Molecular mechanism analysis and network pharmacology of capsaicin in Alzheimer’s and Parkinson’s diseases: an in silico study

Abstract

Aim: Parkinson’s disease (PD) and Alzheimer’s disease (AD) represent critical neurological disorders that have emerged as significant health concerns in the 21st century. The pharmacological interventions currently employed to manage these diseases demonstrate limited efficacy and some adverse side effects. Historically, natural products have been used to develop therapeutic agents targeting neurodegenerative disorders. This study aimed to apply in silico techniques to investigate the pharmacological mechanisms of capsaicin as a possible alternative treatment or coadjutant phytotherapy for PD and AD.
Methods: We obtained target genes for capsaicin, PD, and AD from the HERB database, the Swiss Target Prediction database, the Comparative Toxicogenomics Database, and the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and matched them. Subsequently, we constructed a protein-protein interaction network and performed enrichment analysis of the common targets. Then, the interactions of capsaicin with the proteins with the highest degree were tested using molecular docking. The stability of the complexes was verified using molecular dynamics techniques.
Results: A total of 25 targets were found in common from the databases for capsaicin, AD, and PD. The enrichment analysis revealed that proteins from these targets influenced integrin activity in the IGF1-IGF1R complex, cholinesterase activity, and dopamine neurotransmitter receptor activity, all of which are coupled via protein G_i/G_o, among other cellular processes. From the protein-protein interaction network, we identified the hub proteins IL6, GSK3B, CASP, BCL2, ESR1, SIRT1, NGF, IGF1, and HMOX1. Furthermore, molecular docking studies between hub proteins and capsaicin showed strong binding affinity. Finally, molecular dynamics simulations support a stable interaction between capsaicin and SIRT1, ESR1, HMOX1, and NGF.
Conclusions: This work contributes to understanding the neuroprotective activity of capsaicin in PD and AD. However, these bioinformatic predictions require further experimental validation.

Keywords

capsaicin / molecular docking / molecular dynamics / Alzheimer’s disease / Parkinson’s disease

References

[1] Caligiore D, Giocondo F, Silvetti M. The Neurodegenerative Elderly Syndrome (NES) hypothesis: Alzheimer and Parkinson are two faces of the same disease. IBRO Neurosci Rep. 2022; 13: 330-43.

[2] Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener. 2020; 15: 40.

[3] Dong-Chen X, Yong C, Yang X, Chen-Yu S, Li-Hua P. Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023; 8: 73.

[4] Sveinbjornsdottir S. The clinical symptoms of Parkinson’s disease. J Neurochem. 2016; 139: 318-24.

[5] Gnanaraj C, Sekar M, Fuloria S, Swain SS, Gan SH, Chidambaram K, et al. In Silico Molecular Docking Analysis of Karanjin against Alzheimer’s and Parkinson’s Diseases as a Potential Natural Lead Molecule for New Drug Design, Development and Therapy. Molecules. 2022; 27: 2834.

[6] Rahman MH, Bajgai J, Fadriquela A, Sharma S, Trinh TT, Akter R, et al. Therapeutic Potential of Natural Products in Treating Neurodegenerative Disorders and Their Future Prospects and Challenges. Molecules. 2021; 26: 5327.

[7] Maharjan A, Vasamsetti BMK, Park J. A comprehensive review of capsaicin: Biosynthesis, industrial productions, processing to applications, and clinical uses. Heliyon. 2024; 10: e39721.

[8] Inyang D, Saumtally T, Nnadi CN, Devi S, So PW. A Systematic Review of the Effects of Capsaicin on Alzheimer’s Disease. Int J Mol Sci. 2023; 24: 10176.

[9] Varshney V, Kumar A, Parashar V, Kumar A, Goyal A, Garabadu D. Therapeutic Potential of Capsaicin in Various Neurodegenerative Diseases with Special Focus on Nrf2 Signaling. Curr Pharm Biotechnol. 2024; 25: 1693-707.

[10] Petran EM, Periferakis A, Troumpata L, Periferakis AT, Scheau AE, Badarau IA, et al. Capsaicin: Emerging Pharmacological and Therapeutic Insights. Curr Issues Mol Biol. 2024; 46: 7895-943.

[11] Vaou N, Stavropoulou E, Voidarou CC, Tsakris Z, Rozos G, Tsigalou C, et al. Interactions between Medical Plant-Derived Bioactive Compounds: Focus on Antimicrobial Combination Effects. Antibiotics (Basel). 2022; 11: 1014.

[12] Mahmud S, Uddin MAR, Paul GK, Shimu MSS, Islam S, Rahman E, et al. Virtual screening and molecular dynamics simulation study of plant-derived compounds to identify potential inhibitors of main protease from SARS-CoV-2. Brief Bioinform. 2021; 22: 1402-14.

[13] Wang Y, Cai S, Wen W, Tan Y, Wang W, Xu J, et al. A Network Pharmacology Study and In Vitro Evaluation of the Bioactive Compounds of Kadsura coccinea Leaf Extract for the Treatment of Type 2 Diabetes Mellitus. Molecules. 2025; 30: 1157.

[14] Mirza FJ, Zahid S, Amber S, Sumera, Jabeen H, Asim N, et al. Multitargeted Molecular Docking and Dynamic Simulation Studies of Bioactive Compounds from Rosmarinus officinalis against Alzheimer’s Disease. Molecules. 2022; 27: 7241.

[15] Yousef M, Allmer J. Deep learning in bioinformatics. Turk J Biol. 2023; 47: 366-82.

[16] Salim I, Hamza AB. Classification of Developmental and Brain Disorders via Graph Convolutional Aggregation. Cogn Comput. 2024; 16: 701-16.

[17] Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem 2025 update. Nucleic Acids Res. 2025; 53: D1516-25.

[18] Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019; 47: W357-64.

[19] Davis AP, Wiegers TC, Sciaky D, Barkalow F, Strong M, Wyatt B, et al. Comparative Toxicogenomics Database’s 20th anniversary: update 2025. Nucleic Acids Res. 2025; 53: D1328-34.

[20] Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014; 6: 13.

[21] Fang S, Dong L, Liu L, Guo J, Zhao L, Zhang J, et al. HERB: a high-throughput experiment- and reference-guided database of traditional Chinese medicine. Nucleic Acids Res. 2021; 49: D1197-206.

[22] An interactive tool for comparing lists with Venn’s diagrams [Internet]. [cited 2024 Sep 26]. Available from: https://bioinfogp.cnb.csic.es/tools/venny/

[23] Ge SX, Jung D, Yao R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics. 2020; 36: 2628-9.

[24] Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2021; 49: D545-51.

[25] Luo W, Brouwer C. Pathview: an R/Bioconductor package for pathway-based data integration and visualization. Bioinformatics. 2013; 29: 1830-1.

[26] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. The Reactome Pathway Knowledgebase 2024. Nucleic Acids Res. 2024; 52: D672-8.

[27] Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13: 2498-504.

[28] Assenov Y, Ramírez F, Schelhorn S, Lengauer T, Albrecht M. Computing topological parameters of biological networks. Bioinformatics. 2008; 24: 282-4.

[29] Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021; 596: 583-9.

[30] Liu Y, Yang X, Gan J, Chen S, Xiao Z, Cao Y. CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Res. 2022; 50: W159-64.

[31] Valdés-Tresanco MS, Valdés-Tresanco ME, Valiente PA, Moreno E. gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS. J Chem Theory Comput. 2021; 17: 6281-91.

[32] Burley SK, Bhatt R, Bhikadiya C, Bi C, Biester A, Biswas P, et al. Updated resources for exploring experimentally-determined PDB structures and Computed Structure Models at the RCSB Protein Data Bank. Nucleic Acids Res. 2025; 53: D564-74.

[33] O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform. 2011; 3: 33.

[34] Kim S, Lee J, Jo S, Brooks CL 3rd, Lee HS, Im W. CHARMM-GUI ligand reader and modeler for CHARMM force field generation of small molecules. J Comput Chem. 2017; 38: 1879-86.

[35] Lee J, Cheng X, Swails JM, Yeom MS, Eastman PK, Lemkul JA, et al. CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput. 2016; 12: 405-13.

[36] Bussi G, Donadio D, Parrinello M. Canonical sampling through velocity rescaling. J Chem Phys. 2007; 126: 014101.

[37] Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, et al. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J Comput Chem. 2010; 31: 671-90.

[38] Williams T, Kelley C. GnuPlot Version 5.4 Patchlevel 2 [software]. 2021 Jun 6 [cited 2025 Sept 7]. Available from: https://sourceforge.net/projects/gnuplot/files/gnuplot/5.4.2/#

[39] Çakır M, Yüksel F, Mustafa Özkut M, Durhan M, Kaymak E, Tekin S, et al. Neuroprotective effect of transient receptor potential Vanilloid 1 agonist capsaicin in Alzheimer’s disease model induced with okadaic acid. Int Immunopharmacol. 2023; 118: 109925.

[40] Chung YC, Baek JY, Kim SR, Ko HW, Bok E, Shin WH, et al. Capsaicin prevents degeneration of dopamine neurons by inhibiting glial activation and oxidative stress in the MPTP model of Parkinson’s disease. Exp Mol Med. 2017; 49: e298.

[41] Zhao L, Zhang H, Li N, Chen J, Xu H, Wang Y, et al. Network pharmacology, a promising approach to reveal the pharmacology mechanism of Chinese medicine formula. J Ethnopharmacol. 2023; 309: 116306.

[42] Martínez-Esquivias F, Guzmán-Flores JM, Chávez-Díaz IF, Iñiguez-Muñoz LE, Reyes-Chaparro A. Pharmacological network study on the effect of 6-gingerol on cervical cancer using computerized databases. J Biomol Struct Dyn. 2024; 42: 11750-61.

[43] Liu L, Tian Y. Capsaicin Changes the Pattern of Brain Rhythms in Sleeping Rats. Molecules. 2023; 28: 4736.

[44] Zhang Q, Lu Y, Zhao Y, Ho CT, Zhang Y, Fu Y. Role of capsaicin, circadian clock genes, and TRPV1 in colorectal carcinogenesis: Lessons and future directions. J Adv Res. 2025;S2090-123200768-4.

[45] Rohm B, Holik AK, Somoza MM, Pignitter M, Zaunschirm M, Ley JP, et al. Nonivamide, a capsaicin analog, increases dopamine and serotonin release in SH-SY5Y cells via a TRPV1-independent pathway. Mol Nutr Food Res. 2013; 57: 2008-18.

[46] Zhang J, Zhang G, Liu W. Identification of SNCA and DRD2 as key genes linking Parkinson’s disease and circadian rhythm through bioinformatics analysis. Sci Rep. 2025; 15: 31355.

[47] Xu W, Liu J, Ma D, Yuan G, Lu Y, Yang Y. Capsaicin reduces Alzheimer-associated tau changes in the hippocampus of type 2 diabetes rats. PLoS One. 2017; 12: e0172477.

[48] Harada N, Okajima K. Effect of topical application of capsaicin and its related compounds on dermal insulin-like growth factor-I levels in mice and on facial skin elasticity in humans. Growth Horm IGF Res. 2007; 17: 171-6.

[49] Takeda Y, Dai P. Capsaicin directly promotes adipocyte browning in the chemical compound-induced brown adipocytes converted from human dermal fibroblasts. Sci Rep. 2022; 12: 6612.

[50] Ceci C, Lacal PM, Barbaccia ML, Mercuri NB, Graziani G, Ledonne A. The VEGFs/VEGFRs system in Alzheimer’s and Parkinson’s diseases: Pathophysiological roles and therapeutic implications. Pharmacol Res. 2024; 201: 107101.

[51] De Boer D, Nguyen N, Mao J, Moore J, Sorin EJ. A Comprehensive Review of Cholinesterase Modeling and Simulation. Biomolecules. 2021; 11: 580.

[52] Luo X, Lauwers M, Layer PG, Wen C. Non-neuronal Role of Acetylcholinesterase in Bone Development and Degeneration. Front Cell Dev Biol. 2021; 8: 620543.

[53] Mansalai P, Intanon N, Payaka A, Wattanalaorsomboon S, Chinvongamorn C, Sansenya S. Inhibition potential against acetylcholinesterase of commercial and extracts of capsaicin and dihydrocapsaicin by in vitro and in silico studies. Process Biochem. 2024; 136: 341-50.

[54] Nantakornsuttanan N, Thuphairo K, Kukreja RK, Charoenkiatkul S, Suttisansanee U. Anti-cholinesterase inhibitory activities of different varieties of chili peppers extracts. Int Food Res J. 2016.

[55] Heise NV, Quast J, Csuk R. Revisiting capsaicin and nonivamide: Their analogs exert strong inhibitory activity against cholinesterases. Eur J Med Chem Rep. 2024; 12: 100200.

[56] Radhakrishna GK, Ammunje DN, Kunjiappan S, Ravi K, Vellingiri S, Ramesh SH, et al. A Comprehensive Review of Capsaicin and Its Role in Cancer Prevention and Treatment. Drug Res (Stuttg). 2024; 74: 195-207.

[57] Moriguchi M, Watanabe T, Kadota A, Fujimuro M. Capsaicin Induces Apoptosis in KSHV-Positive Primary Effusion Lymphoma by Suppressing ERK and p38 MAPK Signaling and IL-6 Expression. Front Oncol. 2019; 9: 83.

[58] Louneva N, Cohen JW, Han LY, Talbot K, Wilson RS, Bennett DA, et al. Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer’s disease. Am J Pathol. 2008; 173: 1488-95.

[59] Erekat NS. Apoptosis and its Role in Parkinson’s Disease. In: Stoker TB, Greenland JC, editors. Parkinson’s Disease: Pathogenesis and Clinical Aspects. Brisbane: Codon Publications; 2018.

[60] Wang J, Sun BL, Xiang Y, Tian DY, Zhu C, Li WW, et al. Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice. Transl Psychiatry. 2020; 10: 230.

[61] Xu S, Hao K, Xiong Y, Xu R, Huang H, Wang H. Capsaicin alleviates neuronal apoptosis and schizophrenia-like behavioral abnormalities induced by early life stress. Schizophrenia (Heidelb). 2023; 9: 77.

[62] Jin HW, Ichikawa H, Fujita M, Yamaai T, Mukae K, Nomura K, et al. Involvement of caspase cascade in capsaicin-induced apoptosis of dorsal root ganglion neurons. Brain Res. 2005; 1056: 139-44.

[63] Agu PC, Afiukwa CA, Orji OU, Ezeh EM, Ofoke IH, Ogbu CO, et al. Molecular docking as a tool for the discovery of molecular targets of nutraceuticals in diseases management. Sci Rep. 2023; 13: 13398.

[64] Umesh HR, Ramesh KV, Devaraju KS. Molecular docking studies of phytochemicals against trehalose-6-phosphate phosphatases of pathogenic microbes. Beni-Suef Univ Basic Appl Sci. 2020; 9: 5.

[65] Fatriansyah JF, Rizqillah RK, Yandi MY, Fadilah, Sahlan M. Molecular docking and dynamics studies on propolis sulabiroin-A as a potential inhibitor of SARS-CoV-2. J King Saud Univ Sci. 2022; 34: 101707.

[66] Li X, Feng Y, Wang XX, Truong D, Wu YC. The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations. Aging Dis. 2020; 11: 1608-22.

[67] Gomes BAQ, Silva JPB, Romeiro CFR, Dos Santos SM, Rodrigues CA, Gonçalves PR, et al. Neuroprotective Mechanisms of Resveratrol in Alzheimer’s Disease: Role of SIRT1. Oxid Med Cell Longev. 2018; 2018: 8152373.

[68] Jia XY, Jiang DL, Jia XT, Fu LY, Tian H, Liu KL, et al. Capsaicin improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the hypothalamic paraventricular nucleus. Phytomedicine. 2023; 118: 154951.

[69] Zhu SL, Wang ML, He YT, Guo SW, Li TT, Peng WJ, et al. Capsaicin ameliorates intermittent high glucose-mediated endothelial senescence via the TRPV1/SIRT1 pathway. Phytomedicine. 2022; 100: 154081.

[70] Pikor D, Hurła M, Słowikowski B, Szymanowicz O, Poszwa J, Banaszek N, et al. Calcium Ions in the Physiology and Pathology of the Central Nervous System. Int J Mol Sci. 2024; 25: 13133.

[71] Herskovits AZ, Guarente L. SIRT1 in neurodevelopment and brain senescence. Neuron. 2014; 81: 471-83.

[72] Kozłowiec M, Gałecka M, Orzechowska A, Szemraj J, Gałecki P. Expression of genes ESR1 and ESR2 encoding estrogen receptors and cognitive functioning in patients with depression. J Sex Ment Health. 2023; 21: 12-20.

[73] Chowdhury MR, Reddy RVS, Nampoothiri NK, Erva RR, Vijaykumar SD. Exploring bioactive natural products for treating neurodegenerative diseases: a computational network medicine approach targeting the estrogen signaling pathway in amyotrophic lateral sclerosis and Parkinson’s disease. Metab Brain Dis. 2025; 40: 169.

[74] Liu J, Yuan S, Niu X, Kelleher R, Sheridan H. ESR1 dysfunction triggers neuroinflammation as a critical upstream causative factor of the Alzheimer’s disease process. Aging (Albany NY). 2022; 14: 8595-614.

[75] Pietrowicz M, Root-Bernstein R. Capsaicin (But Not Other Vanillins) Enhances Estrogen Binding to Its Receptor: Implications for Power Sports and Cancers. Life (Basel). 2025; 15: 208.

[76] Wang E, Li S, Li Y, Zhou T. HMOX1 as a potential drug target for upper and lower airway diseases: insights from multi-omics analysis. Respir Res. 2025; 26: 41.

[77] Jia XY, Yang Y, Jia XT, Jiang DL, Fu LY, Tian H, et al. Capsaicin pretreatment attenuates salt-sensitive hypertension by alleviating AMPK/Akt/Nrf2 pathway in hypothalamic paraventricular nucleus. Front Neurosci. 2024; 18: 1416522.

[78] Yang C, Guo W, He R, Meng X, Fu J, Lu Y. Dietary capsaicin attenuates cardiac injury after myocardial infarction in type 2 diabetic mice by inhibiting ferroptosis through activation of TRPV1 and Nrf2/HMOX1 pathway. Int Immunopharmacol. 2024; 140: 112852.

[79] Jordt SE. TRPV1, Regulation by Nerve Growth Factor. In: Schmidt R, Willis W, editors. Encyclopedia of Pain. Berlin, Heidelberg: Springer; 2007. pp. 2574-5.

[80] Aloe L, Rocco ML, Balzamino BO, Micera A. Nerve Growth Factor: A Focus on Neuroscience and Therapy. Curr Neuropharmacol. 2015; 13: 294-303.

[81] Bonnington JK, McNaughton PA. Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J Physiol. 2003; 551: 433-46.

[82] Xhima K, Aubert I. The therapeutic potential of nerve growth factor combined with blood-brain barrier modulation by focused ultrasound for neurodegenerative disorders. Neural Regen Res. 2021; 16: 1783-5.

[83] Khan I, Saeed K, Jo MG, Kim MO. 17-β Estradiol Rescued Immature Rat Brain against Glutamate-Induced Oxidative Stress and Neurodegeneration via Regulating Nrf2/HO-1 and MAP-Kinase Signaling Pathway. Antioxidants (Basel). 2021; 10: 892.

[84] Gatto NM, Deapen D, Stoyanoff S, Pinder R, Narayan S, Bordelon Y, et al. Lifetime exposure to estrogens and Parkinson’s disease in California teachers. Parkinsonism Relat Disord. 2014; 20: 1149-56.

[85] Adams C, Kumar R. The effect of estrogen in a man with Parkinson’s disease and a review of its therapeutic potential. Int J Neurosci. 2013; 123: 741-2.

[86] Zare F, Ataollahi E, Mardaneh P, Sakhteman A, Keshavarz V, Solhjoo A, et al. A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor. Sci Rep. 2024; 14: 7749.