A newer approach to Parkinson's disease: Addressing therapeutic features, repurposing drugs and the latest concepts with future goals

*Corresponding author: Mohini N Rathod Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. A newer approach to Parkinson's disease: Addressing therapeutic features, repurposing drugs and the latest concepts with future goals Uzma S Patel, Ammara J Sufi, Rubin S Mehra, Atiya S Patel, Dr.Malleshappa N Noolvi and Mohini N Rathod * Department of pharmacy, Shree Dhanvantary Pharmacy College, Kim 394110. Surat, Gujrat, India. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 Publication history: Received on 15 December 2024; revised on 23 January 2025; accepted on 26 January 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.21.1.0098 Abstract The article reviews advances in understanding and managing Parkinson’s disease (PD), a progressive neurodegenerative disorder. PD primarily results from neuronal damage in the brain regions controlling movement, causing dopamine deficiency. With over 10 million people affected globally, it poses a significant healthcare challenge. The disease's multifactorial etiology includes genetic, environmental, and epigenetic factors, with aging as a major risk factor.The review discusses the pathophysiology of PD, highlighting α-synuclein aggregation and its role in neurodegeneration, and addresses diagnostic methods like MRI and DAT-SPECT imaging, which enhance diagnostic accuracy. It examines therapeutic avenues, including pharmacological interventions like levodopa, dopamine agonists, and MAO-B inhibitors. Challenges with long-term medication use are also discussed.Emerging therapies such as electroceuticals, gene therapy, and stem cell approaches show promise in disease management. Non-invasive treatments like focused ultrasound and innovative technologies like deep brain stimulation (DBS) aim to modulate brain activity to alleviate symptoms. Complementary approaches, including physical, psychological, and nutritional therapies, offer holistic care, enhancing quality of life.The review underscores the need for personalized medicine and continuous research to address unanswered questions and develop disease-modifying treatments. It concludes by advocating for a multidisciplinary approach and the integration of advanced technologies to improve patient outcomes and address PD’s complexity. Keywords: Parkinson’s disease; Neurodegeneration; Dopamine deficiency; α-Synuclein aggregation; Personalized medicine; Emerging therapies 1. Introduction Parkinson's disease is a progressive neurodegenerative illness that damages and/or destroys the neurones, or nerve cells, in the area of the brain responsible for controlling movement. Even though the brain needs a certain amount of dopamine to regulate movement, weaker neurones produce less dopamine than healthy neurons. Some Parkinson's disease patients have low levels of norepinephrine, a chemical that communicates through nerve endings and controls various bodily functions, such as heart rate and blood pressure. Over 10 million individuals worldwide already suffer from Parkinson's disease, and nearly 1 million instances will occur in the US this year. Over 10 million individuals worldwide suffer from Parkinson's disease (PD), and 60,000 Americans are diagnosed with the disease each year. According to estimates, only 4% of instances of Parkinson's disease are identified before the age of 50, although the condition is increasingly prevalent as people age.[1] Age is the main risk factor for this disease, hence it is anticipated that as the population ages, so will the prevalence of this disorder. According to some estimates, the number of people with Parkinson's disease may treble to almost 12 million cases by 2040.[2] Males are more likely than females to acquire this disease, accounting for 52.5% of cases vs World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 569 47.5%. Likewise, people from nations with medium-to-high sociodemographic indices represent 85.2% of instances, compared to 14.8% in nations with a low sociodemographic index.[3] The use of pesticides, tobacco, coffee, physical activity, and a history of traumatic brain injury are other lifestyle-related risk factors that have been found.[4] Furthermore, PD has been linked to bacteria like Helicobacter pylori and viral microbes including Ebolavirus, Human Immunodeficiency Virus, and Herpes Simplex Virus-1.[5] Nonetheless, the most significant risk factor is genetic, as there are presently over 90 loci linked to this illness.[6] Historically, bradykinesia, postural instability, resting tremor, and stiffness have been used to describe Parkinson's disease.[7] Non-motor and motor aspects comprise the clinical presentation; the traditional presentation includes motor symptoms. Anxiety, sleep issues, gastrointestinal issues, sadness, loss of smell, dysautonomia, and cognitive impairment are examples of non-motor symptoms. Individual differences exist in the clinical presentation and the course of the disease. The condition often develops slowly, taking an average of ten years from symptoms beginning to a medical diagnosis.[8] Constipation, hyposmia, sleep difficulties, or sadness are some of the earliest symptoms that are vague, making it difficult to establish an early diagnosis.[9] The prodromal PD notion emerged as a result of the numerous non-motor symptoms that appear far before motor symptoms.[10] Additionally, the reasons of the disease are specific to each patient, and its aetiology is complicated.[11] Lewy body and Lewy neurite neuronal inclusions, together with cell loss in the substantia nigra and other brain areas, are the hallmark histological hallmarks of Parkinson's disease.[12] Death of dopaminergic neurones in the substantia nigra pars compacta results in the disease's distinctive motor signs.[13] Patients continue to endure increasing weakening despite the availability of surgical, non-pharmacological, and pharmaceutical treatments, such as brain, spinal, and vagus nerve stimulators; no treatment has been proven to be a real disease modulator.[14] Regretfully, despite research efforts, Parkinson's disease (PD) still has many unanswered questions and no treatment or preventative measures.[15] The purpose of this study is to present a thorough analysis of current knowledge on Parkinson's disease (PD), diagnostic methods, therapeutic approaches, and research instruments that show encouraging results for PD patients.Current non-invasive brain stimulation methods and their clinical use in the treatment of Parkinson's disease are examined in detail in this study. The purpose of the therapeutic use of brain stimulation techniques is to either selectively increase adaptive or decrease maladaptive patterns of neuronal activity. The ultimate objective is to restore normal physiology in the afflicted brain networks, which will alleviate the presentation of symptoms. The use of certain biomarkers strengthens this tactic even further. Multiple attempts have been made to improve human brain function by changing the electrical processes in the brain; nevertheless, clinically useful stimulation devices and effective stimulation paradigms have only lately been available.The ultimate goal of this review article is to give a thorough and current summary of electroceuticals as a Parkinson's disease therapy option, assisting both patients and professionals in making informed decisions. 2. Pathophysiology Parkinson's disease has a complex etiology, which originates from a mix of genomic, epigenetic, and environmental factors.[16] The etiology of Parkinson's disease is complicated and stems from a combination of environmental, epigenetic, and genomic variables. The start and progression of the disease are influenced by several genes.[17] The lrrk2 or park8 gene is where the most prevalent mutations linked to Parkinson's disease occur, especially in people 50 years of age and older.[18] In the microglia, they also regulate the oxidative stress and inflammatory response.[19-20] The genes that protect dopaminergic neurones from rotenone, hydrogen peroxide, and mutant synucleins are DJ-1, also known as PARK7, PARK6, and PARK2.[21-22] Another linked gene is PINK1, a mitochondrial kinase that builds up on damaged mitochondrial membranes and recruits parking to control mitophagy and prevent the accumulation of harmful substances that result in the death of neurones.[23-24-25] Deterioration of the substantia nigra pars compacta and a decrease in dopaminergic neurones are two of the hallmarks of Parkinson's disease. The overproduction of α-synuclein, a 140-amino acid protein found in neurones' presynaptic terminals, has been directly connected to this degradation.Mostly found in the substantia nigra, thalamus, neocortex, and cerebellum, α-synuclein is essential for axonal transport, neurotransmitter release, vesicle fusion and movement, and synaptic connection.[26]The α-synuclein gene is in charge of encoding it. Prompt and rapid α-synuclein misfolding and aggregation are linked to SNCA mutations, primarily missense or multiplication variations.[27] Similar to this, mutations in the GBA gene, which codes for glucocerebrosidase, decrease its enzymatic performance. This decrease results in inadequate α-synuclein breakdown and increased exosomal release, which ultimately contributes to the buildup of Lewy bodies.[28] It has been disputed whether α-synuclein is the primary cause of Parkinson's disease. Recent research with new monoclonal antibodies that prevent α-synuclein from aggregating has demonstrated that even when these aggregates are removed, parkinsonian symptoms endure and the illness worsens. This implies that the goal of research should be to find novel World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 570 pathophysiological targets for Parkinson's disease.[29] Using blood samples, Madetko et al.'s study assessed the NLR and PLR in peripheral inflammation in PD and found that PD patients had greater NLR and PLR ratings in relation to the control group. Consequently, this can be a parameter for suspected PD.[30] Figure 1 Pathogenesis of PD (Parkinson disease) 3. Diagnostic method About 10% of patients are misdiagnosed with other illnesses because non-motor symptoms frequently occur before motor manifestations. In order to increase diagnostic precision, the International Parkinson and Movement Disorders Society developed particular standards. Bradykinesia and at least one of the following symptoms—resting tremor (4–6 Hz) or limb rigidity are required for the diagnosis of Parkinson's disease, per their guidelines. Furthermore, it is essential to carefully examine data that can point to possible indications of other illnesses and take into account exclusion criteria in order to rule out PD as a diagnosis.[31-32] The diagnosis of Parkinson's disease is aided by a number of resources in addition to thorough questioning and accurate physical examination. Due to their specificity, imaging methods including structural magnetic resonance imaging (MRI) and dopamine transporter single-photon emission computed tomography (DAT-SPECT) are frequently used. Neuromelanin imaging (NMI), which identifies alterations in the substantia nigra pars compacta and the locus coeruleus is one of the distinctive features of MRI that help detect atypical parkinsonism.[33] Usually, genetic testing is saved for situations where Parkinson's disease is thought to have a genetic foundation. However, given that the discovery of particular genes linked to severe PD symptoms has been linked to a worse prognosis, it is becoming more widely acknowledged that such studies should be regarded as standard.[34] 4. Recommended medications 4.1. Levodopa (Dopamine precursor) The amino acid l-3,4-dihydroxyphenylalanine, often known as levodopa or l-dopa, was the first drug to effectively treat Parkinson's disease.Dopamine's precursor, levodopa, has a much lower concentration in parkinsonism. When given orally in large quantities every day, levodopa can enter the brain and bypass the surviving dopamine neurons' metabolism. Dopamine is produced there by decarboxylating the molecule (removing a carboxyl group, COOH). To boost the amount of levodopa that reaches the brain, carbidopa, a levodopa analogue, is added to levodopa prescriptions. Carbidopa prevents levodopa from converting to dopamine before it reaches the blood-brain barrier because dopamine cannot cross the barrier by itself.Levodopa's primary adverse impact is an elevated likelihood of episodes resembling schizophrenia, which is most likely brought on by an excess of dopamine.[35-36] Parkinson's disease can be effectively treated with carbidogpa-levodopa, a natural chemical that enters your brain and is converted to dopamine. Most often associated with motor issues and most helpful for managing symptoms Dyskinesias are a consequence of prolonged therapy. COMT inhibitors are recommended for improved outcomes.[37-3839] World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 571 4.2. Dopamine agonists Dopamine-receptor agonists function by attaching to dopamine receptors on dopaminergic neurons, which are the neurons that normally make and use dopamine. Activating the receptors increases dopaminergic activity in the brain, reducing the intensity of parkinsonian symptoms. The group that replicates the effects of dopamine in the brain includes apormorphine, pramipexole, ropinirole, and rotigotine (in patch form). It has a longer half-life than levodopa but is less effective. A few adverse effects include obsessive behaviors, drowsiness, and hallucination.[40] 4.3. MAO-B inhibitors These drugs gradually break down dopamine in the brain. It is made up of rasagiline, selegiline, and safinamide. They work by stopping the breakdown of the dopamine inhibiting enzyme monoamine oxidase B. This family of medications can cause personality disorders, headaches, nausea, insomnia, and hallucinations.[41] 4.4. Catechol-O-methyltransferase (COMT) inhibitor The enzyme catechol-O-methyltransferase catalyzes the enzymatic breakdown of dopamine, and COMT inhibitors such as Entacapone and tolcapone prevent this from occurring. Because they prevent levodopa from being broken down by COMT in peripheral tissues, these medications are commonly used in conjunction with levodopa and carbidopa. This lengthens the drug's half-life in the blood and increases the quantity of medication that may pass through the bloodbrain barrier. The primary adverse effects include hallucinations, nausea, vomiting, and dyskinesia.[42] 4.5. Antichollinergics A number of parkinsonian symptoms are caused by the abnormal neurotransmitter activation of acetylcholine. This is mediated by acetylcholine.activity by binding to the brain's muscarinic acetylcholine receptors, which are named for their selectivity for acetylcholine and sensitivity to the substance muscarine. Consequently, medications such as trihexyphenidyl and benztropine mesylate are used to alleviate symptoms, but with few side effects. These medications are also thought to raise dopamine levels in the brain. However, their usage in elderly people is limited because of their sedative effects and adverse effects linked to vision.Negative effects include memory loss, disorientation, constipation, and issues with the micturition reflex.[43] Parkinson's disease patients may experience less tremor and bradykinesia (slow movements) if they take amantadine, an antiviral medication used to treat influenza A infections. symptoms of movement. It has been discovered to cause dopamine to be released from brain cells, albeit it is unclear exactly how it works in this capacity. It also inhibits movement-related neuronal overactivity and excitatory transmission. Amantadine is used to temporarily alleviate the symptoms of mild, early-stage Parkinson's disease when combined with carbidopa-levodopa therapy in the later stages of the disease to lessen dyskinesia, or involuntary movements, caused by carbidopa-levodopa. Among the adverse effects are nausea, vomiting, wooziness, confusion, hallucinations, or swelling of the ankles.[44] 4.6. Intranasal Insulin Insulin receptors are found throughout the basal ganglia, indicating that it plays a role in regulating neuronal growth, synaptic maintenance, and neurotransmission [69]. Intranasal insulin (INI) administration can slow the loss of dopaminergic neurons in Parkinson's disease, improving motor function [69]. It has also been shown to reduce dopamine-dependent cognitive impairment by restoring insulin signaling pathways without the use of medications.[45] 4.7. DPP-4 Inhibitors and GLP-1 Agonist The central nervous system (CNS) has receptors for the hormone glucagon-like peptide 1 (GLP-1), which has been shown to enhance cell survival and prevent apoptosis. GLP-1 is metabolized and removed from the bloodstream by the enzyme dipeptidyl peptidase 4 (DPP-4).[46] Drugs that target these pathways include DPP-4 inhibitors, which prevent the breakdown of GLP-1, and GLP-1 receptor agonists, which mimic the actions of GLP-1. Due to their incretin activity, these medications induce satiety, reduce glucagon production, delay stomach emptying, and increase glucosedependent insulin release.[47] Foltyine et al.'s study demonstrated the possible benefits of GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of neurodegenerative illnesses. Their anti-inflammatory and antiapoptotic qualities enable them to exercise their neuroprotective impact in Parkinson's disease (PD), hence enhancing motor and cognitive function. These substances have also been demonstrated to influence mitochondrial biogenesis, encourage neurogenesis, and reestablish insulin signaling in the central nervous system.[48] According to a cohort research by Brauer et al., those treated with DPP-4 inhibitors and GLP-1 agonists had a 36–60% reduced incidence of Parkinson's disease (PD) than people treated with other antidiabetic drugs [75]. Exenatide, a GLP-1 receptor agonist, was linked to improved motor symptoms, decreased non-motor symptoms, improved cognitive function, and an overall improvement World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 572 in quality of life, according to a 2020 meta-analysis by Wang et al.[49-50] Around the world, metformin, an oral hypoglycemic medication belonging to the biguanide family, is frequently used to treat type 2 diabetes. This drug lowers blood sugar levels by acting on several different locations. It increases the presence of GLP-1, decreases intestinal glucose absorption, increases muscular glucose uptake, and limits hepatic glucose synthesis by decreasing gluconeogenesis and glycogenolysis.[51] The use of metformin in neurodegenerative illnesses is up for controversy because of contradicting literature. It has been linked to cobalamin (vitamin B12) deficiency, which may raise the risk of neurodegenerative illnesses and cognitive impairment, according to certain research. As a cofactor for enzymes involved in the synthesis of genetic material, fatty acid metabolism, and amino acid synthesis, as well as for its neuroprotective function and participation in bone marrow cell maturation and myelin production, vitamin B12 is essential. Sluggett et al.'s study, however, found that long-term metformin use does not increase the risk of Parkinson's disease (PD) and may even lower its occurrence. It is consistent with recent studies showing that metformin has anti-inflammatory and neuroprotective properties.[52] 5. Surgical therapy Parkinson's disease patients may experience less tremor and bradykinesia (slow movements) if they take amantadine, an antiviral medication used to treat influenza. It has been discovered to cause dopamine to be released from brain cells, albeit it is unclear exactly how it works in this capacity. It also inhibits movement-related neuronal overactivity and excitatory transmission. Amantadine is used to temporarily alleviate the symptoms of mild, early-stage Parkinson's disease when combined with carbidopa-levodopa therapy in the later stages of the disease to lessen dyskinesia, or involuntary movements, caused by carbidopa-levodopa. Among the adverse effects are nausea, vomiting, wooziness, confusion, hallucinations, or swelling of the ankles. Numerous surgical methods can help PD patients when drugs don't seem to be working, depending on the disease's stage and progression. Parkinson's disease can be treated with deep brain stimulation, or DBS, a non-invasive surgical technique. It involves putting in place a battery-operated neurostimulator that uses electrical impulses to target particular areas of the brain. For the motor symptoms of Parkinson's disease, this is the most common surgical treatment. Furthermore, in more advanced stages of PD that are being treated medically, it reduces the frequency of "off" episodes, which often occur throughout the day. The two areas of the brain that receive DBS the most are the globus pallidus pars interna and the subthalamic nucleus (STN) (GPi). Similar benefits for motors have been observed in extensive, controlled, randomized studies between these two targets. It is believed that the abnormal brain signalling patterns that cause problems with motor control are blocked by the electrical signals generated by DBS. There is no known cure for Parkinson's disease; its symptoms can only be managed. 5.1. Ablative or Lesioning Procedure Leison surgery Techniques for burning tissue include thalamotomy, sub-thalamotomy, and pallidotomy. A thalamotomy, which entails lesioning or destroying the thalamus, can only affect one side of the brain, whereas a pallidotomy, which involves destroying a small area in the globus pallidus interna, can affect both sides.One novel treatment that offers a less invasive alternative to traditional surgical techniques is focused ultrasound. Targets located deep within the body are the focus of multiple ultrasound beams, and the process is tracked and guided in real time by an MRI. Targeted sonic energy can be used to destroy unwanted tissue or interfere with ineffective brain circuits Pharmacological treatment effectively controls PD symptoms and improves quality of life. However, long-term use at high doses can lead to refractory symptoms and drug-induced side effects in some patients. In cases where pharmacological treatment fails to achieve its objectives, surgical options become a viable alternative. Surgical approaches are tailored to individual needs and may include unilateral procedures like thalamotomy, pallidotomy, or subthalamotomy, along with deep brain stimulator (DBS) placement, aiming to enhance the relief of motor symptoms.[53-54] Since the clinical characteristics of Parkinson's disease can be mimicked by other disorders, it is imperative to confirm a diagnosis before contemplating surgical intervention. Postural instability and significant gait abnormalities are relative contraindications for fetal cell transplantation in Parkinson's disease. The main indication for neurosurgical treatment is for individuals with moderate to severe disease who respond to levodopa medication but have fluctuating motor symptoms that interfere with their ability to live independently on a daily basis.[55] An improvement of at least 30% on the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDSUPDRS III) or Unified Parkinson's Disease Rating Scale (UPDRS III) typically indicates a response to levodopa medication, which is a predictor of surgical results. Surgery usually does not help people who do not respond well to levodopa, with the exception of cases involving tremor relief. For people who benefit somewhat from low-dose levodopa but cannot tolerate higher dosages due to drug-induced side effects such nausea, dystonia, or dyskinesias, surgery may World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 573 be a good choice. Fetal cell transplantation may help functional persons in the early stages of Parkinson's disease preserve their everyday routines and standard of living S. Pallavaram et al. Neurologist consistency in interpreting information provided by an interactive visualization software for deep brain stimulation postoperative programming assistance.[56] Lesioning treatments involve the intentional destruction of certain brain areas to disrupt affected neuronal networks [104]. Examples include unilateral thalamotomy, subthalamotomy, and pallidotomy. While unilateral thalamotomy does not improve bradykinesia, dyskinesia, or motor fluctuations, it may benefit some PD patients with tremors that are resistant to therapy. Unilateral pallidotomy is a safe and efficient treatment for severe dyskinesia and motor fluctuations, with the added advantage of long-term suppression of contralateral dyskinesia. However, because unilateral subthalamotomy has a greater risk of adverse neurological effects, including chronic dyskinesia, it is considered an experimental treatment for advanced Parkinson's disease.[57] An inventive technique for treating tremors in Parkinson's disease is unilateral thalamotomy with MRI-guided focused ultrasonography. An MRI-compatible ultrasonic transducer is used to position the patient in a stereotactic frame during this treatment. The transducer is oriented according to real-time MRI imaging, and successive doses of ultrasonic energy are applied until the target region reaches the therapeutic temperatures needed for lesioning. Clinical evaluations of tremors, while the patient is awake, are used to measure the procedure's efficacy intraoperatively.[57] Radiosurgery is another non-invasive therapy option that targets and damages specific nervous system regions using high doses of ionizing radiation. This approach aims to lessen symptoms by focusing on regions such the ventral intermediate nucleus (VIN), subthalamic nucleus, and internal globus pallidus (GPi). On the other hand, radiosurgical pallidotomy has shown less success than other targets.[58-59] Neural grafting Although nigral transplants are obviously effective in certain PD cases, the method must be refined before it can be applied effectively in a large a number of patients due to the adverse effects it has on them.Dopaminergic neurons from the human embryonic brain were transplanted into the striatum of PD patients in clinical trials conducted in the 1990s, demonstrating the possibility of long-lasting therapeutic benefits. Focused Ultrasound Stimulation (FUS) FUS is a minimally invasive procedure that modifies deep tissues chemically, thermally, or mechanically for therapeutic purposes using focused ultrasonic waves. FUS, which operates at higher frequencies and intensities, focuses energy on certain regions, allowing for targeted treatment with less harm to other tissues. A safer and more accurate substitute for invasive surgical treatments is offered by this cutting-edge technology.[60-61] Figure 2 FUS (Focused Ultrasound Stimulation) FUS has shown great promise in the treatment of Parkinson's disease (PD), especially when combined with highintensity focused ultrasound (HIFU). Unlike conventional diagnostic ultrasonography, HIFU uses high-energy pulses to target tissues accurately while reducing collateral damage. This non-invasive approach successfully accomplishes improved neuromodulation, thermal ablation, and pharmaceutical administration. Because FUS alters deep brain regions in a non-ionizing and reversible manner, it may help PD patients live better lives and experience less motor World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 574 symptoms. To establish FUS as a feasible, less invasive substitute for traditional treatments like deep brain stimulation, ongoing research and clinical trials are being conducted to show its safety and effectiveness. Focused Ultrasound Foundation. Clinical Trial to Disrupt the Blood-brain Barrier for Brain Tumor Treatment Launched at University of Maryland.[62-63] 5.2. Gamma Knife Thalamotomy (GKT) Refractory tremors, particularly those linked to Parkinson's disease, can be treated with GKT, a minimally invasive neurosurgical technique. It disrupts abnormal neuronal circuits that cause tremors by precisely delivering gamma radiation to the ventral intermediate nucleus of the thalamus. GKT has benefits such being less intrusive, avoiding the hazards associated with open surgery, and being appropriate for people who are not candidates for DBS. GKT is safe, according to clinical data, and no notable long-term cognitive, gait, or speech problems have been documented. Risks include the possibility of radiation-induced brain alterations and temporary side effects such headache and nausea, which emphasise the necessity of cautious patient selection and ongoing monitoring.[64-65] 6. Nutritional therapy In conjunction with standard medication therapy, food supplements are widely utilised to treat a variety of chronic illnesses by addressing nutritional deficiencies or promoting particular physiological processes. Over the past few decades, there has been a notable growth in the use of functional foods and food supplements, particularly to make up for improved health and the modern lifestyle.[66-67] 6.1. What ought to be included in your meal? Broccoli, berries, soy nuts, pears, celery, carrots, beetroot, and many more foods contain phytochemical.Foods that contain omega-3 DHA include fish, seafood, and plant oil. Caffeine has neuroprotective properties. Soy (genistein) is beneficial for menopausal women with Parkinson's disease.Foods high in magnesium include spinach, pumpkin seeds, almonds, seeds, and more.Coenzyme Q10, lipoic acid, N-acetyl cysteine, carvacrol, turmeric, creatine, melatonin, niacin, and lycopene are examples of biological substances. Vitamins such as vitamins D3 and C. Plants such as 6-shogaol and gingko biloba extract.Foods high in antioxidants include beans and berries.Foods that include iron and zinc. 6.2. What foods should you stay away from? Steer clear of or substantially reduce foods high in sugar. Foods that have been processed overconsumption of fat, oil, and carbs. Dairy goods too much meat. Foods that are difficult to chew and swallow. Important tips for managing your food intake include: Eating a range of lightly prepared meals throughout the day. Eat foods that control your blood sugar, heart rate, and blood pressure. Assesses the nutritional condition of the body. Get enough vitamin D by being in the sun. Enhance your digestion get tested for dietary intolerances and allergies. Eat meals at regular intervals. Avoid skipping meals. 7. Herbal therapy Withania somnifera (Solanaceae family)WS, sometimes referred to as poison gooseberry or winter cherry, is a plant that has been isolated to produce a number of bioactive compounds. These compounds, which are used to treat a range of neurological deficiencies, including poor memory, depression, epilepsy, and neurodegeneration, include triterpene lactones, alkaloids, tropine, steroidal lactones, and withanolides. Additionally, it was found that the ethanol extract of WS roots significantly boosts dopamine synthesis in the substantia nigra and the locomotor activity of PD mice. Furthermore, their study demonstrated that the ethanol extract of WS roots significantly decreased the concentrations of iNOS (oxidative stress) and GFAP protein, a pro-inflammatory indicator of astrocyte activation, in the brain regions of PD mice. The ethanolic extract of Gastrodiaelata Blume (Family: Orchidaceae) at varying concentrations (10, 100, and 200 g/mL) decreased the Bax/Bcl-2 ratio elevation caused by MPP+ in SH-SY5Y cells, attenuated capase-3 activation and PARP cleavage in a dose-dependent manner, and demonstrated an antioxidant effect with notable radical scavenging activity for DPPH and alkyl radicals, suppressed.[68-69] The aqueous extract of Centella asiatica (Family: Umbelliferae) can be used to treat MPTP-induced parkinsonism for 14 days at a dose of 300 mg/kg. It functions by exhibiting its antioxidant activity in the hippocampus and corpus striatum of the brain. Superoxide dimutase, glutathione peroxidase, catalase, total antioxidants, and xanthine oxidase are all increased by the extract, although protein carbonyl content and lipid peroxidation are decreased.[70] World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 575 When 6-OHDA promotes aptosis in differentiated PC12 cells, the bioactive components of Pueraria thomsonii (Family:Fabaceae), daidzein and genistein, have neurocytoprotective qualities. At 50 μM and 100 μM, respectively, daizein and genistein decreased caspase-8 and partially inhibited caspase-3 activation, providing a defense mechanism against 6-OHDA-induced cytotoxicity in PC12 cells with NGF differentiation. In order to prevent parkinsonism, Plumbago scandens (Family: Plumbaginaceae) reduces palpebral ptosis, catalepsy, and locomotor activity. • Chrysanthemum: Chrysanthemum L extract protects against lipopolysaccharide-induced cytotoxicity in the SHSY5Y cell model, BV-2 Parkinson's disease microglial cells, and 1-methyl-4-phenylpridinium ion. suppresses the mitochondrial apoptotic pathway, decreases ROS aggregation, increases the ratio of Bax to Bcl-2 in SH-SY5Y cells, and lowers SH-SY5Y cell mortality. The fruit tree, Clausenalansium, is indigenous to southern China. Bu-7, a flavonoid obtained from Clausenalansium leaves, is being used as a treatment; it boosted protein phosphorylation and decreased rotenone-induced apoptosis these models. Ocimum sanctum (Lamiaceae family). Leaf extract from Ocimum sanctum has a neuroprotective effect on haloperidolinduced catalepsy in albino mice. Mice with rotenone-induced parkinsonism, catalepsy caused by haloperidol, and muscle stiffness showed neuroprotective effects from O. sanctum extract. Cassia: Tora's Cassiae Semenis Clarissa L. (Tora C.) is the ripe, dried seed of Cassia obtusifolia L. Parkinson's disease (PD) is believed to be caused by alaternin, a substance found in C. tora that has strong peroxynitrite scavenging properties. Additionally, it shields mice from the transient neuronal cell death brought on by cervical hypoperfusion. Cassiae semen extract shows therapeutic properties in mouse hippocampus cultures, 6-OHDA-induced neurotoxicity in PC12 cells, MPTP-induced neuronal degeneration in the animal's PD form, and seed extract in these models.[70] 8. Physical therapy Although no particular treatment is advised for Parkinson's disease, there is enough research and data to demonstrate that exercise improves movement Recent experimental studies have demonstrated the benefits of exercise in preventing and delaying the progression of Parkinson disease. Exercise raisessleep, mood, quality of life, and selfsufficient mobility, Among the short-term effects of this treatment are treadmill gait training, Nordic walking, brisk walking, balance training, virtual reality interventions, dancing, aerobics, and resistance training; all of these activities aid in symptom relief and improve neurophysiological function.[71-72] Massage therapy has two benefits: relaxation and reduced muscle tension. Massage therapy typically promotes relaxation.Urinary stress hormones are involved in the subsequent biological processes. Research shows that therapeutic massage can improve quality of life. Anma and Yin Tui Na have more advantages.[73] Tai-chi is a traditional Chinese practice that involves slow, flowing movements to improve muscle strength, flexibility, and balance. Tai chi may help lower the chance of falling. Tai chi is suitable for people of all ages and physical conditions. A study suggests that tai chi may improve balance more effectively than stretching or weight training in those with mild to moderate balance issues. Parkinson ’ s disease.[74] The Alexander technique, which focuses on muscle posture and balance, can reduce muscle discomfort and stiffness. Yoga and mild stretching exercises can also improve flexibility and balance. Meditation, which involves reflecting in silence and focusing on a concept or picture, can improve well-being and reduce pain and stress.[75-76] 8.1. Practice fall prevent method Older adults can prevent falls by exercising alone. Intense exercise regimens with good balance yield better results. Parkinson's disease patients benefit from rhythmic stimulation and dance, which improve gait and cognitive skills such as spatial memory and motor control.[76-77] 9. Psychological therapy in parkinson Living with Parkinson's disease can be tough as it can be frustrating to adjust to bodily movements and do daily tasks. Walking, conversing, and eating are all time-consuming activities. Most Parkinson's patients face psychological challenges, such as: Depression and anxiety,Mental breakdowns and frustration, Insecurities and low self-esteem -,Lack of emotional expression and motivation,High social anxiety during encounters.[74] World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 576 9.1. Pharmacological approach Serotonin reuptake inhibitors, tricyclic antidepressants, dopamine agonists, and trazodone are examples of antidepressants that have been shown to be effective in treating or reducing depression in Parkinson's disease.Cognitive behavioural therapy (CBT)à PD-tested to be extremely effective helpful in lowering tension andimproving patient calm and flexibility. Mindfulness behavioural therapy (MBT)à displays similar benefits and has been shown to be beneficial, especially when CBT and MBT are used to improveoutcomes, lower anxiety, and lessen depressive features. Acceptance and commitment therapy (ACT)PD technique that was useful but less popular than other ways. Family support can improve PD patients' mindset and reduce frustration and anxiety in social situations. Social acceptance is crucial for those with Parkinson's disease and other illnesses as it reduces the possibility of negative psychological side effects, calms patients, and increases their likelihood of taking medication. 9.2. Non-Pharmacological Treatments 9.2.1. Personalized Medicine Pluripotent Stem Cells Pluripotent stem cells are a promising substitute for cellular therapy in localized neurodegeneration, like Parkinson's disease (PD), and recent developments in genetics and regenerative medicine have sparked the search for novel treatments targeted at stopping or slowing the progression of particular neurodegenerative disorders. The widely varying reactions seen in individuals undergoing L-dopa medication show the presence of diverse biochemical degeneration pathways, even though Parkinson's disease (PD) involves malfunction in multiple systems and neurotransmitters that result in identical symptoms. This emphasizes the necessity of alternate therapeutic approaches. Personalized medicine has the potential to provide more efficient therapies that are customized for each patient.[78-79] The variability of the response to medications used in PD may be related to certain hereditary variables.The possible involvement of single-nucleotide polymorphisms in PD patients and their reaction to pharmacological treatments has been investigated in a number of studies. One such gene of interest is the dopamine active transporter 1 (DAT1) gene, which is crucial for dopamine reuptake in synapses and has a higher chance of making patients experience hallucinations when exposed to dopaminergic medications and developing dyskinesias when treated with L-dopa. Pluripotent stem cells have shown promise as targets for innovative cell therapy developments in regenerative medicine and human disease models. directed differentiation technologies, which are vital for creating these vital cells, to the mesencephalon.[80-81-82] Fetal ventral mesencephalic cell transplantation has been studied for many years as a potential treatment for Parkinson's disease. Dopaminergic, oculomotor, and retinal neurons are included in this cell population. In a research by Li et al., post-mortem brains from recipients of fetal cell transplantation showed that the transplanted cells had significantly grown and innervated the striatum. Additionally, they showed that these neurons can endure in the human brain for more than 20 years. Graft-induced dyskinesia did, however, occur in several transplant recipients [90,92]. Since then, attempts have continued to create standardised procedures for cellular transplants, which are presently being researched.[83-84] Gene Therapy ATP13A2, dardin, DJ-1, alpha-synuclein, leucine-rich repeat kinase 2 (LRRK2), and PINK1 are among the genes linked to Parkinson's disease (PD), even though it is classified as an idiopathic condition. There are more mutations in the GBA1 gene, which codes for the enzyme glucosecerebrosidase. The age of start, intensity of symptoms, and course of cognitive impairment are all impacted by these alterations, which cause neurotoxicity and neuro inflammation.[85-86-87] Despite encouraging outcomes in animal research, the clinical translation of gene therapy for Parkinson's disease is fraught with difficulties. The results of human research have fallen short of expectations, mostly because of problems with gene distribution. As a result, although gene therapy is a major advancement in the treatment of Parkinson's disease, it is still not a viable alternative until more clinical research verifies its effectiveness and safety.[88-89-90-91] 9.2.2. Life Changes Exercise In order to improve motor skills, halt the progression of the disease, and increase functional capacity in people with Parkinson's disease, non-pharmacological treatments including physical activity are advised. Physiotherapy and World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 583 [21] H. Lassmann et al. The molecular basis of neurodegeneration in multiple sclerosis FEBS Let 2011 [22] Zhao Y, et al. Pharmaceuticals (Basel). 2024. [23] J.G. Blackinton et al. Expression of PINK1 mRNA in human and rodent brain and in Parkinson's disease Brain Res. (2007) [24] Huang Z, Ren S, Jiang Y, Wang T (2016) PINK1 and Parkin cooperatively protect neurons against constitutively active TRP channel-induced retinal degeneration in Drosophila. Cell Death. [25] Abdelkader NF, Safar MM, Salem HA. Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations. Mol Neurobiol. 2016. [26] Abdelkader NF, Safar MM, Salem HA. Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson’s Disease: Modulation of Mitochondrial Perturbations. Mol Neurobiol. 2016 [27] Panicker, N.; Ge, P.; Dawson, V.L.; Dawson, T.M. The cell biology of Parkinson’s disease. J. Cell Biol. 2021, 220, e202012095. [28] de Lau LML, MMB B. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006 [29] Vázquez-Vélez GE, Zoghbi HY. Parkinson's disease genetics and pathophysiology. Annu Rev Neurosci. 2021. [30] Paxinou E, Chen Q, Weisse M, et al. Induction of α-synuclein aggregation by intracellular nitrative insult. The Journal of Neuroscience. 2001; [31] Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197–211 [32] Postuma RB, Berg D, Stern M, et al. MDS Clinical Diagnostic Criteria for Parkinson's Disease. Mov Disord 2015; 30: 1591-1600. [33] Bedard, K. & Krause, K. H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245–313 (2007) [34] Melief, E. J. et al. Partial depletion of striatal dopamine enhances penetrance of cognitive deficits in a transgenic mouse model of Alzheimer’s disease. J. Neurosci. Res. 93, 1413–1422 (2015) [35] Arean PA, Cook BL. Psychotherapy and combined psychotherapy/pharmacotherapy for late life depression. Biol. Psychiatry52(3), 293–303 (2002). [36] Tripathi K.D., “Essential of medical pharmacology”, Jaypee Brothers medical publisher, (2013), Antiparkinson drug, 425-434. [37] Floyd M, Scogin F, McKendree-Smith N, Floyd DL, Rokke PD. Cognitive therapy for depression: a comparison of individual psychotherapy and bibliotherapy for depressed older adults. Behav. Modif.28(2), 297–318 (2004). [38] Tripathi K.D., “Essential of medical pharmacology”,Jaypee Brothers medical publisher, (2013), Antiparkinson drug, 425-434. [39] Mohr DC, Likosky W, Bertagnolli A et al. Telephone-administered cognitive–behavioral therapy for the treatment of depressive symptoms in multiple sclerosis. J. Consult. Clin. Psychol.68(2), 356–361 (2000). [40] Allen LA, Woolfolk RL, Gara MA, Escobar JI, Hamer R. Cognitive behavior therapy for somatization disorder. Arch. Intern. Med.166(14), 1512–1518 (2006). [41] Almouahed S, Hamitouche C, Stindel E. Optimized Prototype of Instrumented Knee Implant: Experimental Validation. IRBM. 2017;38(5):250–5. [42] DeRubeis RJ, Crits-Christoph P. Empirically supported individual and group psychological treatment for adult mental disorders. J. Consul. Clin. Psychol.66(1), 37–52 (1998) [43] Goldstein LH, McAlpine M, Deale A et al. Cognitive behaviour therapy with adults with intractable epilepsy and psychiatric co-morbidity: preliminary observations on changes in psychological state and seizure frequency. Behav. Res. Ther.41(4), 447–460 (2003). [44] Butler AC, Chapman JE, Forman EM, Beck AT. The empirical status of cognitive–behavioral therapy: a review of meta-analyses. Clin. Psychol. Rev.26(1), 17–31 (2006). [45] Zhang, H.; Hao, Y.; Manor, B.; Novak, P.; Milberg, W.; Zhang, J.; Fang, J.; Novak, V. Intranasal insulin enhanced resting-statefunctional connectivity of hippocampal regions in type 2 diabetes. Diabetes 2015, 64, 1025–1034. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 584 [46] N.I. Bohnen et al.Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease Parkinsonism Relat. Disord.(2014) [47] Markaki, I.; Winther, K.; Catrina, S.B.; Svennigsson, P. Repurposing GLP1 agonists for neurodegenerative diseases. Int. Rev. Neurobiol. 2020, 155, 91–112. [48] J.A. Santiago et al. System-based approaches to decode the molecular links in Parkinson’s disease and diabetes Neurobiol. Dis. (2014) [49] Hughes, AJ ∙ Daniel, SE ∙ Kilford, L ∙ et al. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinicopathological study of 100 cases J Neurol Neurosurg Psychiatry. 1992; 55:181-184 [50] Holscher C.Potential role of glucagon-like peptide-1 (GLP-1) in neuroprotection. CNS Drugs2012 26: 871–82 Athauda, D.; Foltynie, T. The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson’s disease: Mechanisms of action. Drug Discov. Today 2016, 21, 802–818. [51] Song, S. Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin Am. J. Physiol. Endocrinol. Metab. 2001; 281:E275-E282] [52] Kuan Y-C, Huang K-W, Lin C-L, et al. Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. Prog Neuropsychopharmacol Biol Psychiatry 2017; 79:77–83. [53] Bergman, H ∙ Wichmann, T ∙ DeLong, MR Reversal of experimental parkinsonism by lesions of the subthalamic nucleus Science. 1990; 249:1436-1438 PubMed PMID: 2402638 10.1126/science.2402638] [54] Bucy PC, Case TJ. Tremor. Physiologic mechanism and abolition by surgical means. Arch Neurol Psychiatry 1939; 41: 721-746.S. Pallavaram et al. Neurologist consistency in interpreting information provided by an interactive visualization software for deep brain stimulation postoperative programming assistance Neuromodulation (2014) [55] Neuromodulation (2014) 1 Goetz CG. The history of Parkinson's disease: early clinical descriptions and neurological therapies. Cold Spring Harb Perspect Med 2011; 1: a008862. [56] Almouahed S, Hamitouche C, Stindel E. Optimized Prototype of Instrumented Knee Implant:Experimental Validation. IRBM. 2017;38(5):250–5.. [57] V.J. Odekerken et al. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinson's disease (NSTAPS study): a randomised controlled trial Lancet Neurol(2013) [58] P.F. D'Haese et al.CranialVault and its CRAVE tools: a clinical computer assistance system for deep brain stimulation (DBS) therapy Med Image Anal (2012) [59] 2Limousin P, Pollak P, Benazzouz A, et al. Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 1995; 345: 91-95. [60] Goetz, C.G.; Tilley, B.C.; Shaftman, S.R.; Stebbins, G.T.; Fahn, S.; Martinez-Martin, P.; Poewe, W.; Sampaio, C.; Stern, M.B.; Dodel, R.; et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing results. Mov. Disord. 2008, 23, 2129–2170. [61] Airan, R. D., R. A. Meyer, N. P. K. Ellens, K. R. Rhodes, K. Farahani, M. G. Pomper, S. D. Kadam, and J. J. Green. Noninvasive targeted transcranial neuromodulation via focused ultrasound gated drug release from nanoemulsions. Nano Lett. 17:652–659, 2017. [62] Phenix, C.P.; Togtema, M.; Pichardo, S.; Zehbe, I.; Curiel, L. High Intensity Focused Ultrasound Technology, Its Scope and Applications in Therapy and Drug Delivery. J. Pharm. Pharm. Sci. 2014, 17, 136–153 [63] N.Y. Jung, C.K. Park, M. Kim, P.H. Lee, Y.H. Sohn, J.W. ChangThe efficacy and limits of magnetic resonance–guided focused ultrasound pallidotomy for Parkinson's disease: a Phase I clinical trial J Neurosurg., 130 (2019), pp. 1853-1861 [64] Chao, J.; Leung, Y.; Wang, M.; Chang, R.C.C. Nutraceuticals and their preventive or potential therapeutic value in Parkinson’s disease. Nutr. Rev. 2012, 70, 373–386. [65] Lee A. and Gilbert R. M., Epidemiology of Parkinson disease, Neurologic Clinics. (2016) 34, no. 4, 955–965, [66] Speciale SG. MPTP: insights into parkinsonian neurodegeneration. Neurotoxicol Teratol, 24, 2002,607-20. [67] Balestrino R. and Schapira A. H. V., Parkinson disease, European Journal of Neurology. (2020) 27, no. 1, 27–42 World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 585 [68] Zeng B. Y., Effect and Mechanism of Chinese Herbal Medicine on Parkinson′s Disease, International Review of Neurobiology. (2017) 135, 57–76] [69] Nagrik SU, Patil PA, Nagrik DM, Zagare V, Avchar P,Bahurupi S, Ambhore S. Herbal drugs Used on Parkinson Disease. Journal of Drug Delivery and Therapeutics. 2020 Aug 15;10(4-s):235-9 [70] Ellis T, Cavanaugh JT, Earhart GM, Ford MP, Foreman KB, Fredman L, Boudreau JK, Dibble LE. Factors associated with exercise behavior in people with Parkinson disease. Physical therapy. 2011 Dec 1;91(12):1838-48. [71] Kwok JY, Kwan JC, Auyeung M, Mok VC, Lau CK, Choi KC, Chan HY. Effects of mindfulness yoga vs stretching and resistance training exercises on anxiety and depression for people with Parkinson disease: a randomized clinical trial. JAMA neurology. 2019 Jul 1;76(7):755-63. [72] Sherrington C, Michaleff ZA, Fairhall N, Paul SS, Tiedemann A, Whitney J, Cumming RG, Herbert RD, Close JC, Lord SR. Exercise to prevent falls in older adults: an updated systematic review and metaanalysis. British journal of sports medicine. 2017 Dec 1;51(24):1750-8. [73] Gómez-Cabello A., Ara I., González-Agüero A., Casajús J. A., and Vicente-Rodríguez G., Effects of training on bone mass in older adults: a systematic review, Sports Medicine. (2012) 42, no. 4, 301–325, https://doi.org/10.2165/11597670-000000000-00000, 2-s2.0-84858212861 [74] Herrington C, Michaleff ZA, Fairhall N, Paul SS, Tiedemann A, Whitney J, Cumming RG, Herbert RD, Close JC, Lord SR. Exercise to prevent falls in older adults: an updated systematic review and metaanalysis. British journal of sports medicine. 2017 Dec 1;51(24):1750-8. [75] Connolly B. S., Lang A. E. (2014). Pharmacological treatment of Parkinson disease: A review. The Journal of American Medical Association, 311(16), 1670–1683. [76] Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL. The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2008;23(5):63164018181210 [77] Ahlskog, J.E. The New Parkinson’s Disease Treatment Book: Partnering with Your Doctor to Get the Most from Your Medications; Oxford University Press: Oxford, UK, 2015. [78] Singleton, A.B.; Farrer, M.; Johnson, J.; Singleton, A.; Hague, S.; Kachergus, J.; Hulihan, M.; Peuralinna, T.; Dutra, A.; Nussbaum, R.; et al. alpha-Synuclein locus triplication causes Parkinson’s disease. Science 2003, 302, 841. [79] Jiménez-Jiménez, F.J.; Alonso-Navarro, H.; García-Martín, E.; Agúndez, J.A. Advances in understanding genomic markers and pharmacogenetics of Parkinson’s disease. Expert Opin. Drug Metab. Toxicol. 2016, 12, 433–448 [80] Kalinderi K, Fidani L, Katsarou Z, et al. Pharmacological treatment and the prospect of pharmacogenetics in Parkinson’s disease. Int J Clin Pract. 2011;65(12):1289–1294. [81] P. Brundin et al. Neuropathology in transplants in Parkinson's disease: implications for disease pathogenesis and the future of cell therapy Prog. Brain Res.(2012) [82] Noyce, A.J.; Bestwick, J.P.; Silveira-Moriyama, L.; Hawkes, C.H.; Giovannoni, G.; Lees, A.J.; Schrag, A. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann. Neurol. 2012, 72, 893–901. [83] E. Arenas Towards stem cell replacement therapies for Parkinson’s disease Biochem. Biophys. Res. Commun. (2010) [84] Simon, D.; Tanner, C.; Brundin, P. Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology. Clin. Geriatr. Med. 2020, 36, 1–12 [85] Murthy MN, Blauwendraat C, Guelfi S, Hardy J, Lewis PA, Trabzuni D; UKBEC; IPDGC. Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson’s disease on chromosome 7p15.3 [86] Schiffmann R, Sevigny J, Rolfs A, Davies EH, Goker-Alpan O, Abdelwahab M, Vellodi A, Mengel E, Lukina E, Yoo HW (2020) The definition of neuronopathic Gaucher disease. J Inherit Metab Dis 43, 1056–1059. [87] Ng, J.; Barral, S.; Waddington, S.N.; Kurian, M.A. Gene Therapy for Dopamine Dyshomeostasis: From Parkinson’s to Primary Neurotransmitter Diseases. Mov. Disord. 2023, 38, 924–936. [88] Muramatsu, S.-I.; Fujimoto, K.-I.; Kato, S.; Mizukami, H.; Asari, S.; Ikeguchi, K.; Kawakami, T.; Urabe, M.; Kume, A.; Sato, T.; et al.A Phase I Study of Aromatic L-Amino Acid Decarboxylase Gene Therapy for Parkinson’s Disease. Mol. Ther. 2010, 18, 1731–1735 World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 586 [89] Mittermeyer, G.; Christine, C.W.; Rosenbluth, K.H.; Baker, S.L.; Starr, P.; Larson, P.; Kaplan, P.L.; Forsayeth, J.; Aminoff, M.J.; Bankiewicz, K.S. Long-Term Evaluation of a Phase 1 Study of AADC Gene Therapy for Parkinson’s Disease. Hum. Gene Therapy 2012, 23, 377–381. [90] Christine, C.W.; Bankiewicz, K.S.; Van Laar, A.D.; Richardson, R.M.; Ravina, B.; Kells, A.P.; Boot, B.; Martin, A.J.; Nutt, J.;Thompson, M.E.; et al. Magnetic Resonance Imaging-Guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson’s Disease. Ann. Neurol. 2019, 85, 704–71 [91] Kleim J. A., Neural plasticity and neurorehabilitation: teaching the new brain old tricks, Journal of Communication Disorders. (2011) 44, no. 5, 521–528, [92] Lim S-Y, Tan AH, Ahmad-Annuar A, et al. Parkinson's disease in the Western Pacific region. Lancet Neurol. 2019;18(9):865-879. [93] Hackney ME, Earhart GM. Tai chi improves balance and mobility in people with Parkinson disease. Gait and Posture 2008;28(3):456-60. [94] Tagliati M, Chaudhuri K, Pagano G. Prevalence Of Non-Motor Symptoms In Parkinson’s Disease: A Systematic Review With Meta-Analysis (P2. 053). Neurology. 2014;82(10 Supplement):P2. 053. [95] Remy P., Doder M., Lees A., Turjanski N., and Brooks D., Depression in Parkinson′s disease: loss of dopamine and noradrenaline innervation in the limbic system, Brain. (2005) 128, no. 6, 1314–1322, [96] Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. N Engl J Med 1988; 318: 876–880 [97] Neuhouser, M.L. The importance of healthy dietary patterns in chronic disease prevention. Nutr. Res 2019, 70, 3–6. Henderson, S.T. High carbohydrate diets and Alzheimer’s disease. Med. Hypotheses 2004, 62, 689–700 [98] Brown, E.G.; Goldman, S.M. Modulation of the Microbiome in Parkinson’s Disease: Diet, Drug, Stool Transplant, and Beyond. Neurotherapeutics 2020, 17, 1406–1417. [99] Peeples L. Core Concept: The rise of bioelectric medicine sparks interest among researchers, patients, and industry. Proc Natl Acad Sci 2019;116:24379–24382 - [100] Chang EH: Changing the tune using bioelectronics. Bioelectron Med [Internet]. 2021; 7(1) [101] Kieval R, Burns M, Keith P, et al. . Baroreflex stimulation system to reduce hypertension. U.S. Patent Application. 11/482,662, filed February 15, 2007 [102] Mohammed, M.G.; Kramer, R. All-Printed Flexible and Stretchable Electronics. Adv. Mater. 2017, 29, 1604965. [103] Yitzhak-David SL and Rotenberg MY: Emerging optoelectronic technologies for next-generation leadless bioelectronic modulation. [104] Li C., Guo C., Fitzpatrick V., Ibrahim A., Zwierstra M. J., Hanna P., Lechtig A., Nazarian A., Lin S. J., Kaplan D. L., Nat. Rev. Mater. 2020, 5, 61. [105] Steadman CJ, Abd-El Barr MM, Lad SP, Gad P, Gorgey AS and Hoenig H: Bioelectric medicine: Electrotherapy and transcutaneous electromagnetic stimulation—clinical and research challenges. Arch Phys Med Rehabil [Internet] 2022; 103 [106] Inflammation in the Peripheral Nervous System after Injury. Gu D, et al. Biomedicines. 2024. [107] Electrical stimulation methods and protocols for the treatment of traumatic brain injury: a critical review of preclinical research. Ziesel D, et al. J Neuroeng Rehabil. 2023. [108] Forster RJ: Wirefreeelectroceuticals: 3D electrical and electrochemical stimulation of biological systems. Curr Opin Electrochem [Internet] 2023; 39(101297) [109] Avula, M.N.; Grainger, D.W. Addressing Medical Device Challenges with Drug-Device Combinations. In DrugDevice Combinations for Chronic Diseases; Lyu, S., Siegel, R.A., Eds.; John Wiley & Sons: Hoboken, NJ, USA, 2015. [110] Braunwald E, Vatner SF, Braunwald NS, Sobel BE. Carotid sinus nerve stimulation in the treatment of angina pectoris and supraventricular tachycardia. California Medicine. 1970;112:41-50 [111] Discovery of Neuroprotective Agents Based on a 5-(4-Pyridinyl)-1,2,4-triazole Scaffold Gitto R, et al. ACS Chem Neurosci. 2022. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 587 [112] George MS, Sackeim HA, Rush AJ, et al. Vagus nerve stimulation: a new tool for brain research and therapy. Biol Psychiatry. 2000;47:287–295. [113] Immersive virtual reality-based rehabilitation for subacute stroke: a randomized controlled trial. Huang Q, et al. J Neurol. 2024. [114] Deep brain stimulation versus vagus nerve stimulation for the motor function of poststroke hemiplegia: study protocol for a multicentre randomised controlled trial. Xu J, et al. BMJ Open. 2024. [115] Pascual Valdunciel A, Gonzalez-Sanchez M, Muceli S, Adan-Barrientos B, Escobar-Segura V, Perez-Sanchez JR, et al. Intramuscular stimulation of muscle afferents attains prolonged tremor reduction in essential tremor patients. [116] Bronstein, J. M., Tagliati, M., Alterman, R. L., Lozano, A. M., Volkmann, J., and Stefani, A. (2011). Deep brain stimulation for Parkinson disease: An expert consensus and review of key issues. Arch. Neurol. 68:165. [117] Qualitative studies involving users of clinical neurotechnology: a scoping review. Starke G, et al. BMC Med Ethics. 2024. [118] Saenger, V. M. et al. Uncovering the underlying mechanisms and whole-brain dynamics of deep brain stimulation for Parkinson’s disease. Sci. Rep. 7, 9882 (2017). [119] A. Falaki et al.Systemic effects of deep brain stimulation on synergic control in Parkinson's diseaseClin. Neurophysiol.(2018) [120] Janowicz, P.W.; Leinenga, G.; Gotz, J.; Nisbet, R.M. Ultrasound-mediated blood-brain barrier opening enhances delivery of therapeutically relevant formats of a tau-specific antibody. Sci. Rep. 2019, 9, 9255. [121] Pavese N, Tai YF, Yousif N, Nandi D, Bain PG. Traditional trial and error versus neuroanatomic 3-dimensional image software-assisted deep brain stimulation programming in patients with Parkinson disease. World Neurosurg 2020;134:e98–e102. [122] Rashid Nazir, Liting Bi, Stefania F. Musolino, Olivia H. Margoto, Kuthan Çelebi, Christophe Mobuchon, Mahdi Takaffoli, Abbas S. Milani, Greg Falck, Jeremy E. Wulff. Polyamine–Diazirine Conjugates for Use as Primers in UHMWPE–Epoxy Composite Materials. ACS Applied Polymer Materials 2022, 4 (3),1728-1742. [123] Hubbard DK, Dennis R. Pain Relief and Tissue Healing Using PEMF Therapy: A Review of Stimulation Waveform Effects. Asia Heal. Care J. 2012; 1:26-35 [124] Chen, X.-Q.; Mobley, W.C. Alzheimer Disease Pathogenesis: Insights from Molecular and Cellular Biology Studies of Oligomeric Aβ and Tau Species. Front. Neurosci. 2019, 13, 659. [125] Shealy CN, Taslitz N, Mortimer JT, et al. . Electrical inhibition of pain: Experimental evaluation. Anesth Analg 1967;463:299–305. [126] Breen DP, Rohani M, Moro E, et al. Functional movement disorders arising after successful deep brain stimulation. Neurology. 2018;90(20):931–2. [127] Donati E and Indiveri G: Neuromorphic bioelectronic medicine for nervous system interfaces: from neural computational primitives to medical applications. Prog Biomed Eng (Bristol) 2023; 5(1): 013002. [128] Berthoud, H.R. ∙ Powley, T.L.Interaction between parasympathetic and sympathetic nerves in prevertebral ganglia: morphological evidence for vagal efferent innervation of ganglion cells in the rat Microsc. Res. Tech. 1996; 35:80-86 [129] S. Asirvatham, K. Londoner, M. Aravamudan, T. Deering, H. Heidbuchel, S. Kapa, B. Keenan, E. Maor, S. Mattke, L. T. Middleton, V. Pavlov, D. Weber, Bioelectronic Med. 2020, 6, 1 [130] Pavlov VA, Chavan SS and Tracey KJ: Bioelectronic medicine: From preclinical studies on the inflammatory reflex to new approaches in disease diagnosis and treatment. Cold Spring HarbPerspect Med 2020;10(3): 034140. [131] Anand S, Hotson J. Transcranial magnetic stimulation: neurophysiological applications and safety. Brain Cogn. 2002;50:366–86. [132] Adameyko, I. (2016). Neural circuitry gets rewired. Science (New York, N.Y.), 354(6314), 833–834. [133] Argyelan M, Oltedal L, Deng ZD, et al. Electric field causes volumetric changes in the human brain. Elife. 2019;8:e49115. [134] Adlan AM, Lip GY, Paton JF, Kitas GD, Fisher JP. Autonomic function and rheumatoid arthritis—A systematic review. In Seminars in Arthritis and Rheumatism 2014 Dec 1 (Vol. 44, No. 3, pp. 283-304). WB Saunders. World Journal of Biology Pharmacy and Health Sciences, 2025, 21(01), 568-588 588 [135] Abstracts from the fourth bioelectronic medicine summit: technology targeting molecular mechanisms. Bioelectron [136] A. Kalkal, S. Kumar, P. Kumar, R. Pradhan, M. Willander, et al. Recent advances in 3D printing technologies for wearable (bio)sensors, Addit Manuf, 46(2021):102088. [137] Liu W: Bioelectronic medicine: Treating diseases with miniaturized biomimetic devices. In: 2020 International Symposium on VLSI Technology, Systems and Applications (VLSI-TSA). IEEE; 2020. [138] Title Engineering long-lasting and spatially selective active neural interfaces for bioelectronic medicine. Vasiliki: Author Giagka; [139] Almouahed S, Hamitouche C, Stindel E. Optimized Prototype of Instrumented Knee Implant: Experimental Validation. IRBM. 2017;38(5):250–5. [140] Almouahed S, Hamitouche C, Stindel E. Optimized Prototype of Instrumented Knee Implant:Experimental Validation. IRBM. 2017;38(5):250–5.