Parkinson's disease is a neurodegenerative disease associated with aging. The prevalence of Parkinson's is about 2% in patients over the age of 65. Parkinson's disease is a complex disorder that is difficult to diagnose clinically, especially in its early stages. Parkinson's generally occurs in the substantia nigra (SN) striatum pathway with degeneration of dopaminergic neurons in the SN, resulting in decreased dopamine and the presence of Lewy bodies, which are the main pathology. Parkinson's is a progressive neurodegenerative disease that causes both motor and non-motor symptoms (Chen et al. 2020; Heris et al. 2022). Parkinson's disease is characterized by symptoms of slow movement (bradykinesia), resting tremor, rigidity, and postural instability (Chen et al. 2020; Indonesian Neurologist Association 2024). Current therapy for Parkinson's includes pharmacotherapy (levodopa, DAergic receptor agonists, monoamine oxidase B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors), functional neurosurgery (pallidotomy), deep brain stimulation (DBS), and gene therapy (Chen et al. 2020). Current therapy focuses on improving dopamine levels, with levodopa being the most common choice. This therapy can improve motor symptoms and enhance the quality of life for patients, but levodopa administration has limitations due to side effects such as levodopa-induced dyskinesia, which often occurs with long-term use (Pardo-Moreno et al. 2023). Therefore, other therapeutic innovations, such as stem cell therapy, are needed for Parkinson's disease.

Mesenchymal stem cells (MSCs) are multipotent stem cells that can originate from various sources such as adult bone marrow, adipose tissue, peripheral blood, and various neonatal tissues such as the umbilical cord. MSCs have several advantages, including being hypoimmunogenic, having no risk of teratoma, low tumorigenesis risk, and no ethical issues (Chen et al. 2020; Heris et al. 2022). MSCs have great potential due to their ability to secrete various bioactive molecules such as cytokines, chemokines, growth factors, and extracellular vesicles (exosomes and other extracellular vesicles). These bioactive molecules, called the secretome, can help maintain cell viability, differentiation, protect cells from oxidative stress, prevent apoptosis, and modulate inflammatory processes (Chen et al. 2020; Giovannelli et al. 2023; Heris et al. 2022). Neurodegenerative diseases are generally characterized by neuronal death, neurodegeneration, neuroinflammation, immune dysfunction, and oxidative stress (Giovannelli et al. 2023). Cell-based therapy using MSCs can act as an immunomodulator, modulating inflammation and tissue regeneration in neuroinflammatory and neurodegenerative conditions in Parkinson's (Glavaski-Joksimovic & Bohn 2013).

The mechanism of secretome in Parkinson's disease is generally described in three mechanisms: immunomodulation, neuroprotection, and neurogenesis. In immunomodulation, the secretome modulates the immune response by suppressing pro-inflammatory cytokines and promoting the differentiation of macrophages into the anti-inflammatory M2 phenotype, reducing inflammation and oxidative stress in the brain. In neuroprotection, the secretome contains neurotrophic factors that support the survival and differentiation of damaged dopaminergic neurons in Parkinson's. These factors can also reduce oxidative stress and apoptosis, protecting neurons from further damage. In neurogenesis, the secretome can enhance the differentiation of neural precursor cells into dopaminergic neurons, potentially increasing the production of new neurons in the substantia nigra, the area most affected in Parkinson's (Meiliana et al. 2019; Műzes & Sipos 2022).

In animal studies, MSC therapy can increase the levels of anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1), hepatocyte growth factor (HFG), indoleamine 2,3-dioxygenase (IDO), nitric oxide (NO), interleukin 4 (IL-4), and interleukin 10 (IL-10) while reducing pro-inflammatory cytokines (IL-6, IL-1β, tumor necrosis factor-α (TNF-α)) in the brain and blood (Heris et al. 2022). Other therapeutic effects of MSCs include neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF), which inhibit dopaminergic neuron apoptosis and enhance neurogenesis by secreting proangiogenic and mitotic factors like vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) (d'Angelo et al. 2020; Hofer & Tuan 2016). Currently, there are no clinical trials of MSC-secretome administration in humans for Parkinson's. In animal models, MSC-secretome administration can reduce neuroinflammation, oxidative stress, and abnormal α-synuclein deposition. Administration routes in animal models include substantia nigra and striatum, intravenous, and intraperitoneal (Giovannelli et al. 2023).

Clinical trials for Parkinson's using MSCs are still minimal, with various administration routes (intra-arterial, intravenous, intrathecal, intraventricular), with intravenous being the most common. MSC sources are generally from bone marrow or bone marrow MSCs (BMMSCs). A systematic review by Kabat et al. (2020) showed that intravenous administration is the most commonly used in clinical trials with MSC therapy (43% of trials) (Kabat et al. 2020). A systematic review by Zhao et al. (2024) showed that intravenous administration had higher efficacy compared to intraventricular administration (Zhao et al. 2024).

A study by Brazzini et al. (2010) evaluated the safety and effectiveness of autologous BMMSC administration in Parkinson's patients. Single autologous BMMSC was administered intra-arterially via femoral artery catheterization. No complications were found post-therapy, and the clinical response of patients significantly improved compared to before therapy using parameters such as the Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr staging Parkinson (H & Y scoring), Schwab and England scale of activities of daily living, and Northwestern University Disability Scale (NUDS) within 12 months follow-up (Brazzini et al. 2010). A study by Schiess et al. (2021) using a single-center open-label and dose-escalation method analyzed the safety, tolerability, efficacy, and biomarker changes after single intravenous allogenic BMMSC administration (1, 3, 6, or 10 x 10⁶ cells/kg body weight) in idiopathic Parkinson's patients monitored for 52 weeks. No serious adverse reactions were found post-therapy. At high doses (6 and 10 x 10⁶ cells/kg body weight), there was a significant reduction in inflammatory cytokines and an increase in BDNF at 52 weeks, while at lower doses (1 and 3 x 10⁶ cells/kg body weight), no significant changes were found. At high doses (10 x 10⁶ cells/kg body weight), there were the most significant improvements in motor function based on UPDRS total, UPDRS motor, and H & Y scoring. A study by Boika et al. (2020) using autologous BMMSC with a total dose of 0.5 - 2 x 10⁶ cells/kg body weight administered intravenously in three stages with 7-day intervals in 12 Parkinson's patients and compared with 11 control patients with standard medication (levodopa, dopamine receptor agonists, and amantadine), then monitored for 1 and 3 months. One month after autologous BMMSC therapy, there was a significant improvement in MDS-UPDRS motor parameters, mood, and quality of life compared to the control group.

Existing research shows the potential of cell therapy using MSCs and the effects of secretome on Parkinson's disease. Further research is still needed, especially in clinical trial phases, to determine the safety and efficacy in Parkinson's patients.

Reference:

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