Neuroinflammation and Therapeutic Advances in Parkinson's Disease: Focusing on the TH17/IL17 Pathway

Introduction

Parkinson's Disease (P.D.), a progressive neurodegenerative disorder, primarily affects body movements. The prevalence of P.D. is increasing globally [1]. Parkinson's disease symptoms are tremors, muscle rigidity, and slowness of movement. More often, complications start on one side of the body and eventually affect both sides. One side where it begins mostly remains more affected than the other. Early symptoms can be subtle, like mild tremors and facing problems while putting on a chair. With time, the disease progresses, and more complications occur in patients with P.D. while swallowing, chewing, speaking, sleep disorders, bladder problems, constipation, and cognitive changes; even dementia sometimes develops [2].

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Nerve cells in the substantia nigra part of the brain degenerate, reducing dopamine levels that are responsible for movement control. Parkinson’s disease pathophysiology includes accumulating abnormal alpha-synuclein proteins and impairing cellular mechanisms like the ubiquitin-proteasome system. Genetic mutations and environmental factors contribute to disease development. It is a congenital disease. Individuals with a family history of P.D. are more susceptible to getting P.D., though risks are still relatively low unless many relatives are affected. Its diagnosis is clinical, depending on medical history and neurological examination. Until now, no definitive blood or laboratory tests are available for non-genetic cases of P.D. [3]. To date, there is no proper cure for this disease. Currently, available treatments for P.D. are focused on reducing symptoms. Most frequently, carbidopa-levodopa is used to increase dopamine. Dopamine agonists, COMT inhibitors, MAO B inhibitors, and anticholinergics are chosen according to the patient's condition because these medications have specific side effects and benefits [2].

Scope and Purpose of the Review

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This paper aims to support the latest research on the role of TH17/IL17 in neuroinflammation in P.D. and its implications for treatment. Study providing a detailed overview of Parkinson's Disease, its prevalence, symptoms, and treatments, with a focus on neuroinflammation and potential therapeutic approaches. It highlights recent advancements in P.D. management and outlines future research directions, offering valuable insights for healthcare professionals and researchers.

What do statistics say?

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Nearly one million people in the U.S. are currently living with Parkinson's disease, and researchers expect it to rise to 1.2 million by 2030. Each year, nearly 90,000 people in the U.S. are diagnosed with P.D., which is showing a substantial increase from previous estimates. [4] Parkinson's disease is seen more common in men. People born males are 1.5 to 2 times more likely to develop than females by birth. Parkinson’s disease incidence depends on age. Older adults above 50 are more susceptible to developing disease, but approximately four per cent of people with P.D. are diagnosed before age 50, statistics revealed [6]. On a global stage, over 8.5 million individuals were living with P.D. as records of 2019. This number has doubled in the past 25 years. Compared to other neurological disorders, P.D. rapidly increases disability and death rates. In 2019, P.D. resulted in 5.8 million disability-adjusted life years, an 81% increase since 2000, and caused approximately 329,000 deaths (Launch of Who). Geographically, the incidence of P.D. in people aged 65 and older ranges from 108 to 212 per 100,000 persons in North America. For those aged 45 and older, the incidence ranges from 47 to 77 per 100,000 persons, highlighting geographical variations in P.D. incidence in specific regions such as the “Rust Belt” in the northwestern and midwestern U.S., Southern California, Southeastern Texas, Central Pennsylvania, and Florida. These variations may be influenced by a combination of genetic, environmental, and lifestyle factors [7]. Economic studies show the combined direct and indirect cost of Parkinson's, including treatment, social security payments, and lost income, is estimated to be nearly $52 billion per year in the U.S. alone. Medications for P.D. cost an average of $2,500 a year, while therapeutic surgery can cost up to $100,000 per person[4]

Neuroinflammation in Parkinsons Pathophysiology

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Protein Alpha Nucleon and Lewy Bodies Aggregation and Microglia changes during P.D.

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Neuroinflammation in neurodegenerative diseases is characterized by selective vulnerability of specific neuronal cells, diverse protein aggregation like alpha-synuclein, and abnormal immune responses. A study by Seonidas Stefanis suggested that alpha-synuclein protein aggregation is caused by genetic mutations, oxidative stress, inflammation, and impaired protein clearance mechanisms in the brain [8]. Lewy bodies are formed by misfolding and aggregation of alpha-synuclein and forming toxic proteins in neurodegenerative diseases, including Parkinson's disease. Other factors that exacerbate alpha-synuclein accumulation are environmental toxins, ageing, and mitochondrial dysfunction [9]. These factors contribute to the development and progression of these debilitating conditions.

??nar et al., 2022 suggested Microglia are immune cells of the central nervous system whose activation plays its role in neurodegenerative disorders marked by the death of dopamine-producing neurons in the brain. When alpha-synuclein aggregates, microglia transit from a resting state to an activated state. This activation exacerbates neuronal damage through the release of inflammatory molecules. Microglia exhibit phenotypic changes, ranging from pro-inflammatory, which worsens neuron damage, to anti-inflammatory, which helps healing. Interaction with misfolded alpha-synuclein, a P.D. hallmark, activates microglia more, contributing to neuroinflammation and neuronal degeneration [38].

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TH17/IL17 in Parkinsons Disease

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Parkinson's Disease (P.D.), a neurodegenerative disorder, is a gradually progressing disease in which dopaminergic neurons are reduced in the substantia nigra of the brain [2]. Dopamine, when reduced significantly, causes hallmark symptoms such as tremors, rigidity, and bradykinesia become exposed. The immune system, most commonly the TH17/IL17 axis, garners significant attention in PhD research. TH17 cells are the subset of T helper cells, which play the leading role in the immune system. TH17 is associated with cytokine IL-17, which plays a vital role in immune regulation and inflammation. When microglia become activated immune pathways become dysregulated including TH17 and IL-17 cells.

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Th17 cells are distinct subsets of CD4+ T cells, well recognized in autoimmune and inflammatory responses and are well known for interleukin-17 (IL-17). Development and differentiation of Th17 cell is influenced by a combination of cytokines including transforming growth factor-β (TGF-β), interleukin-1 (IL-1), and interleukin-6 (IL-6). Regulation process include transcription factors like signal transducer and retinoic acid receptor-related orphan receptor-γt (RORγt), activator of transcription 3 (STAT3), and the aryl hydrocarbon receptor [11]

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Cytokine IL-23 is produced by dendritic cells and macrophages, which are crucial for expansion and stabilization of long-term maintenance and functionality of Th17 cells. Under non-inflammatory conditions TGF-β? induces the development of regulatory T cells (Tregs), critical for maintaining immune homeostasis and preventing autoimmunity [12]. Research reported thatTh17 cells are not limited to producing IL-17 but produce cytokines like IL-8, IL-21, IL-22, IL-26, tumour necrosis factor-alpha (TNF-α), granulocyte-monocyte colony-stimulating factor (GM-CSF), CCL20, and occasionally IL-10. These cytokines enable Th17 cells to recruit and activate neutrophils for responding the infection and inflammation. These cells regulate other immune cells aswell with cytokines like IL-21 influencing the differentiation and proliferation of CD8+ T cells and B cells [13]. Dysregulation of Th17 cells has been linked to several autoimmune and inflammatory disorders.

Literature implicated that Th17 cells in the pathogenesis of neurodegenerative diseases like Parkinson's. Th17 cells contribute to neuroinflammation and neurodegeneration, highlighting their role beyond traditional immune responses. This connection is still being explored which shows importance of Th17 cells in a wide range of physiological and pathological processes [14].

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IL=17 family comprises a unique group of cytokines by mean of IL-17A through IL-17F as its members. IL-17 cytokines bind to their specific receptors, IL-17RA through IL-17RE, each with varying affinities for different IL-17 cytokines. For instance IL-17A shows a higher relationship with IL-17RA, and IL-17F binds more effectively to IL-17RC [15].

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Cytokines show broad expression of receptors. This indicates that a wide range of cells responds to IL-17 signalling. The receptor complex, mainly comprising IL-17RA and IL-17RC, possesses unique structural features that medicate signalling pathways distinct from other cytokine receptors. This exclusive singling pathway helps to intercede immune responses at mucosal barriers. It recruits and activates neutrophils, enhancing the body's defence against bacterial and fungal infections [16].

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Additionally, IL-17 cytokines stimulate the production of pro-inflammatory mediators like cytokines, chemokines, and growth factors, amplifying inflammatory responses crucial in host defence and implicated in the pathogenesis of various autoimmune and inflammatory diseases. IL-17 cytokines also induce cytokine production, chemokines, and growth factors, leading to the amplification of inflammatory responses, a mechanism crucial in host defence and a contributing factor in the pathogenesis of autoimmune and inflammatory. IL-17 cytokines maintain the integrity of barrier tissues, such as the gut and respiratory tracts. They achieve this by inducing the expression of antimicrobial peptides and mucins, reinforcing the barrier against pathogen invasion [17].

In Parkinson's Disease, IL-17 and microglia activation results in the production of pro-inflammatory cytokines and reactive oxygen species, damaging neuronal cells, dopaminergic neurons in the substantia nigra. Upon binding to their receptors on neuronal and glial cells, IL-17 cytokines predominantly activate the NF-κB pathway, a central mediator of inflammatory responses. This pathway's activation leads to the transcription and release of various pro-inflammatory cytokines, contributing to the neuroinflammatory milieu in P.D. [18]. Moreover, IL-17 can activate the JAK-STAT signalling pathway in specific contexts, further promoting the transcription of inflammation-related genes [19]. The target genes activated by IL-17 are predominantly those encoding pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. The inflammation driven by IL-17 is believed to be the progression of neuron degeneration, leading to the classic motor symptoms of P.D. IL-17 facilitates the recruitment of peripheral immune cells to the brain, which enhances inflammation. It can also activate astrocytes and glial cells of the brain. Astrocyte activation releases additional inflammatory mediators, resulting in more damage to neurons. Swelling driven by IL-17 becomes chronic, which aids Parkson’s disease progression. This dysregulation damages dopaminergic neurons, which outcome in the worsening of motor symptoms as well as the deterioration of non-motor functions in P.D. patients[18]

Parkinsons Disease Emerging Therapies

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Older medications include Carbidopa/Levodopa Formulations, which were effective drugs for treating P.D. symptoms. Carbidopa helps prevent the breakdown of levodopa before it reaches the brain. Dopamine Agonists mimic dopamine effects in the brain and are available in various forms like immediate-release, long-acting, patches, and injectable forms. Catechol-o-methyltransferase (COMT) Inhibitors include drugs like Entacapone and Tolcapone, which inhibit the breakdown of levodopa, enhancing its effects[20]. Monoamine Oxidase B (MAO-B) Inhibitors, such as Selegiline and Rasagiline, impede the brain's dopamine breakdown. Anticholinergics were widely used to help control tremors associated with P.D. Amantadine, Originally used for influenza, but can be used to ease P.D. tremors and muscle stiffness [21]

Since 2017, new treatments include Istradefylline (Nourianz?), which is an adenosine A2A receptor antagonist, approved in the U.S. in 2019 as an add-on therapy for OFF time in P.D. Opicapone (Ongentys?), A once-daily COMT inhibitor approved in the U.S. in 2020 as an add-on therapy to levodopa for motor fluctuations. Safinamide (Xadago?) was Approved in 2017 as an add-on therapy to carbidopa/levodopa for OFF time. It's a selective MAO-B inhibitor with other mechanisms like inhibition of glutamate release [22].

Levodopa is a precursor to dopamine used to treat P.D. Levodopa Inhalation Powder (Inbrija?) is a newly launched formula approved by the FDA in 2018, used as needed if medication effects wear off between oral doses of carbidopa/levodopa[23]. Apomorphine HCl Sublingual Film (Kynmobi?) is a dopamine agonist used as a rescue medication for OFF episodes. Amantadine formulations (Gocovri? and Osmolex ER?) are now being used for Dyskinesias. Amantadine formulations originally formed for influenza are directly observed to decrease dyskinesias caused by levodopa[24].

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For surgeries, Deep Brain Stimulation (DBS) Involves placing an electrode in critical brain parts controlling movement, connected to a small battery in the chest. Lesion Surgery is used to make small lesions in deep parts of the brain that help control P.D. symptoms. Neural grafting, or brain tissue transplantation, is an experimental medical procedure where neural tissue is transplanted to any part of the brain or spinal cord. It's a form of regenerative medicine that aims to restore the function of the nervous system in conditions including Parkinson's disease. This innovative approach holds the potential for improving life quality for patients suffering from neurodegenerative diseases or nerve damage. Despite these treatments, P.D. remains a challenging condition, significantly as it advances. Research continues to focus on both improving motor and non-motor symptoms and discovering treatments that can slow down or halt disease progression [25]

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The specific therapies targeting TH17 and IL17 in Parkinson's Disease (P.D.) include monoclonal antibodies designed to neutralize IL-17A, a pro-inflammatory cytokine implicated in neuroinflammation[26]. This approach aims to mitigate the inflammatory processes associated with P.D. Additionally, small molecule inhibitors are being explored; these drugs target signalling pathways essential for Th17 cell differentiation and function, potentially reducing inflammation. Another category comprises immunomodulatory drugs aimed at modulating the immune system's overall response, thereby altering the activity of Th17 cells and IL-17A.

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Discussion:

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Parkinson's disease is a neurological disorder that primarily affects movement and is characterized by symptoms such as tremors, stiffness, and changes in coordination. Symptoms of Parkinson's disease typically develop gradually and may include a slight tremor in one hand, loss of the sense of smell, coordination problems, changes in gait, constipation, facial expression loss, and more. While genetic factors contribute to about 10% of cases, the exact cause of Parkinson's disease is unknown. Environmental factors, such as exposure to toxins like pesticides, metals, solvents, and pollutants, increase the risk. Parkinson's disease is more common in males than females and typically occurs in people over the age of 60. [26]Previous studies suggested black people are less susceptible to developing D.P. compared to other ethnicities in the U.S. Although Parkinson's disease cannot be entirely prevented, certain lifelong habits may help reduce the risk, including avoiding exposure to toxins, protecting against head injuries, regular exercise, and maintaining a healthy diet. Turmeric, with curcumin in curries, soups, and teas, may reduce Parkinson's risk by countering oxidative stress and alpha-synuclein clumping. Flavonoids in berries, apples, tea, and red grapes also lower Parkinson's risk. Avoiding aldehydes in reused cooking oils, like sunflower oil, is crucial, as they're linked to Parkinson's and other diseases[26]

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In a groundbreaking development, a recent study by the University of Maryland School of Medicine (UMSOM) in 2023 unveiled a non-surgical and FDA-approved treatment for Parkinson's disease using focused ultrasound. This innovative therapy significantly improved symptoms in 70 per cent of patients, compared to only 32 per cent in the control group, offering hope to the one million Americans living with this neurodegenerative condition. The device used in the study, Exablate Neuro, received FDA approval based on the positive findings from the UMSOM clinical trial. Unlike traditional treatments, focused ultrasound requires no incision, anaesthesia, or in-patient stay, making it a promising and minimally invasive option for managing Parkinson's disease symptoms, such as tremors and mobility issues. Although not yet covered by insurance, the potential of this treatment represents a remarkable leap forward in Parkinson's disease management and underscores ongoing advancements in medical research and innovation[27].

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Traditional diagnosis techniques for Parkinson's Disease involve medical history, physical and neurological examinations, bradykinesia and tremors, observing medication response, and MRI or C.T. scan imaging or blood tests. No definitive test exists; diagnosis relies on clinical assessments, exclusion of other causes, and expert consultation when needed.

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Recently, researchers at the University of Oxford have utilized machine learning algorithms and wearable sensors to track the progression of Parkinson's Disease, offering a more objective measurement tool than traditional clinical rating scales. Combined with machine learning, these wearable devices, placed on the trunk, wrists, and feet, can detect progression in as little as 15 months. This advancement is critical for clinical trials and early detection of effective treatments for Parkinson's Disease, potentially accelerating drug development[28] A recent article in Forbes published by Juergen Echardt in 2023 discusses various novel approaches to treating Parkinson's disease. It highlights the potential of stem cell therapy, where reprogrammed stem cells are implanted into the brain to replace lost cells, and BlueRock Therapeutics' Phase I trial showed promising results with dopamine-producing neurons derived from pluripotent stem cells. Other approaches include using a protein called glial cell line-derived neurotrophic factor (GDNF) to support nerve cell survival, investigating gene therapy to deliver GDNF to affected brain regions, and exploring drugs like exenatide and Ambroxol to stabilize and inhibit the formation of toxic alpha-synuclein clumps. [29]

Advanced Parkinson’s disease (APD) presents significant challenges in motor and non-motor fluctuations. Traditional therapies, like levodopa, often face limitations due to unpredictable intestinal absorption and motor complications. Novel drug delivery systems, such as subcutaneous apomorphine and levodopa/carbidopa jejunal infusion, have emerged as effective alternatives, validated by randomized studies and extensive clinical experience [30]

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A notable advancement is the introduction of a levodopa/carbidopa infusion gel that includes the catechol-O-methyl transferase inhibitor Entacapone. This formulation allows for a reduced daily dose of levodopa, improving patient compliance and potentially reducing side effects. [31]Additionally, two new soluble formulations of levodopa/carbidopa (ND0612 and ABBV-951) are set to revolutionize treatment by ensuring subcutaneous delivery through a portable pump infusion system. ABBV-951 mainly utilizes foslevodopa/foscarbidopa prodrugs to enhance absorption and tolerability[32]

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Advanced drug delivery systems offer several significant advantages in managing Parkinson's disease. First, they improve motor symptom management by providing consistent and effective control, reducing periods of poor mobility (OFF time), and enhancing functional independence. Second, these systems minimize motor complications by decreasing the development of dyskinesia and other fluctuations associated with pulsatile stimulation from oral medications, thanks to their continuous dopaminergic stimulation. Third, they enhance bioavailability by bypassing gastrointestinal issues that can affect the absorption of oral medications, leading to more stable drug levels. Fourth, integrating COMT inhibitors, like in the new levodopa/carbidopa/entacapone gel, allows for more efficient dosing, potentially reducing side effects and improving patient adherence. Finally, portable pump systems offer convenience and flexibility, potentially improving patients' quality of life and commitment to therapy [32].

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Future directions in APD treatment should focus on early detection of candidates for these device-aided therapies, improving access and availability globally, and integrating remote monitoring technologies for better management. Understanding the comparative benefits of each treatment is essential for selecting the most appropriate therapy, tailored to the patient’s specific needs and conditions, to optimize symptom control and enhance quality of life.

Challenges

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Medications for Parkinson's Disease (P.D.) offer symptom relief but also bring various complications. Carbidopa/Levodopa, central to P.D. treatment, can lead to motor complications like dyskinesia and fluctuations in drug effectiveness over time. Dopamine Agonists, while mimicking dopamine effects, may cause sleepiness, hallucinations, a drop in blood pressure upon standing, and impulse control disorders like compulsive behaviours. COMT Inhibitors, including Entacapone and Tolcapone, can induce gastrointestinal issues and, in rare cases, liver toxicity, particularly with Tolcapone. MAO-B Inhibitors, such as Selegiline and Rasagiline, have side effects, including insomnia and nausea, and can react adversely with certain foods or medications. Anticholinergics, used for tremor control, are associated with cognitive side effects like memory impairment, and confusion, and physical issues like urinary retention and dry mouth. Lastly, Amantadine, though beneficial for dyskinesia, might cause hallucinations, ankle swelling, and skin discolouration. Managing these complications necessitates careful monitoring and collaboration between patients and healthcare providers, emphasizing the need for personalized treatment plans [32]

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Future directions

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The future of Parkinson's disease (P.D.) research in Calabresi et al., 2023, 2023 is marked by several promising avenues to enhance our understanding and management of the disease. A significant focus is on the pathological form of alpha-synuclein, a protein associated with dopaminergic neuron death in P.D. Researchers have identified various proteins interacting with this pathological form, many involved in RNA processing and protein synthesis. These insights could lead to new treatments targeting these interactions, offering hope for slowing or halting P.D. progression[33].

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Genetic research is another critical area, particularly studies on GBA mutations and their role in P.D. development. This research has revealed dysregulation in genes related to alpha-synuclein degradation, ageing, and amyloid processing, particularly in individuals with P.D. who have a GBA mutation. Understanding these genetic factors opens the door to novel intervention strategies [34]

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Karuppagounder et al., 2023 stated there are several innovative treatments under investigation. These include Butanetap, which suppresses the translation of neurotoxic proteins like alpha-synuclein; Sulfuraphane, an antioxidant with potential cognitive and motor benefits; IKT-148009, a molecule that reduces c-Abl kinase activity linked to neurodegeneration; Bemdaneprocel, a cell-based therapy involving dopaminergic neuron precursor cell transplantation; RO-7486967, a molecule targeting inflammation; and KM819, which inhibits Fas-associated factor1 (FAF1) to reduce cell death[37]. There's a growing shift towards human-specific research methods, moving away from traditional animal-based studies. New approach methodologies (NAMs) are being integrated to address the complexity of P.D. at various levels, from molecular to population. This shift is also seen in learning from advances in Alzheimer's disease research and emphasizing collaborative efforts across disciplines[35]. Such directions in P.D. research signify a broader move towards more targeted, molecular-based therapies and a deeper understanding of the genetic and cellular mechanisms underlying Parkinson's disease. This integrative and innovative approach is crucial for developing effective treatments and potentially finding a cure for P.D.

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Conclusion

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We can conclude that Parkinson's Disease (P.D.) emphasizes the critical role of neuroinflammation, particularly the involvement of TH17 cells and IL-17 cytokines, in the disease's progression. P.D. is characterized by the degeneration of dopamine-producing neurons and the buildup of alpha-synuclein proteins, with neuroinflammation significantly contributing to this process. TH17 cells and IL-17 cytokines are known for their roles in immune regulation, are dysregulated in P.D., exacerbating neuroinflammation and neuronal damage. This study suggests emerging therapies targeting these inflammatory processes, such as monoclonal antibodies and immunomodulatory drugs, to slow the progression of P.D. Future research is directed towards developing molecular-based therapies and understanding P.D.'s genetic and cellular mechanisms. This involves integrating human-specific research methods and learning from other neurodegenerative diseases. The article highlights the necessity of interdisciplinary collaboration for effective treatment development and potential cures, underscoring the importance of continued research into neuroinflammation's role in P.D. and developing new therapeutic strategies.

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Tables and figures:

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