Therapeutic Approaches for the Management of Parkinson’s Disease

 

Jhakeshwar Prasad*, Ashish Kumar Netam, Ritika Singh, Manisha Sahu, Trilochan Satapathy, S. Prakash Rao, Purnima Baghel, Mahendra Kumar Sahu

Columbia Institute of Pharmacy, Tekari, Raipur (CG) pin 493111.

*Corresponding Author E-mail: jhakeshwarprasad03@gmail.com

 

ABSTRACT:

Parkinson‘s disease (PD) is a chronic, neuro generative and movement disorder, which involves progressive fall of motor function due to loss of dopamine producing cells particularly in the substantial nigra area of the brain. It is the most common neurodegenerative disorder, which develops gradually and the symptoms may worsen over the time. It is characterized by progressive loss of muscle control leading to rigidity, tremors and hypokinesia. It has an interesting pathophysiology in which acetylcholine shows hyperactivity. In recent times, the important role of oxidative stress in neurological deformity, including Parkinson‘s disease, have been mostlyexhort. The progression of PD and the degree of impairment vary from individual to individual. Most individuals who develop PD are 60 years or older. Men are one and a half times more likely to have PD than women. More than 10 million people worldwide are living with PD. Some people with PD live long productive lives, but others grow to bedisablea good dealextrarapidly. Hallmarks of PD include protein α-synuclein also called Lewy bodies found not only in midbrain but also in the brain stem and olfactory bulb. Although there is no cure available for this disease some drugs like Levodopa and Carbidopa proved partially effective. Herbal approaches can be a new advancement in this field. When it comes to the effectiveness of medicines and traditional medicines, often over time, the response to Parkinson's symptoms will stop responding. We suggest that treatment with herbal-based medicines may be a fruitful approach for the management of PD.

 

KEYWORDS: Parkinson‘s disease, Neurogenerative disorder, Antioxidant remedies, Herbal medicines.

 

 


INTRODUCTION:

In 1817, James Parkinson was first described the clinical syndrome that later to bear his name. Parkinson's disease is a chronic (persistent or long-term) disorder of part of the brain.[1] Parkinson’s disease (PD) is a common degenerative neurological disorder that affects a person’s control of their body movements is a synucleinopathy Itis mostly affects the approach the brain co-ordinates the movements of the muscles in different parts of the body. It is thought to be genetic in a very small percentage of cases.

 

Parkinson's disease should be accompanied by tremors, stiffness, slowing, balance problems all patients with Parkinson's disease should be referred natural to a specialist in differential diagnosis[2] Parkinson's disease is less common (prevalence 0.2%),.[3] The sympathetic of the pathophysiology of Parkinson’s disease (PD) is a mainbefore condition for developing new treatment and diagnosis strategies for this common disease. While significant progress which have been made in our knowledge of the scientific deficits of PD, the complete pathophysiology of Parkinson's disease at rest a problem that is not so far solve. Because of its rhythmic character and recent advances in methodology for analysis of periodic phenomenon, most of the basic investigate is oriented toward the revise of tremor.[4]



Fig: 1. Etiology of Parkinson’s disease.


 

ETIOLOGY OF PARKINSON'S DISEASE:

Parkinson's disease  is multifactorial disease with genetics, aging, environmental agents.Their etiology are an Idiopathic Parkinson's disease is supposed to a permutation of genetic and environmental factors.[5] An environmental risk factors allied with the development of Parkinson's disease include use of pesticides, living in a rural setting, using up well water, exposure to herbicides, and immediacy to industrial plants or quarries, although cigarette smoking and caffeine consumption have some protective role. Several individuals have been identified that developed parkinsonism after self-injection of l-mcthyl4-phenyl-l,2,3,6-tetrahydropyridine,8 The oxidation hypothesis suggests that dopamine oxidative metabolism produces free radicals that could playa role in the development or progression of PD. The metabolism of dopamine leads to the formation of hydrogen peroxide. Hydrogen peroxide usually is vacantquicklyvia glutathione. If hydrogen peroxide is not cleared adequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage.[6] In PD, the levels of reduced glutathione are decreased, suggesting the loss of protection against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons, thereby promoting the formation of free radicals. Increased iron accumulation in substantia nigra could be the cause of hyperechogenicity seen in most PD patients on transcranialsonography", Thus, PD is associated with an increased dopamine turnover, decreased protective mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation. Mutations in the alpha-synuclein gene can cause PD. It is now clear that these mutations are an exceedingly rare cause of PD. Alpha-synuclein is a major component of Lewy bodies in all PD cases. Lewy bodies contain alpha-synuclein and most also contain ubiquitin, which conjugates with proteins targeted for proteolysis. Abnormal aggregation of alpha-synuclein into filamentous structures may precede ubiquitization. One hypothesis states that the mutation alters the configuration of alpha-synuclein from alpha helix to beta-structure that could aggregate into sheets. Therefore, PD may be associated with abnormal folding of alpha-synuclein, leading to excessive aggregation causing neuronal death.[7]

 

 

Fig. 2 Etiology of Parkinson's disease.

 

Genetics Factors:

PD is generally a sporadic disease; there are a increasing numberof single gene mutations which have been known., These are genes have been mapped via genetic linkage along with six genesknown: a-synuclein (SNCA), ubiquitin C-terminal hydrolase like 1(UCH-L1), parkin (PRKN), LRRK 2, PINK 1 and DJ-1 genes.[8] Thesesingle gene defects with the notable allowance of LRRK 2 are in controlfor only a small number of patients with PD, although more importantlytheir identification and the proteins that they encode for areproviding significant understanding into the disease mechanisms that may beresponsible for PD and other neurodegenerative diseases.[9] A point mutation of SNCA gene occurs in early fall of PD of affected members in an autosomal influenza form. In the affected members, repetition or triplications of the SNCA gene leads to the symptoms of PD which increases the likelihood of being born in the later age of the fourth or fifth, which can be a factor in the highly toxic sputum disease of SNCA. PD symptoms developing at a later age in the fourth or fifth decades raising the possibility that overexpression of SNCA may be a factor in sporadic disease. Lewybodies have been known in some LRRK 2 cases. Many of theLRRK2 patients informed have typical features of PD with onset inmiddle or late onset. Symptoms at onset might be characteristic of idiopathic.[10]

 

Environmental factors:

The environmental factors that predispose to the developmentof PD have been proved indescribable. Living in a rural environment seems toconverse an increased risk of PD, and maybe causally linked to thissome but not all the epidemiological studies have been a relationshipbetween exposure to pesticide use and wood preservatives. The only consistent environmental factor is a strong negative correlationbetween cigarette smoking and the development of the disease. It isalso possible that mitochondrial dysfunction in PD is triggered by oneor more environmental toxins.[11]

 

PATHOPHYSIOLOGY:

The major neuropathological discovery in PD is the loss of chromated dopaminergic neurons, which is compact and the presence of Lewy body of substantia nigra. Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and dense cores composed mainly of alpha-synuclein, Lewy bodies blur for alpha-synchicine and also ubiquitin. [11] The presence of Lewy bodies within pigmented neurons of the substantia nigra is characteristic of idiopathic PD. Lewy bodies are also found in other parts of the brain such as locus ceruleus, nucleus basalis, intermediolateral column of the spinal cord, cortex, and other areas. Mid brain and nigrostriatal dopaminergic neurons, archicortex and primary and associative parts of the cortex.[12] The pathological results of Parkinson’s disease (PD) are marked loss of dopaminergic neurons in the substantianigracompacta (SNc), which causes dopamine depletion in the striatum, and the presence of intra cytoplasmic inclusions known as Lewy bodies in the remaining cells.[13] It remains unclear why dopaminergic neuronal cell death and Lewy body formation occur in PD. The pathological changes in PD are seen not only in the SNc but also in the locus coeruleus, raphe nucleus, dorsal motor nucleus ofthe vagal nerve, olfactory bulb, parasympathetic as well as sympathetic post-ganglionic neurons, mynertnucleus.[14] Wide spread neuropathology in the brainstem and cortical regions are responsible for various motor and non-motor symptoms of PD. Although dopamine replacement therapy improves the functional prognosis of PD, there is currently no treatment that prevents the progression of this disease.[15]

 


 


Fig. 3 Pathophysiology of Parkinson’s disease.

 

 

 

 


MANAGEMENT OF PARKINSONS DISEASE:

Treatment, as always, should be tailored to the needs of the individual. Patients should be helped to make informed decisions about their care, and try to involve the carers as much as the patient will allow. The management of Parkinson’s disease has developed rapidly over the last 10 years with the advent of new drugs, new classes of drug, and the recovery of interest in surgery. [16] Although there has been a move to patients being cared for by neurologists or geriatricians with a different interest in the condition, along with a Parkinson’s disease for the probable future most general neurologists will continue to treat patients with the condition.[17] The current review uses an evidence based approach to provide an inform on the current place of medical treatment for Parkinson’s disease. Inappropriately, it is not always possible to be prescriptive and many treatment decisions must be left to the judgement of the individual clinician and the desires of patients.[18]Treatment, as always, patients should be able to the individual make informed results about their care, and try to include as much as will permits.[19]


 

 

 


Diagnosis:

The criteria is diagnostic of Parkinson's disease which  are diagnosed; there is no ultimate test for diagnosis previously, pathological authentication of Lewy Bodies identification on the standard for diagnosis is measuredcondition ".[20] Diagnostic criteria have been developed by the UK Parkinson's Disease Society Brain Bank" and National Institute of Neurological Disorders and Stroke (NINDS) Differentiating PD from other forms of Parkinsonism can be challenging early in thecourse of the disease, when signs and symptoms overlapwith other syndromes.[21]

 

TREATMENT OF PARKINSONS DISEASE:

The medicines for PD are the most common medicine; there is a need to correct the deficiency of target dopamine; It is a shortage of medicinal remedies usually starts when the symptoms are disabled or interrupted daily. [22] Treatment can be different according to the symptoms of patients, age and responses to specific medicines. It often takes time to find the best combination of drugs for each patient. Parkinson's disease can't be cured, but medications can help control symptoms, often dramatically.[23] Pharmacological treatment of PD includes L-dopa usually combined with 3.4-dihydroxyphenylalanine (DOPA) decarboxylase inhibitors (such as carbidopa and benserazide that reduce decarboxylation of levodopa before it reaches the brain), selective monoamine oxidase-B (MAO-B) inhibitors (selegiline and rasagiline), catechol-O-methyltransferase (COMT) inhibitors (entacapone and tolcapone), dopamine receptor agonists (pramipexole and ropirinile), amantadine and anticholinergics. Patients with PD respond to these agents with improvement in disease signs and symptoms.[24]

 

The following medications used to treat Parkinson’s disease are:-

·        Levodopa

·        Dopamine agonists

·        MAO-B inhibitors

·        COMT-inhibitors

·        Amantadine

·        Anticholinergics[25]

 

Levodopa:

Levodopa has a specific useful effect in PD efficacymore than that of any other drug used only. It is natural by itself, but is the immediate precursor of the transmitter DA.[26] Levodopa is used mainly combination with peripheral dopa decarboxylase inhibitor (PDI) carbidopa or benserazide. Levodopa, a dopamine precursor, is careful to be the most effective antiparkinsonian agent. [27] In randomized trials comparing levodopa and a dopamine agonist, activities of daily living and motor features of PD improved with levodopa by about 40% to 50% (as compared with approximately 30% with dopamine agonists).[28]

 

Dopamine agonists:

Dopamine agonists, e.g. ropinirole or pramipexole, may be measured as an alternative first-line treatment for motor symptoms in patients with Parkinson’s disease, particularly in those aged under 40 years.[29] Dopamine agonists are also frequently used in combination with levodopa for patients who have not achieved adequate symptom control and may “smooth-out” motor fluctuations.[30] Patients taking dopamine agonists may understanding fewer motor problems than patients taking levodopa treatment. compared to levodopa, dopamine agonists cause more sleepiness, oedema and hallucinations, and are informed to be associated with higher “dropout” rates in clinical trials. [31] Dopamine agonists are slightly less effective than levodopa, they are alternative first-line agents for PD, especially in younger patients. [32] In general, anticholinergic agents are not used for PD because of associated adverse effects. However, they are sometimes added if tremor is particularly difficult and unresponsive to other drugs, although evidence is lacking to support particular efficacy of these agents in treating tremor.[33] MAO-B inhibitors and amantadine have fewer adverse effects and require little titration to reach therapeuticDoses"[34] The central objective of using any of the above medications is to control or manage motor symptoms. Since these symptoms are largely due to the increasing supply of dopamine in the brain, most symptomatic medications are designed to replenish, mimic or enhance the effect of this chemical that medication usage is only a part of the whole treatment plan for effectively treating PD.[35] Regular exercise, physical therapy, occupational therapy, speech therapy, holistic practices, nutritional consultation, support groups, education, psychological counseling, intelligent use of assistive devices and caregiver relief are all importantaspects of the greatest treatment plan.[36]


 

 

Figure 4. Pharmacologic treatment options available for PD.

 


Monoamine Oxidase type B inhibitor:

Selegilinemay be appropriate for patients with Parkinson’s disease who have mild motor symptoms and can delay the need for levodopa treatment. Selegiline can be given alone or in combination with a levodopa-dopa-carboxylase inhibitor combination. Selegiline inhibits the catabolism of dopamine and may also be combined with levodopa treatment to reducesymptoms in patients with advanced Parkinson’s disease. [37]

 

Catechol-O-methyl transferase inhibitors:

 The patients with advanced Parkinson’s disease originate to experience “end-of-dose” fall that cannot be stabilised by adjusting the regimen of current medicines, catechol-O-methyltransferase (COMT) inhibitors, i.e. entacapone and tolcapone, may be used as combination treatment with levodopa and dopa-decarboxylase inhibitors. COMT inhibitors, like dopa-decarboxylase inhibitors, prevent the peripheral conversion of levodopa to dopamine. [38]

 

Amantadine:

Amantadine is a weak dopamine agonist and is a potential treatment possibility for people with early onset Parkinson’s disease, but should not be considered as a first line treatment. Amantadine may be used in combination with other treatment, usually levodopa, to control dyskinesis once patients have activated to display motor fluctuations. The effect of amantadine is thought to be modest and to last less than eight months. However, a recent trial recommends that amantadine may help control dyskinesis for several years. [39]

 

Antimuscarinicagents:

Medicines are less effective than dopaminergic treatments. Antimuscarinic medicines, e.g. benztropine, procyclidine and orphenadrine hydrochloride. Parkinsonian symptoms in patients being treated with antipsychotics, but are generally not used in patients with Parkinson’s disease. However, benztropine may be considered for the treatment of levodopa-resistant tremor in younger patients. Antimuscarinic medicines are poorly tolerated by older patients and are associated with cognitive impairmentand sedation. [40]

 

CONCLUSION:

Parkinson‘s disease (PD) is a chronic Neurogenerativedisorder, which have involves progressive fall of motor function due to loss of dopamine producing cells particularly area of brain such as in the substantial nigra. It is a syndrome involving slowed mobility (bradykinesia), and at least one of the following three features: tremor, rigidity and postural instability. In future research may reveal disease specific biomarkers allowing for its variation from other neurodegenerative disorders. These can be useful for diagnosing the disease in affected persons, it will be suitable for identifying family members or populations at risk, thus providing an opportunity to initiate neuroprotective therapy at an asymptomatic stage.

 

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Received on 02.06.2018       Modified on 30.06.2018

Accepted on 12.07.2018       ©A&V Publications All right reserved

Res.  J. Pharmacology and Pharmacodynamics.2019; 11(1): 46-52.

DOI: 10.5958/2321-5836.2019.00009.0