Neuroinflammatory Pathways in Parkinson's Disease: Understanding Triggers and Treatment Approaches

Received: 16-Sep-2025, Manuscript No. JDAR-25-171062; Editor assigned: 18-Sep-2025, Pre QC No. JDAR-25-171062 (PQ); Reviewed: 02-Oct-2025, QC No. JDAR-25-171062; Revised: 09-Oct-2025, Manuscript No. JDAR-25-171062 (R); Published: 16-Oct-2025, DOI: 10.4303/JDAR/236457

Introduction

PD is the second most prevalent neurodegenerative disorder globally, with approximately 90% of cases being occasional and only 10% linked to genetic mutations. In recent years, both the occurrence and death rates of PD have risen significantly, making it a main health concern, particularly for individuals aged 45 to 70, who show a notably higher occurrence of the disease [1-3].

The hallmark symptoms that facilitate the diagnosis of PD include asymmetric, gradually worsening resting tremors, cogwheel rigidity, bradykinesia, and impaired postural reflexes. Non-motor symptoms may also emerge years before the onset of motor issues, such as anosmia, constipation, depression or apathy, sleep disturbances, and memory impairment. As the disease progresses, additional symptoms may develop, including autonomic dysfunction, pain, cognitive decline, language difficulties, and psychosis [4].

The onset and advancement of PD symptoms are primarily linked to a substantial loss of Dopaminergic neurons (DA neurons) in the Substantia Nigra Pars Compacta (SNPc), coupled with the presence of Lewy bodies (LBs) intracytoplasmic inclusions composed of insoluble and misfolded aggregates of α-synuclein (α-syn) [5-7]. The presence of LBs and α-syn aggregates is considered a key molecular hallmark of PD. These pathological changes are more commonly observed in regions such as the basal ganglia, locus coeruleus, raphe nuclei, thalamus, amygdala, and cerebellum [8-10].

Although PD being first characterized over 200 years ago, its underlying causes remain incompletely understood. Nevertheless, the role of neuroinflammation in the pathophysiology of PD has gained increasing recognition [11-13]. Neuroinflammation refers to the inflammatory processes occurring within the Central Nervous System (CNS), involving both inborn and adaptive immune replies. This process is complex, as it can simultaneously activate neuroprotective and neurodevelopmental mechanisms while also contributing to neuronal damage, thereby playing a role in the neurodegeneration seen in diseases like PD [14-16].

In this context, a multi-level approach to studying PD is crucial for deepening our understanding of the disease and its link to neuroinflammation, along with the developing of new therapeutic methods.

Inflammation in PD

Persistent inflammatory processes are widely acknowledged as key pathogenic and etiological factors driving neurodegeneration. Unlike acute inflammation, which is generally protective and aids in the immediate repair of brain tissue following environmental stressors (such as traumatic injuries, viral infections, or toxins), chronic inflammation is more commonly linked to the onset and progression of neurodegenerative diseases [17- 19]. While the exact triggers of neuroinflammation in PD remain unclear, factors like α-synuclein misfolding, immune-related gene polymorphisms, and mitochondrial dysfunction have been proposed as potential contributors [20,21].

The delicate balance between the physiological influence of acute neuroinflammation and the pathological outcomes of prolonged neuroinflammatory replies is regulated by the activity of various cell types engaged either in inborn or adaptive immunity [22-24]. These include not only Central Nervous System (CNS)-resident glial cells (such as microglia, astrocytes, and oligodendrocytes), but also peripheral circulating myeloid cells (including monocytes, macrophages, and dendritic cells) and T lymphocytes, which strongly contribute to the neuroinflammatory procedure by penetrating into the brain. Automatically, succeeding neuronal injury, CNS-resident glial cells liberate signaling molecules (such as cytokines, chemokines, growth factors, and other metabolites) that captivate peripheral myeloid cells to the place of injury [25-28]. Sequentially, these myeloid cells can engage additional immune cells, like T lymphocytes, into the CNS, thereby increasing the inflammatory reply. It’s important to highlight that not only glial cells, but also neurons can bluntly output inflammatory agents that stimulate immune cells. This is a key point to consider when understanding the sequence of events (neurodegeneration vs. neuroinflammation) that cause unchangeable cell death in Parkinson’s disease [29-31].

Actually, independent changes within SNpc dopaminergic neurons (such as mitochondrial dysfunction, impaired protein clearance, and α-synuclein release) can initiate an inflammatory reply in the surrounding environment, or even at a systemic grade, through the release of signaling molecules. This can impact other neuronal and nonneuronal cell types engaged in the neuroinflammatory course [32-36].

Factors contributing to neuroinflammation in PD

Neuroinflammation is a key feature of various neurological conditions, including PD. Immune cells in the Central Nervous System (CNS), equal to microglia and astrocytes, manage inflammation by discharging agents such as Interleukins (IL), Tumor Necrosis Factor-α (TNF-α), NF-κB, inducible Nitric Oxide Synthase (iNOS), NOD-Like Receptor Family Pyrin domain-containing 3 (NLRP3) inflammasome, and Reactive Oxygen Species (ROS) [37,38]. The secretion of these agents triggers an inflammatory reply that is harmful to neurons. As a result, superfluous and unregulated microglial stimulation significantly contributes to PD pathology by promoting the discharge of pro-inflammatory cytokines, IL, and ROS, initiating apoptosis, and leading to the degeneration of dopaminergic neurons [39-41].

Microglia

Microglia make up about 10% of the general brain cell population. Apart from their homeostatic roles, they serve as the first line of protection in the brain’s immune system. The density of microglia varies across different brain regions, with the highest concentrations found in the hippocampus, olfactory bulb, basal ganglia, and Substantia Nigra (SN), while lower densities are observed in the putamen, transentorhinal, cingulate, and temporal cortices [42,43].

Microglial cells emit neurotrophic elements, clear toxic substances, and play a role in neuronal improvement, remodeling, and synaptic pruning. In the normal physiological circumstances, microglial stimulation supports brain evolution by removing programmed neural cells and promoting neuronal survival+the production of trophic and anti-inflammatory factors [44-47]. However, when microglia become overactive, they can exert significant neurotoxic effects by immoderately liberating harmful factors like superoxide, Nitric Oxide (NO), and Tumor Necrosis Factor-α (TNF-α). The dysregulated expression of α-syn or duplications in the SNCA gene in PD lead to the accumulation of toxic α-syn fibrils that are the primary components of Lewy bodies and neurites. These Lewy bodies and neurites are harmful and contribute to the loss of dopaminergic neurons in PD [48,49]. Additionally, α-syn pathology can activate microglia by stimulating Toll- Like Receptors (TLR) on the microglial surface, triggering an inflammatory reply. This reply causes the production of pro-inflammatory cytokines and stimulates the NF-KB signaling pathway, further amplifying the inflammatory process [50-53].

α-Synuclein (α-syn) is an endogenous protein primarily located at the presynaptic terminal, though its exact physiological function remains unclear. Various in vitro and in vivo studies under pathological conditions have demonstrated that incorrect folding or accumulation of α-syn plays a key role in the pathogenesis of PD [54- 57]. Extracellular α-syn oligomers activate immune receptors on the surface of microglia, involving Toll-Like Receptor 2 (TLR-2), which subsequently stimulates NF- κB and p38 a protein engaged in the Mitogen-Activated Protein Kinase (MAPK) signaling pathway via TLR-2 signaling. Stimulation of the TLR 1/2 receptor by α-syn also enhances the activity of the IL-1 Receptor-Associated Kinase (IRAK) complex, leading to the activation of TNF Receptor-Associated Factor 6 (TRAF6). These chronological processes result in the activation of Inhibitory Kappa Kinases (IKKs), which trigger the degradation of inhibitory kappa B alpha (IκB-α) [58-60]. Consequently, pro-inflammatory cytokines are produced through the MAPK pathway and the nuclear displacement of NF-κB, c-Jun N-terminal Kinase (JNK), and p38 activation. The generation and emission of pro-inflammatory cytokines following the phagocytosis of α-synuclein fibrils contribute to cell death and quicken the development of Parkinson’s disease. Furthermore, the cooperation of α-synuclein fibrils, TLR, and NF-κB enhances NLRP3 upregulation [61- 63].

Activation of the NF-κB pathway via TLRs or cytokines escalates the expression of NLRP3 by promoting pro- IL-1β and pro-IL-18, resulting the activation of the NLRP3 inflammasome. Once activated, NLRP3 converts procaspase-1 into active caspase-1, which then processes pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18, both of which contribute to neuroinflammation. In addition, caspase-1 plays a role in pyroptosis, an inflammatory model of cell death [64-66].

Injured dopaminergic neurons emit Matrix Metalloproteinase 3 (MMP3), a proteinase that breaks down the extracellular matrix, α-synuclein, and neuromelanin, leading to microglial activation. Overactivated microglia produce Reactive Oxygen Species (ROS) and liberate pro-inflammatory cytokines, which contribute to the death of dopaminergic neurons. This self-perpetuating cycle accelerates the progression of Parkinson’s disease [67-69].

Astrocytes

Astrocytes are the most plentiful type of glial cell in the central nervous system. Their cytoplasmic additions connect neurons to blood vessels, facilitating substance exchange between them. Astrocytes provide metabolic support to neurons by supplying lactate for mitochondrial respiration, assisting in tissue recovery, and exuding trophic factors essential for neuronal viability and synaptogenesis [70- 72]. Additionally, they play a crucial role in regulating Blood- Brain Barrier (BBB) permittivity, defending cerebral blood flow, and maintaining ion homeostasis [73].

Astrogliopathy in the Substantia Vigra (SN) and striatum

Astrogliopathy in the Substantia Vigra (SN) and striatum has been observed in the 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine (MPTP) form of Parkinson’s disease. As astrocytes lose their usual characteristics, such as providing nutrients to neurons and regulating synaptic activity, they begin exuding IL-1α, complement Component 1q (C1q), and TNF-α. In their reactive state, astrocytes release neurotoxic factors that lead to the death of neurons and oligodendrocytes. However, astrocytes also upregulate several neurotrophic factors, which are thought to have neuroprotective effects [74-77].

Reactive astrocytes are commonly observed in Parkinson’s disease. α-synuclein-positive inclusions are found both in neurons and in astrocytes in postmortem brain tissue of PD patients. Neuronal α-synuclein aggregates are transferred to neighboring astrocytes, where they create pathological inclusion bodies. The accumulation of α-synuclein in astrocytes results in increased production of pro-inflammatory cytokines (such as IL-6 and TNF-α) via TLR4 signaling, along with elevated expression of Intercellular Adhesion Molecule 1 (ICAM1) and Reactive Oxygen Species (ROS), further exacerbating the disease pathology [78-81].

Leukotrienes

Leukotrienes (LTs) are a class of lipid mediators based on arachidonic acid through the 5-Lipoxygenase (5-LOX) enzyme. After the 5-LOX enzyme synthesizes LTA4 from free arachidonic acid, LTA4 is further metabolized into LTB4, LTC4, LTD4, and LTE4. LTC4, LTD4, and LTE4 are together known as Cysteinyl Leukotrienes (CysLTs) due to the presence of an additional cysteinyl group, primarily activating two receptors, CysLT1R and CysLT2R [82- 85]. LTs play key roles in inflammatory replies, including leukocyte chemotaxis, vascular permeability, and cell proliferation. Under normal physiological conditions, CysLT1R and CysLT2R activation in the brain is restricted. Nevertheless, their levels rise in different conditions such as Alzheimer’s Disease (AD) and PD. Connecting CysLTs with microglial CysLT1R enhances the inflammatory response via upregulation of the NF-κB-mediated MAPK pathway, leading to increased emission of cytokines like IL-1β and TNF-α [86-89].

What triggers neuroinflammation in PD?

The development of PD is multifaceted, including various cases and processes. There is no unified agreement on what exactly provokes neuroinflammation in PD. Earlier studies have suggested that damaged dopaminergic neurons can initiate microglia, leading to neuroinflammation. Nonetheless, more recent research on PD pathogenesis points to factors such as aberrant α-synuclein, immune- related gene polymorphisms, mitochondrial dysfunction, and gut microbiome dysbiosis as potential triggers for neuroinflammation [90-93]. This suggests that microglial activation may occur prior to neuronal degeneration. The following sections outline the common materials and processes that contribute to neuroinflammation. A summary of the main triggers and molecular mechanisms of neuroinflammation in PD is provided in Table 1.

Table 1: Triggers and mechanisms of neuroinflammation in Parkinson’s disease.

α-Synuclein aggregation and neuroinflammation

Microglia are essential innate immune cells that play a key role in the central nervous system’s first border of protection. They support homeostasis by negotiating phagocytosis and inflammatory responses. The accumulation of aberrant α-synuclein can trigger microglial activation. When excessively initiated, microglia can stimulate other innate immune elements within the central nervous system and provoke peripheral adaptive immune responses, ultimately leading to significant neuronal damage [94- 96]. This phenomenon was first observed in cell culture and animal examples of PD. In a mouse case of PD, where human α-synuclein was amplified using a recombinant Adeno-Associated Virus Vector, serotype 2 (AAV2), a significant growth in CD68-positive microglia was noted four weeks after injecting AAV2 and human α-synuclein into the substantia nigra. In cultivated BV-2 microglia, exposure to extracellular α-synuclein was shown to induce an NF-κB positive response and the manufacture of pro- inflammatory cytokines [97-99]. Additionally, the existence of α-synuclein-reactive T cells was verified, with the highest levels observed shortly after PD diagnosis. Later, it was proved that morbid α-synuclein activated a strong inflammatory reply in human monocytes from PD patients [100-102]. Recent advances in understanding the molecular mechanisms behind microglial activation have revealed the following key pathways: (1) Membrane receptor pathway: α-synuclein (α-syn) can specifically connect with TLR2, TLR4, and CD36 receptors on the surface of microglial membranes, triggering receptor-mediated inflammatory signaling pathways. (2) Intracellular signaling pathway: α-syn can elevate STAT3 levels and initiate the JAK/STAT signaling pathway in microglia, causing the expression of MHC-II molecules and pro-inflammatory genes. (3) Inflammasome route: α-syn can trigger the NLRP3 inflammasome via the Fyn signaling pathway, resulting in enhanced IL-1β secretion. (4) RNA-connecting protein route: α-syn can also stimulate the appearance of the RNA- connecting protein Caspase8, which promotes further release of IL-1β [103-105].

Genetic factors and neuroinflammation

Genetic forms of PD represent approximately 5% to 10% of cases and are typically associated with early-onset. Genes generally connected with PD include LRRK2, SNCA, VPS35, PRKN, DJI, PINK1, and PARK7. Of these, LRRK2, VPS35, PRKN, and PINK1 have a significant meaning in the immune system. LRRK2, in particular, is not only a key gene in autosomal dominant PD but also associated with sporadic forms of the disease. Additionally, LRRK2 is highly represented in peripheral blood mononuclear cells [106-108]. Preceding research has demonstrated that LRRK2 influences microglial role in various ways. Transcriptomic analysis of LRRK2 knock-out microglial cells revealed a reduced induction of mitochondrial SOD2 in response to α-synuclein pre-formed fibrils, suggesting that microglial LRRK2 may promote PD pathogenesis through altered oxidative stress signaling [109, 110]. In a manganese exposure animal model, activated microglia were shown to liberate numerous inflammatory cytokines, with an upregulation in LRRK2 expression. Moreover, inhibiting LRRK2 reduced the expression of inflammatory cytokines and restored microglial autophagic function. Additionally, last findings suggest LRRK2 plays a role in vesicular trafficking, being vital to the autophagy/lysosomal pathway and necessary for proper lysosomal role. LRRK2 can associate with the intracellular sorting protein VPS35 to regulate the phosphorylation of RabGTPases, which in turn intercede phagocytosis, extracellular secretion, and autophagy in immune cells by controlling vesicle transport [111-113]. Autophagy, sequentially, affects inflammation by facilitating the transport of disintegrative material to the lysosome. LRRK2 mutations may contribute to inflammatory responses by affecting intracellular dealing. Similarly, PRKN and PINK1 are generally associated with Parkinson’s disease. Research has shown that both acute and chronic mitochondrial stress in vivo can trigger a STING- mediated type I interferon response in mice lacking parkin or PINK1 [114,115]. Moreover, raised cytokine levels have been observed in the serum of asymptomatic PRKN mutation carriers, suggesting that parkin and PINK1 help to impede inflammation by releasing harmed mitochondria. Co-expression of parkin and PINK1 has been found to hinder the antigen introduction of MHC-I molecules, which can activate CD8+ T cells. Mutations in these genes may result in an overactivation of immune cells. These findings indicate that LRRK2, PRKN, and PINK1 play significant roles in regulating the immune system [116- 118].

In last years, Genome-Wide Association Studies (GWAS) have revealed that polymorphisms in definite gene loci enhance receptivity to sporadic PD. In 2017, a GWAS determined 17 different PD loci and discovered that a few recently determined PD risk genes are involved in lysosomal function and autophagy. To further expand the understanding of genetic risk in PD, a 2019 GWAS identified 90 autonomous standard genetic risk factors, almost doubling the previously recognized risk variants [119]. This study also highlighted intracranial and putaminal volume as potential future PD biomarkers and determined cognitive performance as a PD dangerous factor. The majority of gene loci are associated with autoimmunity, and polymorphisms in HLA alleles have been strongly linked to the danger of PD. Several Single Nucleotide Polymorphisms (SNPs) within the HLA class II gene locus have been reported to increase genetic receptivity to PD, along with rs3129882, rs75855844, rs2395163, rs660895, and rs4248166 [120-123]. It was identified a connection between the rs3129882 polymorphism and PD risk. This variant, located in the noncoding area of the HLA-DRA gene, can control the expression of HLA-DR and HLA-DQ genes. A meta-analysis of genome-wide following studies further confirmed that the rs75855844 polymorphism in the HLA-DRB5 gene is connected with PD [124,125].

A meta-analysis conducted in 2012 identified the rs660895 polymorphism in the HLA-DRB1 gene as a defensive agent against PD [126]. MHC-II particles, codified by HLA genes, are expressed on the surface of various activated immune cells and identify epitopes, which trigger adaptive immune responses through antigen presentation. Single nucleotide substitutions in the coding regions of the HLA-DR, HLA-DQ, and HLA-DP genes can impair the function of MHC-II molecules. The expression of HLA class II genes is regulated by sequences in the noncoding regions, which can influence the expression of multiple structural genes simultaneously [127,128]. Consequently, changes in both coding and noncoding regions of HLA class II genes can impact MHC-II molecule functionality. In the central nervous system, MHC-II molecules are primarily emerged from microglia, with astrocytes and vascular endothelial cells demonstrating miserable grades of expression [129- 131].

Initiated microglia express MHC-II molecules, which can trigger adaptive immune replies and cause neuronal destruction by stimulating T cells. These researches suggest that polymorphisms in the HLA gene locus can control the expression of MHC-II molecules on the surface of microglia, leading to a neuroinflammatory response in Parkinson’s disease [132,133].

Mitochondrial dysfunction and neuroinflammation

Mitochondrial disorder and increased oxidative stress have been observed in the Substantia Nigra (SN) of PD patients and animal examples. In tissues from patients with the LRRK2 (G2019S) mutation, mitochondrial membrane potential and intracellular ATP grades were reduced, while mitochondrial elongation and interconnectivity raised, suggesting that the LRRK2 mutation may impact both mitochondrial function and morphology [134-136]. The DJ1 protein is located in the mitochondrial matrix and intermembrane space, and its removal results in impaired mitochondrial dynamics and triggers cell apoptosis. Mutations in PINK1 can also disturb mitochondrial morphology and work. Additionally, α-synuclein aggregation can impede proteasome complex 1 activity, disturb calcium homeostasis within the mitochondrial matrix, support mitochondrial fragmentation, restrain fusion, and ultimately lead to mitochondrial dysfunction [137-140]. When mitochondrial function is endangered, huge amounts of Reactive Oxygen Species (ROS), mitochondrial fragments, and mitochondrial DNA (mtDNA) fragments are generated. ROS act as a main pro-inflammatory trigger by stimulating nuclear factor κB. Additionally, mtDNA fragments can initiate inflammation by cooperating with Toll-Like Receptors (TLRs), Nucleotide-binding Oligomerization Domain (NOD)- like receptor family pyrin domain containing 3 (NLRP3) inflammasomes, and the cytosolic cyclic GMP-AMP Synthase (cGAS)-Stimulator Of Interferon Genes (STING) DNA-sensing pathway [141-143].

Once liberated, these substances can operate as Damage- Associated Molecular Patterns (DAMPs), provoking an innate immune inflammatory response by joining danger signal receptors, with mtDNA fragments playing a particularly significant role. Mitochondria are unique organelles with their own genetic material. The proteins codified by mtDNA form four proteasome compounds on the interior mitochondrial membrane, which are crucial for electron transfer and ATP synthesis. Destruction of mtDNA and proteasome compounds can lead to mitochondrial trouble. The frequency of mtDNA mutations, removals, duplications, and alterations in PD is considerably higher compared to standard controls, showing that mtDNA is damaged in PD. Consequently, mitochondrial disorder can trigger a neuroinflammatory response [144-146].

Gut microbiome dysbiosis and neuroinflammation

The Gut Microbiome (GM) has an important meaning in the development, distinction, and role of microglia. Research in 2015 demonstrated that colonization with a complex microbiota modulates microglial activation and maturation, whereas in the absence of intestinal microbes, the innate immune response of microglia is weakened. In Germ- Free (GF) mice, supplementation with short-chain fatty acids microbial metabolites was able to restore impaired microglial maturation, highlighting the importance of gut microbiota and metabolites for proper microglial development and activation [147-150]. Gut microbiome dysbiosis, persistent intestinal mucosal inflammation, and α-synuclein accumulation in the enteric nervous system have been observed in PD patients. The microbial communities in the mucosal and fecal samples of PD patients show a proinflammatory dysbiosis distinct from that of control subjects. In α-synuclein-overexpressing mouse cases, colonization with microbiota from PD patients led to a greater motor dysfunction in contrast with transplants from healthy human donors [151- 154]. Moreover, managing specific microbial metabolites to germ-free mice induced neuroinflammation and motor symptoms. This suggests that signals from gut microbes are necessary to trigger neuroinflammatory responses in PD models. Therefore, gut microbiome dysbiosis may drive neuroinflammation [155].

Therapeutic strategies to target neuroinflammation in PD

Several drugs have shown promise in preclinical and clinical investigations for potentially treating or delaying PD. However, the absence of truly effective treatments has driven the search for new therapeutic approaches. Notably, neuroinflammation is emerging as a key characteristic that can be purposed in PD. This section will explore advanced pharmacological methods aimed at treating PD by addressing neuroinflammation [156-158].

Immunotherapy for alpha-synuclein aggregation

As earlier mentioned, toxic forms of α-Syn can impair neuronal role and initiate various immune pathways and cells. These detrimental effects may arise due to the breakdown in liquidation of α-Syn aggregates. Given that PD patients exhibit insignificant grades of α-Syn antibodies, it appears that the clearance mechanisms are compromised. An immunotherapeutic strategy could potentially impede the development of extracellular α-Syn assemblies, thereby inhibiting oligomerization, fibrillization, and/or conglomeration of α-Syn, which would stop its multiplication between cells [159-161]. Targeting neuroinflammatory issues in PD, passive immunization (introducing antibodies from an external source) or active immunization (stimulating the body to produce antibodies through antigens) have shown promise as therapeutic methods. Notably, the first vaccine developed, PD01A, showed promising results, leading to the production of antibodies against aggregated α-Syn, decreased deposition, and better memory and motor feature in mouse examples. In PD patients, PD01A was found to be harmless and well-tolerated in a phase I clinical trial, though further trials are required to confirm its productiveness [162,163].

Vagotomy and appendectomy

The communication between the gut and brain, along with the subsequent accumulation of α-Synuclein (α-Syn) from the gastrointestinal tract to the lower brainstem, suggests that procedures like vagotomy and appendectomy could potentially mitigate the jeopardy of advancing Parkinson’s disease. Some accessory researches have indicated that truncal vagotomy, but not selective vagotomy, may offer a protective effect against PD [164,165]. Specifically, Svensson and colleagues reported that individuals who experienced truncal vagotomy had a 15% lower risk of advancing PD [166]. These findings suggest that the vagus nerve plays a role in the transmission of pathological α-Syn along the gut-brain axis, and that vagotomy may postpone, but not completely annihilate, the risk of PD. Furthermore, another accessory research showed that the appendix could play a key role in PD through its influence on inflammation and the microbiota, as it serves as a long-term channel of aberrant α-Syn. Early removal of the appendix was associated with a reduced risk of developing PD. Overall, a deeper understanding of the relationship between the gut-brain axis, gut microbiota, and PD could pave the way for new diagnostic and therapeutic approaches [167-169].

Nonsteroidal anti-inflammatory agents

Anti-inflammatory tools like Nonsteroidal Anti- Inflammatory Drugs (NSAIDs) can potentially slow the progression of the inflammatory response, reducing the risk of exacerbated feedback in PD. Among the most promising NSAIDs is ibuprofen, which exerts its anti-inflammatory effects by nonselectively inhibiting Cyclooxygenase (COX), an enzyme involved in the synthesis of prostaglandins that is elevated in the dopaminergic neurons of PD patients [170-173]. Additionally, ibuprofen appears to possess antioxidant properties that offer neuroprotection through a mechanism independent of COX inhibition. In animal model studies, ibuprofen reduced dopaminergic neurodegeneration by restricting the development of oxidative types. Nonetheless, this pharmacological strategy has yet to undergo clinical validation in the case of PD [174,175].

In addition to ibuprofen, other NSAIDs like aspirin and celecoxib have demonstrated protective effects in PD pathology. Aspirin, another COX obstacle, impacts neuroinflammatory processes and neuronal degeneration, helping to restrain the exhaustion of striatal dopamine. Consequently, further investigation into the use of NSAIDs as a therapeutic approach could enhance the modulation of neuroinflammatory events linked to PD [176].

Dietary interventions and physical activity

Dietary interventions appear to help reduce gut permeability, oxidative stress, and intestinal inflammation, eventually restoring microbiota balance. Utilizing probiotics (such as Lactobacillus and Bifidobacterium), prebiotics (including inulin, galactooligosaccharides, fructooligosaccharides, and short-chain fatty acids), and synbiotics (a combination of probiotics and prebiotics) to aim the gut-brain axis and regulate gut microbiome homeostasis offers a favourable approach. Additionally, consuming high levels of polyunsaturated fatty acids may have anti-inflammatory benefits and could reduce NLRP3 inflammasome initiators, such as α-Syn accumulation and mitochondrial disorder [177-179].

A nutritious diet that includes fresh vegetables, fruits, nuts, seeds, non-fried fish, olive oil, wine, coconut oil, fresh herbs, and spices characteristic of the Mediterranean diet—along with foods rich in flavonoids such as tea, apples, oranges, and red wine, may help to prevent or slow the progression of PD. Furthermore, studies suggest that caffeine intake is associated with a lower risk of developing PD [180].

In addition to a healthy diet, engaging in physical activity enhances both motor and non-motor symptoms of PD. It helps to stanch the disease progression, reduces neuroinflammation, delays the deprival of Dopaminergic neurons (DAn), and promotes synaptic bond. Studies have shown that aerobic exercise in PD patients can elevate serum grades of Brain-Derived Neurotrophic Factor (BDNF) while lowering inflammatory markers such as VCAM and TNFα [181-183]. This results in reduced microglial activation and oxidative stress, along with increased levels of dopamine and neuroplasticity. Furthermore, physical exercise lessens the impact of key molecular features of PD, such as the accumulation of α-synuclein and mitochondrial dysfunction, which helps preserve DAn in rodent models of the disease, enhances antioxidative capacity, and decreases the pro-inflammatory cytokine IL-1β. Overall, exercise has neuroprotective properties and reduces inflammation associated with PD.

It is important to note that several clinical trials have been conducted to address the debilitating conditions of patients with Parkinson’s disease (PD) [184-186]. Most of these trials have focused on reducing or inhibiting extracellular α-synuclein, increasing autophagy, or stimulating molecular chaperones related to the lysosomal enzyme GCase. Lately, modern clinical tests have utilized PET ligands like GE180 (NCT03702816) and [18F] DPA-714 (NCT03457493), which bind to the mitochondrial Translocator Protein (TSPO) connected with inflammation. TSPO is found in the mitochondria of activated microglia, allowing for the noninvasive analysis of regional and global inflammation in living patients through PET imaging. The primary objective of these studies is to determine whether PD patients exhibit higher levels of neuroinflammation compared to healthy individuals. So far, no publicly available results have been reported, but these studies could enhance our knowledge of inflammation in Parkinson’s disease [187-188].

An overview of current and emerging therapeutic strategies targeting neuroinflammation in PD is presented in Table 2.

Table 2: Therapeutic strategies targeting neuroinflammation in PD.

Conclusion

PD remains a complex and multifaceted neurodegenerative disorder, intricately linked to neuroinflammation and its diverse driving factors. This review highlights that neuroinflammatory processes play a pivotal role in the onset and progression of PD, contributing to dopaminergic neuron degeneration and the subsequent emergence of both motor and non-motor symptoms. Understanding the various triggers of neuroinflammation ranging from α-synuclein accumulation and genetic predispositions to mitochondrial dysfunction and gut microbiome dysbiosis reveals critical insights into the disease’s pathophysiology.

The exploration of therapeutic strategies targeting neuroinflammation, including immunotherapy, nonsteroidal anti-inflammatory drugs, and lifestyle modifications, offers promising avenues for managing PD. As researchers continue to unravel the complexities of neuroinflammatory pathways, it is essential to adopt a holistic approach integrating pharmacological, dietary, and lifestyle interventions. This multidisciplinary strategy not only aims to mitigate inflammation but also seeks to enhance neuroprotection and improve the quality of life for PD patients.

Continued research into the intricate connections between neuroinflammation and PD will be vital for identifying novel therapeutic targets and advancing personalized treatment options. Ultimately, a deeper understanding of these mechanisms will pave the way for effective interventions, potentially altering the trajectory of this debilitating disease and offering hope for millions affected worldwide.

Funding

This research was funded by Russian Science Foundation, grant number 25-75-10016.

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