Uday as emerging therapeutic strategies is being

Uday Raj Sharma*, Anjali SuvarnanAbstractThe Parkinson’s disease can be referred to the second most commonly occurring neurodegenerative disorder in prevalence to Alzheimer’s disease affecting population above the age of 60. The exact cause of the disease is not yet clear even though there exists proposed hypothesis.

The brief account of the disease, history, pathogenesis, diagnosis, management as well as emerging therapeutic strategies is being dealt with in this outlook. IntroductionThe neurodegenerative disorders are referred to the group of chronic as well as progressive degenerative disorders that are characterized by the gradual loss of neurons of the central nervous system (CNS), mainly the brain.1It involves degeneration of a circumscribed group of neurons that may be functionally or neuroanatomically connected2. There occurs deterioration of neuron tissues during the process or progression of neurodegenerative disorders. Neurons that get degenerated cannot be replaced which may lead to dementia, cognitive loss, Parkinson’s disease, Amyotrophic lateral sclerosis, Alzheimer’s disease and degeneration of the cerebellum.

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Thus any pathological process which results in the neuronal death have irreversible consequences.3 The Parkinson’s disease (PD) may affect 1 or 2 persons among 1000 at any point of time. Prevalence of it increases with age and affects 1% of the population above 60 years. The onset of the disease is usually at an age of 65 to 70 years. The inception before 40 years was reported in less than 5% from the cohort based population studies.

4The loss of the dopaminergic neurons occurring progressively present in the substantia nigra pars compacta (SNpc) of the midbrain, and thereafter to the dorsal striatum is an important characteristic feature of PD. Even though the exact cause of is not yet clear, excitotoxicity induced by glutamate neurotransmitters, oxidative stress, apoptosis and certain environmental factors are believed to be the cause for degeneration of dopaminergic neurons. Rather than dopamine, the various other neurotransmitters that have been reported in the involvement of PD are acetyl choline, GABA and glutamate.5 The pathological conclusions designate the presence of Lewy bodies, containing alpha synnuclein and the loss of dopaminergic neurons, which may lead to reduction in the voluntary movements. The lewy bodies may invade the cortical and neocortical regions of the brain in the later stages as the disease progresses. PD is mainly described as a movement disorder characterized by three visible signs such as bradykinesia, tremor and rigidity4.

PD can be defined as chronic and progressive, since it persists over a long period of time, and the symptoms worsen along with time respectively. The patients observe motor impairment, stiffness of the limbs or the trunk, tremor and impaired balance because the neurons in the certain areas get irreversibly impaired or die due to apoptosis. They may also experience difficulty in communication, locomotion and completion of simple tasks.6HISTORYThe symptoms of PD, were mentioned in Ayurveda in which it was referred as Kampavata and they used wild legume known as Mucuna pruriens for the treatment since it was known to contain high quantities of Levodopa from older times. Hence, it can be regarded as the natural source of levodopa. The ancient Chinese literature on medicine named Su Wen has also described the symptoms of the disease. There are also claims to the references on the symptoms in Holy Bible.

The greek physician named Galen has reported on tremors of the hand at rest, palpitation, motor impairment, shivering and convulsions. He has also differentiated the various forms of shaking of the hand or limb on based upon criteria such as origin and appearance. It was first officially described as Shaking Palsy by a physician from London named James Parkinson in his book titled, “An Essay on the Shaking Palsy” in 1817, based upon the symptoms reported in the medical history of six patients. As a result the disease was eventually attributed to his name7.PATHOGENISISThe characteristic feature in PD is neurodegeneration in the SNpc and the nigrostriatal (dopaminergic) tract. This leads to the deficiency of dopamine (DA) in the striatum, responsible for muscle tone and motor coordination.

Thus, there occurs an imbalance between cholinergic (excitatory) and dopaminergic (inhibitory) system of the striatum resulting in motor impairments. Even though the cholinergic system is not directly affected, anticholinergics can be used to restore the induced cholinergic imbalance. The exact cause of selective neurodegeneration is not identified and appeared to be multifactorial.

The free radicals are generated in the presence of Fe2+ ions (basal ganglia-store house of iron) by the oxidation of DA by aldehyde dehydrogenase and monoamine oxidase B. They are quenched by glutathione and other protective mechanisms. They are also responsible for the damage of lipid membranes and DNA, thereby resulting in neuronal degeneration as a consequence of age related or defects in protective mechanism of antioxidants.The environmental toxins and genetic factors attenuate damage to the certain regions of the brain. The genetic predispositions may also contribute to the increased vulnerability of neurons in SNpc.

Ageing induces defects in mitochondrial electron transport chain. A synthetic toxin called N-methyl-4-phenyl tetrahydropyridine (MPTP), which was present as a contaminant of some illicit drugs, produces nigrostriatal degeneration and symptoms similar to PD by impairing energy metabolism in dopaminergic neurons. Excess of the excitatory transmitter glutamate can cause ‘excitotoxic’ neuronal death by inducing Ca2+ overload through NMDA receptors. Drug- induced temporary or reversible symptoms parkinsonism is caused by administration of neuroleptics, metoclopramide (dopaminergic blockers) which is common nowadays, while action of reserpine (DA depleter) is previously known8.The Lewy body is a rounded eosinophilic inclusion present in the soma of the cells and neurites of certain nerve cells, most observable in the SnPc9.

The genes that are responsible for the formation of lewy bodies are PARK1, PARK2 and PARK5 that encode for ?-synuclein, parkin and UCHL1 respectively10,11. Gene responsible for PD normally encodes for ?-synuclein. The mutations in the two independent missense in PARK1 may lead to the substitutions in the single amino acid sequence of the ubiquitin protein12,13. The ?-synuclein filaments are 200–600 nm in length and 5–10 nm in diameter14. Other than ubiquitin15, several other proteins are involved in the pathogenesis of the disease such as proteasome subunits16, heat-shock proteins17 and neurofilaments18, which are constituents of the lewy body.

The ?-synuclein when present in whole length, are present in a natively unfolded state and at high concentrations, it undergoes folding that results in the formation of ?-pleated sheets oligomers, referred to as protofibril. Overexpression of ?-synuclein by the small spherical aggregates, formed by cells are considered identical to the protofibrils of ?-synuclein19.The examination of protofibrils and ?-synuclein cell aggregates correspond to the Golgi apparatus disruption, thereby forming an initial stage of cell damage20. The proteins that get damaged or misfolded normally such as in response to the attack of free radicals are degraded by the UPP (Ubiquitin Proteasome Pathway)21. The degradationpathway begins with the ubiquitination of unwanted proteins. Most of the patients with mutations of PARK2 gene have mutations in both alleles22, indicating the functional deficit in the wild type of protein and they present degradation of dopaminergic neurons in absence of Lewy bodies23.

Parkin induce functional damage of ?-synuclein with the participation of it in the ubiquitination by interaction with protein, synphilin 1 which is a presynaptic protein of unidentified role and adhered to synaptic vesicles24,25. The functional cutback in the UPP obstruct cellular functions which usually depend on the degradation of proteins and culminate defective clearance of protofibrils resulting in toxicity. The disturbances in the dopamine homeostasis and increased oxidative stress are the consequences of the aggregation of dysfunctional ?-synuclein26.In 1990s neuro-inflammation, microglial activation and neuro-glial interactions were described in the animal models of PD. The postmortem analysis of the diseased animal models revealed the presence of inflammatory biomarkers such as up-regulation MHC molecule, NO synthetase, COX-1, COX-2, BDNF, gliosis in brain.

The increase in levels of TNF?, ?2 microglobulin in the cerebrospinal fluid of humans is identified27,28. The microglial cells triggered by the inflammatory mechanisms adhere to the dopaminergic neurons eventually initiating its destruction by phagocytosis, apoptosis and oxidative stress especially in the midbrain neurons are high in number with high iron content and low in glutathione making them more prone for degeneration and oxidative stress28. 1529798-3370884 DiagnosisThe diagnosis mainly depends upon the occurrence of the of slowness (bradykinesia) or absence of movements (akinesia) and tremor at rest of the limbs or opposition to motion at the joints (rigidity), or both29,30. The anomalism in the posture is observed in the later stages and may notbe specific, thus providing lesser significance at the initial stages of the disease. The most common manifestations are: tremor, weakness or clumsiness of limb, stiffness of limb, and movement impairments30.The tremor at rest begins in a limb, at one of the hands that might cease along with the voluntary activity.

It may usually arise at the hands during the time a person walks. The patient portray bradykinesia to the weakness of limb and such abnormalities cannot be diagnosed through strength testing. The agility assessment is performed by tapping of fingers and toes which reveals the diminished, decreased magnitude of activity, and erratic rhythm obvious with the movement32. Large movements are least affected.

The patient may initially recognize struggle to operate minor tools, buttoning etc. Monotonous activities are also disturbed such as in case of brushing of teeth. Rigidity is attributed to the inflexibility correlated with pain and uneasiness of limbs that might be hypothesized as musculoskeletal ailments, most probably tendonitis and bursitis. The progression of symptoms generally occurs from arm to the shoulder32.Initial phases are marked by the sluggishness or indifference of the stride, creeping of feet, and decline in the oscillatory movements of arms. All these can hint a mild hemiparesis.

The other expressions are the struggle in moving outside from cars, ascending from deep seats and undulatory movements on the bed. Straggled motion, rigidity and collapse aren’t commonly observed in the earlier stages33.An attentive investigation of the medical history and physical inspection provide necessary evidences for the ultimate diagnosis. The diagnosis cannot be accurately confirmed by imaging studies or laboratory based investigations. The Magnetic resonance Imaging (MRI) studies of the brain are convenient in the cases with notable physical anomalies. In Photon Emission Computed Tomography (PET) imaging technique, the ligands that adhere with the dopamine transporters can be visualized to yield the density of dopaminergic neuron terminals. The ligands are accessed from Europe and testing procedures are conducted in USA.

The Dopamine-transporter (DAT) imaging technique cater favorable diagnostic clues for prophylaxis contingent upon the ambivalent or vague clinical conclusions34,35. The response of the subject to a diagnostic trial employing levodopa was recommended for the diagnostic test but is ethically questioned, if and only if the symptomatic stringency does not justify its prophylaxis for longer duration36.Differential diagnosisThe physician should be able to differentiate between the cases of drug induced parkinsonism and parkinsonism plus syndromes during practice.Drug-induced Parkinsonism is essential to take into consideration due to its recoverable nature.

The setback might take weeks or months even after the discontinuance of offending medicament. In a study based on population, it has been reported in 20% of the subjects37. The Dopamine receptor antagonists which are inclusive of neuroleptics, antiemetics and calcium channel blockers can promote PD.

Drugs including amiodarone, valproic acid, and lithium also induce Parkinsonism, but their occurrence is rare and the mechanism is unknown.For about 25% of the subjects, who have acquired PD as a consequence of other ailments are referred to as parkinsonism-plus syndromes31. The other signs are falls or dementia during initial stages, gait deformities, aberrant eye movements, Babinski response, orthostatic hypotension, urinary retention, notable disability in a period of five years subsequently the commencement of the initial symptoms. Their reaction to anti parkinsonian drugs is unsatisfactory and possesses impaired diagnosis.Pharmacological therapyThe drug treatment is initiated only if the subject is distressed adequately by symptoms or if severe impairment is induced. The decisions regarding pharmacotherapy are undertaken by priorities of patients.

The drugs used for the initial prophylaxis of locomotor symptoms are levodopa, dopamine agonists, anticholinergic agents, amantadine, and selective monoamine oxidase B (MAO-B) inhibitors38,39.The potency of dopaminergic agonists is higher when compared to other drugs such as anticholinergics, amantadine, and selective MAO-B inhibitors as evident from the clinical practice. As a result they are the first line drugs suggested for patients suffering from annoying symptoms. The guidelines from the American Academy of Neurology40 and the evidence-based review of the Movement Disorder Society38 illustrate the initiation of therapy with levodopa or a dopamine agonist is judicious.LevodopaLevodopa is the precursor of dopamine. It is believed as the better efficacious antiparkinsonian drug in comparison with dopamine agonists. During randomized trials conducted using dopamine agonist and levodopa, there has been progression in the performance of day to day tasks and locomotor characteristics with levodopa therapy for around 40-50%41-43.

The combination of levodopa with a peripheral decarboxylase inhibitor such as carbidopa, cut down its peripheral decarboxylation before entry into the brain, which can be obtained in form of immediate as well as sustained release formulations. There is another combination of carbidopa- levodopa with a catechol O-methyltransferase inhibitor (COMT), such as entacapone, devised to extend the action of levodopa by inhibiting its O-methylation40,44.The reasons for the failure of response to levodopa comprise insufficiency in doses or prophylactic period and drug-drug interactions (e.g.

, adjuvant therapy with metoclopramide or risperidone). A confirmatory trial of it is to be supervised, for three months in which there should be steady increase in doses up to 1000 mg/day (immediate-release form) or prior to manifestation of adverse events to arrive into the conclusion that response to levodopa is not observed in a patient31. Levodopa may drop potency over time, since more than 80% of patients who have undergone treatment greater than 10 years encounter dyskinesia and ”on-off” periods45.

This result in increased variations of clinical condition, by which bradykinesia and rigidity may deteriorate abruptly for minutes or hours, and reverse back to normal. This event is not observed in case of untreated patients or those in treatment with other drugs. The ‘off effect’ is that there occurs sudden cessation in movement mostly while patient walks and finds frozen to that point, inability to arise from seated position even if sat few moments earlier.

Fluctuating plasma levels of levodopa may give rise to dyskinesia. The capability of neurons for the storage of dopaminediminishes with the progression of disease. Therefore, the efficacy depends upon the uninterrupted synthesis of dopamine, which can be met by continued external delivery of levodopa46.Dopamine agonistsThe dopamine agonists are first line agents for the treatment of PD even though they are less efficacious when compared to levodopa.

They exert action DA receptors on striatum for patients at the advanced stages of disease, whose competence for the formation, accumulation and discharge of DA from precursor levodopa is disoriented. They retain extended duration of action and activate DA receptors as well as its subtypes that are particularly affected in PD. They do not add up to the degeneration of dopaminergic neurons by the mechanism of oxidative metabolism as observed with levodopa8.

Bromocriptine, pergolide and cabergoline act mainly on D2 or D3 receptors than D1 receptors. Yet the application of these agents is restricted considering the incidence of adverse effects, for instance nausea, vomiting, fibrosis of lungs, peritoneum and pericardium. As a result they are being interchanged with other drugs such as pramipexole and ropinirole, which are selective for D2 or D3 receptors and do not exhibit the variations in plasma levels as observed in levodopa. They may lead to lethargy, coma and hallucinations. Current researches reveal the susceptibility to behavioral disorders like disproportionate gambling, gourmandizing and exuberant sexual behaviour46.MAO B inhibitorsSelegiline is a highly selective MAO-B inhibitor that do not possess undesirable peripheral issues as observed with other non-selective MAO inhibitors. It does not induce ‘cheese reaction’ or exhibit dug-drug interactions.

The repression of MAO-B enzyme safeguard dopamine from extraneuronal metabolism and was used in addition with levodopa at the beginning. The combination of selegiline and levodopa is found to be more potent rather than use of levodopa alone has resulted in the suppression of symptoms and prolongation of life which is evident from long term clinical trials. It is degraded to amphetamine that may give rise to excitement, anxiety disorders and insomnia. Rasagiline, a comparable drug to it that can be used for mitigation of symptoms and deceleration of disease advancement. A relatively new drug, safinamide is presently undergoing clinical trials that blocks reuptake of dopamine and MAO-B.

AnticholinergicsThe atropine was used for the treatment of PD for more than 100 years until the discovery of levodopa. Generally muscarinic receptors or acetylcholine exercise hinder dopaminergic neuronal terminals. Therefore muscarinic receptors have to be blocked to assure the adequate supply of dopamine. The adverse effects include dry mouth, constipation, vision impairment, urinary retention which may be discomfort able for a few.

These drugs are rarely used nowadays, except for treatment PD symptoms in exception to the patients administering neuroleptic drugs46.COMT inhibitorsThe levodopa and dopamine are metabolized mainly by MAO and COMT enzymes. The COMT enzymes are implicated in the relocation of a methyl group from S-adenosyl-L-methionine, a donor occasioning the synthesis of pharmacologically inert species such as 3-methoxy tyramine and 3-O-methyl DOPA by disintegration of dopamine and levodopa respectively. Approximately 99% of levodopa given orally get metabolized peripherally, thereby retarding its entry into the CNS. Levodopa is mostly converted into DA by aromatic L-aminoacid decarboxylase (AADC) leading to nausea and hypotension. The inclusion AADC inhibitors like carbidopa scale down the production of DA however enhances the fragment of levodopa that is methylated by COMT. The primary mechanism of COMT inhibitors is the blockade of the peripheral transformation of levodopa, thereby elevating its plasma half-life in conjunction with segment of every single dose entering the CNS.

Entacapone and tolcapone are the most commonly used drugs.AmantadineAmantadine, an antiviral agent commonly prescribed for the prevention and management of influenza A. It was observed to modify discharge of dopamine at the striatum, possess antimuscarinic action properties and hinder NMDA glutamate receptors. The mechanism responsible for antiparkinsonian activity is not defined.

It is used as mild therapy of mild PD and as an adjunct in patients on levodopa with the dose related fluctuations and dyskinesias47.2340864104543Non Pharmacological managementPsychological support and education should be offered to the patients once PD is diagnosed. The patients should be made clear that the disease may extend its course longer than ten years, the degree of disease advancement diverges considerably in person-person and treatments focus on the amelioration of symptoms. The persons who are associated in the support of patients in their advanced stages should be more vigilant than those in the initial stages of the disease. Timely counselling should be given regarding exercises, inclusive of physical stretching and strengthening, vigor of cardiovascular system and balance training. However, there are evidences only from the short-term studies that the exercises may enhance day to day tasks, performance, posture, speed, and body balance48,49.Physical exercisesThe patients with parkinsonism tend to move gradually with the advancement of disease.

Occasionally they experience difficulty or inability in walking, physical imbalance and motor incoordination. The muscles steadily may develop weakness due to its reduced activity. The physical exercises and sports target to decelerate muscular weakness. The exercises comprise of stretching, strength training, muscular awaking and relaxation, balance restoration, dancing, musical therapy, tai chi, qigong, walking, running, etc.The physiotherapist can be employed for support since they are capable to provide physical training or exercises to patients and also demonstrates to perform on their own later on. The type and the utility of exercises rely on the individual priorities as well as overall bodily state.

For example, vigorous exercises are executed in the primary phases of the disease when the symptoms aren’t severe. The therapy possesses diverse focal points considering the stages of the ailment. In the initial phases the prominence is typically on the maintenance of physical fitness and resilience. At the advanced stages, the attention is delivered to rigidity of joints and evasion of falling.

The researches have confirmed the promising beneficial results exercises such as improvement in flexibility and hastiness of movement in a short tenure. They have also developed voluntary coordination as well as enhancement in balance making it simpler to accomplish everyday tasks50.Occupational therapyThe occupational therapy intends to elevate a patient’s occupational performance and involvement in daily tasks and life and practices a customer adjusted approach51. Even if the virtues of it aimed at patients suffering from PD is extensively acknowledged by physicians and evident from promising short term studies, however stringent studies evaluating the exact beneficial effects of it PD patients is not available52-53.Speech therapyAbout 89% of population with PD suffers from disordered communication skills. The limitations in communication are inclusive of softness of voice, monotone, hoarseness of voice and imprecise diction and reduced facial expression (masked faces)54-57. The elasticity of muscles presents in the larynx, tongue and face declines with time.

The patient may struggle to deliver the accurate words or comprehending others.The speech therapy involves practice of talking aloud with clarity and precision. It also focuses on exercises to improve the zygomorphic muscles, facial expressions and respiration employing specific relaxation and speech skills or vocal techniques. The aim is to be able to express yourself better again. Patients have a tendency to refrain from communication with other people as they fear of insecurity and embarrassment.

Therefore, the treatment should aim to offer confidence in conversation. The difficulties in swallowing is also dealt with58,59.Psychological supportSerious psychological strain is predominantly prevalent in the later stages. Even at the initial phases, patients find it challenging to comprise with the disease and the aggravation of symptoms over time.

Consequently, they have to be supported by psychological counselling. The signs of depression may also arise amid the period of illness, thereby requiring adequate treatment. There are also numerous options for psychological support from clinicians, along with various self-help organizations for the patients and those involved in patient support.60Unified Parkinson’s disease Rating Scale (UPDRS)The UPDRS can be termed as a scale generated in order to integrate components from other prevailing scales, to offer widespread, well-organized as well as flexible measures to screen disabilities interconnected with PD61. Accordingly investigators use UDPRS to assess the effectiveness of antiparkinson drugs and oversee disease advancement as follows:Part I assesses intellection, conduct, temper and humor.

Part II involves self assesment of the day to day undertakings besides communication, ingestion, writing, clothing, hygiene, salivation, etc.Part III is based upon scoring of motor activities by clinician, where the patients are considered for speech, tremor, facial expression, mobility, postural tremor of hands, rigidity, finger taps, hand movements, rapid alternative pronation– supination movement of hands, leg agility, ease of arising from a chair, posture, postural stability, gait, and bradykinesia. Each item is evaluated on a scale of 0 to 4.

A rating of 0 on the motor performance evaluation scale indicates normal performance.A rating of 4 on the motor performance evaluation scale indicates severely impaired performancePart IV is the Hoehn and Yahr staging of severity of PD (As given in the table below)62Stages Characteristics0 No clinical signs evidentI Unilateral involvement, including the major features of tremor, rigidity, orbradykinesia; minimal functional impairmentII Bilateral involvement but no postural abnormalitiesIII Mild to moderate bilateral disease, mild postural imbalance, but still abilityto function independentlyIV Bilateral involvement with postural instability; patient requires substantialassistanceV Severe disease; patient restricted to bed or wheelchair unless aidedNewer Therapeutic interventionsNowadays immense advancement has been presented for the management of PD. Numerous hopeful treatments are arising as a consequence of innovations made in experimental therapeutics. Though levodopa endures to be the highly effective drug for managing thesymptoms, however is linked alongside substantial complications like the “wearing off” phenomenon, levodopa stimulated dyskinesia in addition to further motor complications. The COMT inhibitors, dopamine agonists and other non-dopaminergic drugs are substitutes implemented in the therapy of PD or alongside levodopa.63The probable newer interventions are adenosine receptor antagonists (istradefylline, preladenant), serotonin antagonists (eltoprazine,landipiridine), glutamate antagonists besides improved COMT and MAO inhibitors.

All these drugs are presently being subjected to the various stages of the clinical trials.64The deep brain stimulation (DBS) has emerged as a pioneering surgical technique, where the electrodes are implanted onto the particular sections of the brain which are competent to sense electrical impulses delivered from a medical accessory called brain pacemaker or neurostimulator surgically deposited beneath the collarbone.65 This outcomes in activation of the thalamus (ventral intermediate nucleus region) in brain offering significant relief from tremor as well as PD.

Likewise, activation of the globus pallidus (interior section or subthalamic nucleus) considerably diminish bradykinesia, rigidity, gait abnormalities and tremor.66Cell transplantation has been initially investigated as a hopeful treatment for PD in 1985.67 The transplantation utilizing ventral mesencephalic cells of foetus that are rich in dopamine, appeared as a assuring therapy since it has presented momentous symptomatic relief.68The gene therapy is fundamentally explored for management of genetic disorders by means of alteration or modification of defective genes.

69,70 Direct injection of genes did not yield promising results. Subsequently, there occurred the requirement of utilizing diverse types of vectors to ensure effective provision of genes into the central nervous system. Gene therapy for PD comprises in cooperation of viral and non-viral vectors however viral vectors have exhibited productive outcomes. Lentivirus and adeno related viruses are the most recurrently used vectors.71Transcranial magnetic stimulation (TMS) is a non-intrusive technique exercised for activation of brain, centered according to the strength of magnetic field in order infiltrate through skull and meninges of brain and successive generation of electric impulses into the neurons involved in the production of action potential and depolarization. The principle take in operation of magnetic stimuli across the stimulation coil affixed to the intact head of the patient.

72 Repetitive Transcranial Magnetic Stimulation (rTMS) has been enforced to the greater extend in the last twenty years in PD so as to improve, augment and reestablish motor activity. Extended studies are recommended for the recognition of finest treatment parameters and evaluation of possible adjuvant usage of rTMS in cases with DBS implants.73Early surgery for movement disorders treated tremor by variety of lesions such as the ablation of the cerebral cortex74,75, sectioning of the pyramidal tract at the cervical level76, sectioning of the cerebral peduncles in the midbrain77 and ablation of the basal ganglia78,79.

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