Short Communication

EGCG Mediates Neuroprotection in a Parkinson’s Disease Model via a Caspase-3-Independent Pathway

Priya Nugraha1, Widjiati Widjiati2*, Muhammad Hamdan3, Bambang Purwanto4, Sulistiawati5, Paulus Sugianto6, Arifa Mustika7, Andrianto8, Viski Fitri Hendrawan9

1Doctoral Program of Medical Science, Faculty of Medicine, Airlangga University, (Campus A) Prof. DR. Moestopo No. 47 Street Pacar Kembang, Surabaya City, East Java, Indonesia 60132; 2Department of Veterinary Anatomy, Faculty of Veterinary Medicine, Airlangga University, (Campus C) Dharmahusada Permai No. 1 Street, Mulyorejo, Surabaya City, East Java, Indonesia 60115; 3Department of Neurology, Faculty of Medicine, Airlangga University, (Campus A) Prof. DR. Moestopo No. 47 street Pacar Kembang, Surabaya City, East Java, Indonesia 60132; 4Department of Physiology and Medical Biochemistry, Faculty of Medicine, Airlangga University, (Campus A) Prof. DR. Moestopo No. 47 Street Pacar Kembang, Surabaya City, East Java, Indonesia 60132; 5Department of Public Health, Faculty of Medicine, Airlangga University, (Campus A) Prof. DR. Moestopo No. 47 Street Pacar Kembang, Surabaya City, East Java, Indonesia 60132; 6Department of Neurology, Faculty of Medicine, Airlangga University, (Campus A) Prof. DR. Moestopo No. 47 Street Pacar Kembang, Surabaya City, East Java, Indonesia 60132; 7Department of Anatomy, Histology and Pharmacology, Faculty of Medicine, Airlangga University, (Campus A) Prof. DR. Moestopo No. 47 Street Pacar Kembang, Surabaya City, East Java, Indonesia 60132; 8Department of Cardiology and Vascular Medicine, Faculty of Medicine, Airlangga University, (Campus A) Prof. DR. Moestopo No. 47 Street Pacar Kembang, Surabaya City, East Java, Indonesia 60132; 9Department of Veterinary reproduction, Brawijaya University, Puncak Dieng Street, Kunci-Kalisongo, Malang, East Java, Indonesia 65151.

Received | October 14, 2025; Accepted | November 14, 2025; Published | December 09, 2025

*Correspondence | Widjiati Widjiati, 2Department of Veterinary Anatomy, Faculty of Veterinary Medicine, Airlangga University, (Campus C) Dharmahusada Permai No.1 street, Mulyorejo, Surabaya city, East Java, Indonesia 60115; Email: [email protected]

Citation | Nugraha P, Widjiati W, Hamdan M, Purwanto B, Sulistiawati, Sugianto P, Mustika A, Andrianto, Hendrawan VF (2025). EGCG mediates neuroprotection in a Parkinson’s disease model via a caspase-3-independent pathway. Adv. Anim. Vet. Sci., 13(12):2615-2622.

DOI | https://dx.doi.org/10.17582/journal.aavs/2025/13.12.2615.2622

ISSN (Online) | 2307-8316

Copyright: 2025 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

INTRODUCTION

Parkinson’s disease is a neurodegenerative disease of neurons of the substantia nigra pars compacta. Histologically it is accompanied by the presence of protein α-synuclein containing eosinophil cytoplasmic inclusions (Lewy bodies) thus reducing neurotransmitters in the form of dopamine which is useful for regulating movement and is characterized by motor symptoms such as tremors at rest, muscle and joint stiffness (rigidity), slowness of movement (bradykinesia) and speech and postural instability (Kouli et al., 2018). In Parkinson’s disease, α-synuclein radicals misfolding and aggregation disrupt other normal system functions. Aggregates of the oligomeric form of α-synuclein cause loss of dopaminergic neurons in the substantia nigra pars compacta, thereby causing dopamine deficiency in the striatum region (Kumari et al., 2023). This dopaminergic neuronal loss is attributed to increased rate of apoptosis and pyroptosis. Among all enzymes regulating apoptosis, caspase-3 is the most important apoptosis-regulating enzyme in neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease (Wójcik et al., 2024). Caspase-3 has important final executor role and is activated by caspase-9 and caspase-8 (Li et al., 2022). In addition to being activated by caspase-9 and caspase-8, caspase-3 itself also activates both enzymes. The involvement of caspase-9 and caspase-8 also indicates that caspase-3 responds to both extrinsic and intrinsic inducers, in which the latter is associated with oxidative mitochondrial stress (Sun, 2024).

Oxidative stress is an important mechanism of α-synuclein aggregation in Parkinson disease. In Parkinson’s disease, α-synuclein become radicalized through reactive oxygen species (ROS) (Kumar et al., 2016). These ROS attacks methionine residues of α-synuclein, converting them into methionine sulfoxides (Uceda et al., 2023; Glaser et al., 2005). Failed intracellular repair attempt of oxidation-damaged α-synuclein leads to the accumulation of chemically and functionally altered α-synuclein in cells, triggering apoptosis, and slowly resulting as neuronal impairment in the Parkinson’s disease (Binolfi et al., 2016). Epigallocatechin gallate (EGCG) is one of the most abundant and important active polyphenols of tea (Camellia sinensis) (Shaukat et al., 2023). Various polyphenols from C. sinensis are often studied as an apoptosis modulator in cancer cells (Seo et al., 2016; Rajabi et al., 2021; Karatuğ et al., 2019). However, not many studies have linked the potential of EGCG as an therapeutic adjuvants in neurodegenerative diseases. The finding that EGCG is able to regulate the cell death response suggests that there is potential for EGCG to work in neurodegenerative diseases, especially those induced by ROS (Utami et al., 2023). The ROS itself is known to affect biomarkers of inflammation and apoptosis such as TNF-α (Dong-Chen et al., 2023), NF-κB (Dolatshahi et al., 2021), caspase-3 (Qian et al., 2022; Vringer and Tait, 2023) and PKCδ (Dong-Chen et al., 2023).

It is not yet known how EGCG can affect biomolecular processes in Parkinson’s disease. This study will explore on how the mechanism of EGCG may affect Parkinson’s disease, especially in the regulation of neuronal apoptosis. We focused on how the EGCG will affect apoptosis pathways, whether it is extrinsic or intrinsic by examining the activity of neuronal caspase-3 in Parkinson’s disease animal model.

MATERIALS AND METHODS

Study design

This study is a laboratory experimental study using randomized post-test only control group design. The use of animal models was chosen due to homogeneity criteria and the same characteristics between population units, as well as difficulty to obtain sample of human midbrain.

In this study, the independent variable is the type of therapy administered, specifically epigallocatechin gallate (EGCG). The dependent variable is the extent of neuronal cell death presented as caspase-3 and Bcl-2 level. Controlled variables encompassed various factors to ensure consistency across experimental conditions, including the diet and water intake of the test animals, their overall health status, the characteristics and conditions of the animal housing, the care and handling of the test animals, the procedures used to establish the Parkinson’s disease model, the method and timing of treatment administration, and the techniques used for evaluating the test subjects. This study ethical clearance is issued by Animal Care and Use Committee of Faculty of Veterinary Medicine, Airlangga University, with clearance No. 2.KEH.061.04.2024

Methods

The experimental subjects used in this study were male Wistar strain rats (Rattus norvegicus) with white fur, aged four months, and weighing between 180 and 200 grams. The rats were in a healthy condition as confirmed by a veterinary consultant and met both the inclusion and exclusion criteria. The inclusion criteria required that the rats be male to eliminate the potential influence of hormonal fluctuations observed in females, be at an adult stage with an age of four months, and have a pre-treatment body weight within the range of 180–200 grams. Additionally, all selected rats were confirmed to be free from disease and had no potential for transmitting infections.

Exclusion criteria were applied to eliminate any rats that exhibited signs of illness before the study began or those that died prior to the experiment. Furthermore, dropout criteria were established to account for accidental losses due to factors beyond the researchers control, including stress, starvation, illness during the study, or contamination. Additionally, any rats that had been exposed to the experimental treatment before data collection was completed were also considered dropouts.

Materials for injection preparation included cotton, 70% alcohol, and povidone iodine. For anesthesia prior to MPTP injection, ketamine was used at a dose of 7 mg per 100 grams of body weight, administered intraperitoneally. To achieve Parkinson’s disease, intraperitoneal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used in group K2 and K4. The neurotoxin MPTP was prepared as an injectable solution and administered at a total dose of 16 mg/kg body weight. The placebo used in this study consisted of a 10% dextrose solution (glucose 10%) dissolved in distilled water, administered via oral gavage. The experimental treatment involved EGCG extract at a dose of 30 mg/kg body weight, which was administered orally using a gavage pipette.

The experimental rats underwent an acclimatization period of seven days before being assigned to their respective groups according to the study design. Following this adaptation phase, the rats were divided into five groups: A normal group without any manipulation (K0), a normal control group receiving a placebo (K1), a Parkinson’s disease model control group receiving a placebo (K2), a normal group receiving EGCG treatment (K3), and a Parkinson’s disease model group receiving EGCG treatment (K4). Each group was subjected to its respective treatment conditions as outlined in the research protocol.

The MPTP injections were administered intraperitoneally at a total dose of 16 mg/kg body weight, divided into four separate injections over a 24-hour period with a two-hour interval between each injection. Following the final injection, a 24-hour observation period was implemented to monitor the animals for any signs of dropout, such as severe illness or mortality, before proceeding with further experimental procedures. Both EGCG and placebo were given in 7 days to the respective groups prior to histological sampling. On the seventh day, animals were sacrificed. Blood sample was taken from caudal veins. Histological sample was taken from substantia nigra.

Extrinsic and intrinsic pathway was examined by comparing caspase-3 and Bcl-2 level. Expression of caspase-3 is defined as cells underwent apoptosis through extrinsic pathway. Bcl-2 expression was examined to determine whether substantia nigra underwent apoptosis through intrinsic pathway. Sample examination was conducted using light microscopy on 100x, 4000x, and 1000x magnification on the substantia nigra of the experimental animals, utilizing immunohistochemical staining to assess the expression of caspase-3.

RESULTS

A total of fifty rats were subject to placebo and intervention. During acclimatization, four rats died in the group, causing the study to take maximum six rat per groups with total of thirty rats. The rats were divided into five groups with corresponding allocations and interventions. The negative control group were sacrificed at zeroth day as pre-test. The remaining rats are assigned as post-test group, all survived the seventh day of intervention and sacrificed for sampling. Sample from substantia nigra were harvested and underwent light microscopy under ten different field location.

Bcl-2 level

One-way ANOVA were performed for Bcl-2 with F = 1.099 under p = 0.379, suggesting non-significance between groups. There is no difference of Bcl-2 level between any of placebo-treated groups and EGCG-treated groups (p > 0.05). Post-hoc LSD were performed between pre-test and post-test group. The full post-hoc test result is presented in Table 1.

 

Table 1: Data analysis of Bcl-2 levels.

Group	N	Mean ± SD	95% CI		p-value (Post Hoc LSD)
			Lower	Upper	K0	K1	K2	K3	K4
K0	6	5.93 ± 3.20	3.47	8.15	-	0.052	0.259	0.286	0.487
K1	6	3.28 ± 0.94	2.63	3.90	0.052	-	0.385	0.352	0.192
K2	6	4.43 ± 2.04	2.78	5.88	0.259	0.385	-	0.949	0.657
K3	6	4.52 ± 2.45	2.98	6.47	0.286	0.352	0.949	-	0.704
K4	6	5.02 ± 2.01	3.53	6.52	0.487	0.194	0.657	0.704	-
Levene Sig.		0.131

 

Table 2: Data analysis of Caspase-3 levels.

Group	N	Mean ± SD	95% CI		p-value (Post Hoc LSD)
			Lower	Upper	K0	K1	K2	K3	K4
K0	6	4.38 ± 1.86	2.97	5.70	-	0.885	0.536	0.503	0.702
K1	6	4.57 ± 1.87	3.13	5.87	0.885	-	0.635	0.416	0.812
K2	6	5.17 ± 3.21	2.72	7.35	0.536	0.635	-	0.203	0.812
K3	6	3.53 ± 1.90	2.23	4.92	0.503	0.416	0.203	-	0.296
K4	6	4.87 ± 1.59	3.77	6.05	0.702	0.812	0.812	0.296	-
Levene Sig.		0.181

 

Table 3: Data analysis of neuronal degeneration.

Group	N	Mean ± SD	95% CI		p-value (Post Hoc LSD)
			Lower	Upper	K0	K1	K2	K3	K4
K0	6	0.23 ± 0.23	0.07	0.40	-	0.000	0.008	0.066	0.024
K1	6	0.80 ± 0.22	0.67	1.00	0.000	-	0.240	0.040	0.105
K2	6	0.63 ± 0.15	0.53	0.73	0.008	0.240	-	0.345	0.635
K3	6	0.50 ± 0.37	0.23	0.77	0.066	0.040	0.345	-	0.635
K4	6	0.57 ± 0.15	0.47	0.67	0.024	0.105	0.635	0.635	-
Levene Sig.		0.181

 

Caspase-3 level

One-way ANOVA were performed for Caspase-3 with F = 0.490 under p = 0.743, suggesting non-significance between groups. There is no difference of caspase-3 level between any of placebo-treated groups and EGCG-treated groups (p > 0.05). Post-hoc LSD were performed between pre-test and post-test group. The full post-hoc test result is presented in Table 2.

Neuronal degeneration

One-way ANOVA were performed for neuronal degeneration count with F= 4.491 under p= 0.007, suggesting significant difference of neuronal degeneration between groups. There is higher neuronal degeneration in all treatment groups compared to neutral control, except in K3 group (p < 0.05). In all groups, Parkinson’s disease model receiving placebo showed highest neuronal degeneration compared to neutral control (p < 0.001) but not placebo (p = 0.240). The Parkinson’s disease model group receiving EGCG (K4) showed no neuronal degeneration difference compared to Parkinson’s disease model receiving placebo (K2) (p = 0.105). Post-hoc LSD were performed between pre-test and post-test group. The full post-hoc test result is presented in Table 3.

DISCUSSION

This study showed no reduction of caspase-3 between EGCG-treated and non-treated group. The caspase cascade is an apoptotic pathway mediated by caspase enzyme. In Parkinson’s disease, the presence of caspase-3 activity indicates the activation of extrinsic and intrinsic pathways due to the formation of α-synuclein radicals (Kumar et al., 2016). The α-synuclein protein in healthy brain cells has small levels and is neuroprotective through MAPK regulation (Musgrove et al., 2013). However, on activation of the extrinsic pathway that ends in caspase-3, there is an increase in cytochrome-c activity that leads to an increase in free oxide radicals. This increase in free oxide radicals leads to the formation of α-synuclein radicals (Wójcik et al., 2024). Aggregates of α-synuclein radicals can activate the NLRP3 inflammasome which triggers the inflammatory process through the activation of pro-IL-1β into IL-1β (Huang et al., 2023; Akbal et al., 2022). The inflammatory activity of IL-1β itself is known to activate caspase-3 through the IL-1β/Fas/caspase-8 pathway which ultimately triggers extrinsic apoptosis, especially in Parkinson’s disease (Hui et al., 2017). The results of this study, along with evidence from the literature, show that neuronal apoptosis in Parkinson disease model is not solely controlled through caspase-3-dependent pathways, suggesting the role of alternative pathways.

Caspase-3 is a well-known apoptosis pathway in Parkinson’s disease. In Parkinson’s disease, the activation process of the intrinsic pathway is initiated by an increase in α-synuclein which causes activation of MMP-3 in the endoplasmic reticulum (Bluhm et al., 2022). Increased MMP-3 activity can cause endoplasmic reticulum stress that activates Apaf-1 protein of apoptosome. Apaf-1 ultimately activates caspase-3 through caspase-9 (Kim et al., 2014; Wright et al., 2007). MPTP is converted into its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP⁺), through metabolism by monoamine oxidase-B (MAO-B) present in astrocytes. The resulting MPP⁺ is subsequently transported into dopaminergic (DA) neurons via the dopamine transporter (DAT). Inside these neurons, MPP⁺ disrupts mitochondrial oxidative phosphorylation, ultimately inducing neuronal necrosis. This neurotoxic process replicates the pathology of Parkinson’s disease (PD) by selectively destroying DA neurons, particularly within the substantia nigra and diencephalon. The degeneration of these neurons leads to hallmark PD symptoms, including tremors and muscle rigidity, as well as a marked reduction in dopamine levels and neuronal density in affected brain regions. Because of its ability to closely reproduce the biochemical and cellular features of PD, MPTP serves as a valuable experimental model for studying PD and related neurodegenerative disorders (Anichtchik et al., 2003). In Parkinson’s disease induced by MPTP, caspase-9 also has an important role in activating the Bid protein-mediated apoptotic pathway through caspase-8 (Viswanath et al., 2001) via caspase-3 activation (Kim et al., 2014; Wright et al., 2007). Although caspase-3 pathway activity has been shown to cause apoptosis in Parkinson’s disease, studies show that direct and complete inhibition of caspase-3 is not a solution. Complete inhibition of the caspase-3 pathway through Casp3 gene deletion leads to activation of a more destructive necrosis pathway due to activation of more inflammatory pathways (García-Revilla et al., 2024). This suggests that regulation of apoptosis is much more important at the pre-cascade level of caspases as well as at the ligand level. At the pre-cascade level, modulation of apoptosis may involve the caspase-3 pathway may be assisted by ubiquitylation through the XIAP pathway of caspase-9 (Unnisa et al., 2023). Modulation of the extrinsic caspase-3 pathway may involve free radical control through regulation of the Bax/cytochrome-c pathway (Eid and El-Shitany, 2021). The intrinsic apoptosis pathway that led to caspase-3 activation is characterized by expression of Bcl-2. Bcl-2-induced apoptosis is mainly related to MOMP (mitochondrial outer membrane permeabilization) which is widely associated with ROS (Qian et al., 2022). Permeabilized mitochondria trigger inflammation, in part, through the release of mitochondrial-derived damage-associated molecular patterns (DAMPs). Caspase, although it can cause cell death during mitochondrial apoptosis, inhibits the activation of pro-inflammatory pathways following MOMP (Vringer and Tait, 2023). If MOMP occurs, the pro-apoptotic protein Bcl-2 located in the mitochondrial membrane gap is released into the cytoplasm, triggering a caspase cascade that promotes cell apoptosis (Qian et al., 2022).

While there are overwhelming evidences on how caspase-3 controls apoptosis in Parkinson’s disease, alternative apoptosis pathway to caspase-3 also has been suggested. The PKCδ apoptosis pathway is one of the apoptosis pathways that does not involve caspase. This pathway can be activated through various mediators. Studies in mice have shown that activation of PKCδ by IL-1β is known to promote apoptosis through activation of the JNK and p38-MAPK signaling pathways (Lu et al., 2023). Studies show that PKCδ can be activated cytosolically due to ROS. This pathway involves dysfunction of the p65 protein due to a response to oxidative stress. The PKCδ modulates inflammation at least in part through NF-κB-mediated chemokines (Ren et al., 2014).

The conclusion on whether C. sinensis extract is able to regulate apoptotic pathway is heavily affected by compounds isolate of the C. sinensis extract. For example, the flower saponin of C. sinensis has been studied to significantly upregulate Bax and Bad proteins while downregulate Bcl-xL and Bcl-2 proteins, thus modulating the apoptosis rate in ovarian cancer cells through intrinsic pathways (Ren et al., 2020). Meanwhile another C. sinensis compound, quercetin, has been studied to affect caspase-3 but not decrease the mitochondrial membrane potential and did not affect the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX), suggesting extrinsic pathway role (Seo et al., 2016). Based on the aforementioned evidences, the C. sinensis EGCG extract in should show regulatory role in the extrinsic apoptotic pathway, which is not proven in our study.

It should be emphasized that evidences on the modulation of apoptosis by C. sinensis compounds are heavily dependent on the cellular state. There are at least two evidence categories that classify such cellular state. The first category of evidence includes a group of studies in animal models using apoptosis-aberrant cells such as cancer cells without additional cellular stressors (Seo et al., 2016; Xin et al., 2018; Rajabi et al., 2021; Karatuğ et al., 2019) which leads to increased apoptosis rather than reduction (Chaudhry et al., 2022). The second evidence category includes a group of studies on models using apopotosis-normal cells, in which various compounds of C. sinensis have been instead reported to reduce inflammation and oxidative-stress-related apoptosis (Seo et al., 2021; Priyandoko et al., 2023; Ahmed et al., 2019; Dey et al., 2021). The neuronal pyroptosis in Parkinson’s disease is associated with NLRP3 inflammasome activation by α-synuclein radicals, as well as IL-1β activities (Huang et al., 2023; Akbal et al., 2022). This showed that the neuronal pyroptosis in Parkinson’s disease falls into the latter category, suggesting the anti-inflammatory and apoptosis-reducing role of C. sinensis extract in Parkinson’s disease if given before neuronal insult happen.

This study has several limitations. The first limitation is we did not isolate a specific compound from C. sinensis, but instead using premade C. sinensis EGCG extract. This may affect the result interpretation which target overall C. sinensis capability rather than its specific compound. The second limitation is while neuronal apoptosis is detected in the models, the use of MPTP in rat is known to non-specifically target dopaminergic neuron compared to MPTP in mice. This suggest that clinical signs of Parkinson’s disease in our model are also affected by other neuronal deaths outside substantia nigra pars compacta. The third limitation includes the study scope beyond non-caspase-3 apoptosis pathway, in which there is no examination on PKCδ as alternative apoptosis pathway.

CONCLUSION

This study suggests the neuroprotective and preventive role of C. sinensis compounds, especially EGCG in Parkinson’s disease models. This study is unable to provide evidence on neuroprotection against Bcl-2 and caspase-3-dependent apoptotic activities such as Parkinson’s disease, but suggest such neuroprotective effect in normal neuron might be achieved through modulation of caspase-3-independent pathway. This study emphasis the neuroprotective role of EGCG in normal brain, while confirming its inability to protect against direct damage that causes neuronal apoptosis, such as MPTP. Considering the well-known safety of various C. sinensis preparates, we suggest future clinical investigation of C. sinensis EGCG efficacy in reducing Parkinson’s disease progressivity in human subject.

ACKNOWLEDGMENT

The authors would like to thank Airlangga University for their general support during the research.

Novelty Statement

This study is unique in that it suggests that EGCG exerts a neuroprotective effect on dopaminergic neurons via a caspase-3-independent pathway.

AUTHOR’S CONTRIBUTION

PN and WW performed the expression assays and evaluated the results. PN, WW, MH, BP, S, PS, AM, and A. participated in the study design, sampling, and statistical analysis. PN. VFH drafted the manuscript. All authors read and approved the final manuscript.

Generative AI and AI-assisted technology statement

The author declares that no Genrative AI was used in the creation of this manuscript.

Conflict of interest

The authors have declared no conflict of interest.

REFERENCES

Ahmed OM, Abdul-Hamid MM, El-Bakry AM, Mohamed HM, El-Zahraa F, Rahman SA (2019). Camellia sinensis and epicatechin abate doxorubicin-induced hepatotoxicity in male Wistar rats via their modulatory effects on oxidative stress, inflammation, and apoptosis. J. Appl. Pharm. Sci., 9: 30–44. https://doi.org/10.7324/JAPS.2019.90405

Akbal A, Dernst A, Lovotti M, Mangan MSJ, McManus RM, Latz E (2022). How location and cellular signaling combine to activate the NLRP3 inflammasome. Cell Mol. Immunol., 19: 1201–1214. https://doi.org/10.1038/s41423-022-00922-w

Anichtchik OV, Kaslin J, Peitsaro N, Scheinin M, Panula P (2003). Neurochemical and behavioural changes in zebrafish Danio rerio after systemic administration of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J. Neurochem., 88(2): 443–453. https://doi.org/10.1111/j.1471-4159.2004.02190.x

Binolfi A, Limatola A, Verzini S, Kosten J, Theillet F-X, May Rose H, Bekei B, Stuiver M, van Rossum M, Selenko P (2016). Intracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites. Nat. Commun., 7: 10251. https://doi.org/10.1038/ncomms10251

Bluhm A, Schrempel S, Moceri S, Stieler J, Feja M, Schiling S, Schulze A, Hörsten, SV, Hartlage-Rübsamen M, F, Steffen Roßner S (2022). Alpha synuclein processing by MMP-3 – implications for synucleinopathies. Behav. Brain Res., 434: 114020. https://doi.org/10.1016/j.bbr.2022.114020

Chaudhry GS, Md Akim A, Sung YY, Sifzizul TMT (2022). Cancer and apoptosis: The apoptotic activity of plant and marine natural products and their potential as targeted cancer therapeutics. Front. Pharmacol., 2022. https://doi.org/10.3389/fphar.2022.842376

Dey A, Perveen H, Khandare AL, Banerjee A, Maiti S, Jana S, Chakraborty AK, Chattopadhyay S (2021). Arsenic-induced uterine apoptotic damage is protected by ethyl acetate fraction of Camellia sinensis (green tea) via Bcl-2-BAX through NF-κB regulations in Wistar rats. Environ. Sci. Pollut. Res., 28: 41095–41108. https://doi.org/10.1007/s11356-021-13457-w

Dolatshahi M, Ranjbar HMH, Sabahi M, Rostamkhani S (2021). Nuclear factor‐kappa B (NF‐κB) in pathophysiology of Parkinson disease: Diverse patterns and mechanisms contributing to neurodegeneration. Eur. J. Neurosci., 54: 4101–4123. https://doi.org/10.1111/ejn.15242

Dong-Chen X, Yong C, Yang X, Chen-Yu S, Li-Hua P (2023). Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther., 8: 73. https://doi.org/10.1038/s41392-023-01353-3

Eid BG, El-Shitany NA (2021). Captopril downregulates expression of Bax/cytochrome C/caspase-3 apoptotic pathway, reduces inflammation, and oxidative stress in cisplatin-induced acute hepatic injury. Biomed. Pharmacother., 139: 111670. https://doi.org/10.1016/j.biopha.2021.111670

Glaser CB, Yamin G, Uversky VN, Fink AL (2025). Methionine oxidation, alpha-synuclein and Parkinson’s disease. Biochim. Biophys. Acta, 1703: 157–169. https://doi.org/10.1016/j.bbapap.2004.10.008

García-Revilla J, Ruiz R, Espinosa-Oliva AM, Santiago M, García-Domínguez I, Camprubí-Ferrer L, Bachiller S, Deierborg T, Joseph B, de Pablos RM, Rodríguez-Gómez J. A, Venero JL (2024). Dopaminergic neurons lacking Caspase-3 avoid apoptosis but undergo necrosis after MPTP treatment inducing a Galectin-3-dependent selective microglial phagocytic response. Cell Death Dis., 15: 625. https://doi.org/10.1038/s41419-024-07014-9

Huang Q, Yang P, Liu Y, Ding J, Lu M, Hu G (2023). The interplay between α-Synuclein and NLRP3 inflammasome in Parkinson’s disease. Biomed. Pharmacother., 168: 115735. https://doi.org/10.1016/j.biopha.2023.115735

Hui Q, Asadi A, Park YJ, Kieffer TJ, Ao Z, Warnock GL, Marzban L (2017). Amyloid formation disrupts the balance between interleukin-1β and interleukin-1 receptor antagonist in human islets. Mol. Metab., 6: 833–844. https://doi.org/10.1016/j.molmet.2017.05.016

Karatuğ KA, Ersöz M, Sezekler I, Coşkun ZM (2019). The effects of camellia sinensis extract on proliferation, apoptosis and oxidative stress in insulinoma INS-1 cells. Bezmialem Sci., 7: 80–85. https://doi.org/10.14235/bas.galenos.2018.2287

Kim EM, Shin EJ, Lee JA, Son HJ, Choi DH, Han JM, Hwang O (2014). Caspase-9 activation and Apaf-1 cleavage by MMP-3. Biochem. Biophys. Res. Commun., 453: 563–568. https://doi.org/10.1016/j.bbrc.2014.09.124

Kouli A, Torsney KM, Kuan W-L (2018). Parkinson’s disease: Etiology, neuropathology, and pathogenesis. In: Park. Dis. Pathog. Clin. Asp. Codon Publications, pp. 3–26. https://doi.org/10.15586/codonpublications.parkinsonsdisease.2018.ch1

Kumar A, Ganini D, Mason RP (2016). Role of cytochrome c in α-synuclein radical formation: implications of α-synuclein in neuronal death in Maneb- and paraquat-induced model of Parkinson’s disease. Mol. Neurodegener., 11: 70. https://doi.org/10.1186/s13024-016-0135-y

Kumari S, Taliyan R, Dubey SK (2023). Comprehensive review on potential signaling pathways involving the transfer of α-synuclein from the gut to the brain that leads to parkinson’s disease. ACS Chem. Neurosci., 14: 590–602. https://doi.org/10.1021/acschemneuro.2c00730

Li L, Wang S, Zhou W (2022). Balance cell apoptosis and pyroptosis of caspase-3-activating chemotherapy for better antitumor therapy. Cancers (Basel), 2022. https://doi.org/10.3390/cancers15010026

Lu J, Yu M, Li J (2023). PKC-δ promotes IL-1β-induced apoptosis of rat chondrocytes and via activating JNK and P38 MAPK pathways. Cartilage. 2023. https://doi.org/10.1177/19476035231181446

Musgrove REJ, King AE, Dickson TC (2013). α-Synuclein protects neurons from apoptosis downstream of free-radical production through modulation of the MAPK signalling pathway. Neurotox Res., 23: 358–369. https://doi.org/10.1007/s12640-012-9352-5

Priyandoko D, Widowati W, Lenny L, Novianti S, Revika R, Widya Kusuma HS, Sholihah IA (2023). Green tea extract reduced lipopolysaccharide-induced inflammation in L2 cells as acute respiratory distress syndrome model through genes and cytokine pro-inflammatory. Avicenna J. Med. Biotechnol., https://doi.org/10.18502/ajmb.v16i1.14172

Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J (2022). The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front. Oncol., 12: 985363. https://doi.org/10.3389/fonc.2022.985363

Rajabi S, Maresca M, Yumashev AV, Choopani R, Hajimehdipoor H (2021). The most competent plant-derived natural products for targeting apoptosis in cancer therapy biomolecules, 11: 534. https://doi.org/10.3390/biom11040534

Ren N, Chen L, Li B, Rankin GO, Chen YC, Tu Y (2020). Purified Tea (Camellia sinensis (L.) Kuntze) flower saponins induce the p53-dependent intrinsic apoptosis of cisplatin-resistant ovarian cancer cells. Int. J. Mol. Sci.,

Ren J, Wang Q, Morgan S, Si Y, Ravichander A, Dou C, Kent KC, Liu B (2014). Protein Kinase C-δ (PKCδ) Regulates proinflammatory chemokine expression through cytosolic interaction with the NF-κB Subunit p65 in vascular smooth muscle cells. J. Biol. Chem., 289: 9013–9026. https://doi.org/10.1074/jbc.M113.515957

Seo HS, Ku JM, Han-Seo C, Choi YK, Woo J, Kim M, Kim I, Na CH, Hur H, Jang B, Shin YC, Ko S (2016). Quercetin induces caspase-dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in HER2-overexpressing BT-474 breast cancer cells. Oncol. Rep., 36: 31–42. https://doi.org/10.3892/or.2016.4786

Seo H, Lee S-H, Park Y, Lee H-S, Hong JS, Lim CY, Kim DH, Park S-S, Suh HJ, Hong K-B (2021). Epicatechin-enriched extract from camellia sinensis improves regulation of muscle mass and function: Results from a randomized controlled trial. Antioxidants, 10: 1026. https://doi.org/10.3390/antiox10071026

Shaukat H, Ali A, Zhang Y, Ahmad A, Riaz S, Khan A, Mehany T, Qin H (2023). Tea polyphenols: Extraction techniques and its potency as a nutraceutical. Front. Sustain. Food Syst., 2023. https://doi.org/10.3389/fsufs.2023.1175893

Sun G (2024). Death and survival from executioner caspase activation. Semin. Cell Dev. Biol., 156: 66–73. https://doi.org/10.1016/j.semcdb.2023.07.005

Uceda AB, Frau J, Vilanova B, Adrover M (2023). On the effect of methionine oxidation on the interplay between α-synuclein and synaptic-like vesicles. Int. J. Biol. Macromol., 229: 92–104. https://doi.org/10.1016/j.ijbiomac.2022.12.262

Unnisa A, Greig NH, Kamal MA (2023). Inhibition of caspase 3 and caspase 9 mediated apoptosis: A multimodal therapeutic target in traumatic brain injury. Curr. Neuropharmacol., 21: 1001–1012. https://doi.org/10.2174/1570159X20666220327222921

Utami A, Sitompul DT, Thomas F (2023). Artikel review : Stres oksidatif dan penyakitnya.

Viswanath V, Wu Y, Boonplueang R, Chen S, Stevenson FF, Yantiri F, Yang L, Beal MF, Andersen JK (2001). Caspase-9 activation results in downstream caspase-8 activation and bid cleavage in 1-Methyl-4-Phenyl-1,2,3,6-tetrahydropyridine-induced parkinson’s disease. J. Neurosci., 21: 9519–9528. https://doi.org/10.1523/JNEUROSCI.21-24-09519.2001

Vringer E, Tait SWG (2023). Mitochondria and cell death-associated inflammation. Cell Death Differ., 30: 304–312. https://doi.org/10.1038/s41418-022-01094-w

Wójcik P, Jastrzębski MK, Zięba A, Matosiuk D, Kaczor AA (2024). Caspases in Alzheimer’s Disease: Mechanism of activation, role, and potential treatment. Mol. Neurobiol., 61: 4834–4853. https://doi.org/10.1007/s12035-023-03847-1

Wright KM, Vaughn AE, Deshmukh M (2007). Apoptosome dependent caspase-3 activation pathway is non-redundant and necessary for apoptosis in sympathetic neurons. Cell Death Differ., 14: 625–633. https://doi.org/10.1038/sj.cdd.4402024

Xin Y, Ben P, Wang Q, Zhu Y, Yin Z, Luo L (2018). Theanine, an antitumor promoter, induces apoptosis of tumor cells via the mitochondrial pathway. Mol. Med. Rep., 2018. https://doi.org/10.3892/mmr.2018.9459