959)}.
Levodopa comes in two formulations: one for long-acting or "controlled-release" release, and the other for standard (or instant) release. Because controlled-release prolongs the time it takes for the medication to be absorbed by the gastrointestinal tract, it may have a longer duration of action. Dizziness, dry mouth, nausea, and vomiting are possible side effects. As the dosage is raised, dyskinesias (abnormal movements) could happen. Levodopa may induce disorientation, delusions, or psychosis in certain people ^{(Barbeau, 1969)}.

Dopamine Agonists

Bromocriptine, pergolide, pramipexole, and ropinirole are medications that mimic the role of chemical messengers in the brain, causing the neurons to react as they would to dopamine. They can be prescribed alone or with levodopa and may be used in the early stages of the disease or administered to lengthen the duration of the effectiveness of levodopa. These medications generally have more side effects than levodopa, so that is taken into consideration before doctors prescribe dopamine agonists to patients ^{(Birkmayer, 1961)}. Side effects may include drowsiness, nausea, vomiting, dry mouth, dizziness, and feeling faint upon standing. While these symptoms are common when starting a dopamine agonist, they usually resolve over several days. In some patients, dopamine agonists may cause confusion, hallucinations, or psychosis ^{(Bertler, 1959)}.

COMT Inhibitors

Entacapone and tolcapone are medications that are used to treat fluctuations in response to levodopa. COMT is an enzyme that metabolizes levodopa in the bloodstream. By blocking COMT, more levodopa can penetrate the brain and, in doing so, increase the effectiveness of treatment. Tolcapone is indicated only for patients whose symptoms are not adequately controlled by other medications, because of potentially serious toxic effects on the liver. Patients taking tolcapone must have their blood drawn periodically to monitor liver function. Side effects may include diarrhea and dyskinesias ^{(Spiegel, 1971)}.

Selegiline

This medication slows down the activity of the enzyme monoamine oxidase B (MAO-B), the enzyme that metabolizes dopamine in the brain, delaying the breakdown of naturally occurring dopamine and dopamine formed from levodopa. When taken in conjunction with levodopa, selegiline may enhance and prolong the effectiveness of levodopa. Side effects may include heartburn, nausea, dry mouth, and dizziness. Confusion, nightmares, hallucinations, and headaches occur less often and should be reported to the doctor ^{(Spiegel, 1971)}.

Anticholinergic medications

Trihexyphenidyl, benztropine mesylate, biperiden HCL, and procyclidine work by blocking acetylcholine, a chemical in the brain whose effects become more pronounced when dopamine levels drop. These medications are most useful in the treatment of tremor and muscle rigidity, as well as in reducing medication-induced parkinsonism. They are generally not recommended for extended use in older patients because of complications and serious side effects. Side effects may include dry mouth, blurred vision, sedation, delirium, hallucinations, constipation, and urinary retention. Confusion and hallucinations may also occur ^{(Aams, 1964) (Babinski, 1921)}.

Amantadine

This is an antiviral medication that also helps reduce symptoms of Parkinson’s (unrelated to its antiviral components) and is often used in the early stages of the disease. It is sometimes used with an anticholinergic medication or levodopa. It may be effective in treating the jerky motions associated with Parkinson's. Side effects may include difficulty concentrating, confusion, insomnia, nightmares, agitation, and hallucinations. Amantadine may cause leg swelling as well as mottled skin, often on the legs ^{(shenyu Zhai, 2018)}.

Deep Brain Stimulation (DBS)

DBS offers a safer alternative to pallidotomy and thalamotomy. It utilizes small electrodes which are implanted to provide an electrical impulse to either the subthalamic nucleus of the thalamus or the globus pallidus, deep parts of the brain involved in motor function. Implantation of the electrode is guided through magnetic resonance imaging (MRI) and neurophysiological mapping, to pinpoint the correct location. The electrode is connected to wires that lead to an impulse generator or IPG (similar to a pacemaker) that is placed under the collarbone and beneath the skin. Patients have a controller, which allows them to turn the device on or off. The electrodes are usually placed on one side of the brain. An electrode implanted in the left side of the brain will control the symptoms on the right side of the body and vice versa. Some patients may need to have stimulators implanted on both sides of the brain. This form of stimulation helps rebalance the control messages in the brain, thereby suppressing tremors. ^{(Bottaro, 2007) (Calabresi, 2006)}.

Pallidotomy

This procedure may be recommended for patients with aggressive Parkinson's or for those who do not respond to medication. Pallidotomy is performed by inserting a wire probe into the globus pallidus – a very small region of the brain, measuring about a quarter inch, involved in the control of movement. Most experts believe that this region becomes hyperactive in Parkinson’s patients due to the loss of dopamine. Applying lesions to the global pallidus can help restore the balance that normal movement requires. This procedure may help eliminate medication-induced dyskinesias, tremors, muscle rigidity, and gradual loss of spontaneous movement ^{(Natalia, 2018)}.

CONCLUSION

Parkinson’s disease has been anguishing humans for thousands of years and was described in detail in ancient medical writings. With the discovery of dopamine in the twentieth century and the subsequent development of dopamine replacement therapy, plus surgical techniques such as deep brain stimulation (DBS), many of the debilitating symptoms are now successfully treated—at least for a time ^{(Natalia, 2018)}. Diagnosis is made based on presenting symptoms and tested by medicating with levodopa. Research into the non-motor symptoms of Parkinson's Disease is the focus of intense research, and there is hope of developing treatments that not only arrest the progress of the disease but stop it in its tracks ^{(Tyler, 1992)}. While research into the genetic basis of Parkinson's Disease continues, pharmacologic treatment remains the mainstay. However, it is becoming more sophisticated as new delivery methods (such as inhaled dopamine and intestinal gel) are becoming available, allowing better control of symptoms ^{(Spiegel, 1971) (Tyler, 1992)}.

Despite these advances, the medical management of PD is complex, requiring knowledge of multiple medications that interact in sometimes unforeseen ways. Deep brain stimulation has helped some patients control some symptoms but does not provide across-the-board improvement. A number of gene therapy trials are under way and are showing promise, most focusing on the dopamine pathway. Stem cell therapy appears promising but results are currently inconclusive ^{(Bologna, 2018)}. In light of these challenges, research into neuroprotective therapies is occurring at a feverish pace. Of particular interest, Parkinson's Disease research is uncovering what may turn out to be a common pathophysiologic mechanism underlying dementia and Parkinson's Disease. For now, healthcare providers must continue to educate themselves about currently available treatments and hope for better alternatives shortly ^{(Spiegel, 1971) (Natalia, 2018) (Von)}.

ELP-3 protein plays a vital role in cell motility and neuron maturation. It also modulates transcriptional silencing, and DNA repair and facilitates RNA polymerase. Recent discoveries of ELP-3 protein show that it has an important part in various neurodegenerative diseases including Parkinson’s disease. Due to Environmental factors, oxidative stress and various harmful chemicals like pesticides lead to the generation of ROS which is responsible for the inhibition of ELP- 3 protein, which ultimately causes the degeneration of neurons. Activation of ELP-3 protein will help in neuroprotection in PD, by preventing oxidative free radicals and misfolding of ?- synuclein protein ^{(Yang, 2016)}.

Conflict of interest

We declare that we have no conflict of interest.

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