Evaluating the effectiveness of gabapentin and ginkgo biloba in the neuroinflammatory process within a co-culture model of GBM and neurons
Year 2025,
Volume: 53 Issue: 2, 39 - 48, 01.04.2025
Çiğdem Sevim
,
Ali Taghizadehghalehjoughi
Abstract
This study aimed to investigate the anti-inflammatory effects of Ginkgo Biloba extract and Gabapentin on a neuron-Glioblastoma cell line. Utilizing advanced co-culture techniques, we simulated a tumor environment that closely mimics in vivo conditions and performed a detailed genetic analysis of cytokine expression. Testing a range of doses from 20 to 80 µg/ml, we found that the combination of Gabapentin (80 µg/ml) and Ginkgo Biloba extract (80 µg/ml) did not alter levels of proinflammatory cytokines such as IL1β, IL6, IL8, and TNF-α. However, it significantly increased the levels of the anti-inflammatory cytokine IL10 compared to other groups. These findings suggest that the co-administration of Gabapentin and Ginkgo Biloba can modulate the inflammatory response, maintaining it at levels similar to the control group. Determining the precise effective dosage range and understanding the mechanisms to halt neuroinflammation will be crucial for advancing therapeutic options for glioblastoma multiforme. This research provides a promising foundation for developing new treatment strategies aimed at reducing inflammation in glioblastoma patients.
Ethical Statement
This study does not involve human or animal subjects that require ethical approval. Therefore, ethical committee approval was not necessary. All ethical principles and relevant guidelines were fully adhered to during the study.
Supporting Institution
This study did not receive any financial or institutional support.
References
- 1. D. Laug, S.M. Glasgow, B. Deneen, A glial blueprint for gliomagenesis, Nature Reviews Neuroscience 19 (2018) 393-403.
- 2. S. Nasir, S. Nazir, R. Hanif, A. Javed, Glioblastoma Multiforme: Probing Solutions to Systemic Toxicity towards High-Dose Chemotherapy and Inflammatory Influence in Resistance against Temozolomide, Pharmaceutics 15 (2023) 687.
- 3. A.F. Tamimi, M. Juweid, Epidemiology and outcome of glioblastoma, Exon Publications (2017) 143-153.
- 4. N.T. Cini, M. Pennisi, S. Genc, D.A. Spandidos, L. Falzone, P.D. Mitsias, A. Tsatsakis, A. Taghizadehghalehjoughi, Glioma lateralization: Focus on the anatomical localization and the distribution of molecular alterations (Review), Oncology Reports 52(4) (2024) 139.
- 5. A. Seidlitz, T. Siepmann, S. Löck, T. Juratli, M. Baumann, M. Krause, Impact of waiting time after surgery and overall time of postoperative radiochemotherapy on treatment outcome in glioblastoma multiforme, Radiation Oncology 10 (2015) 1-10.
- 6. Z. Tan, H. Xue, Y. Sun, C. Zhang, Y. Song, Y. Qi, The role of tumor inflammatory microenvironment in lung cancer, Frontiers in Pharmacology 12 (2021) 688625.
- 7. F. Colotta, P. Allavena, A. Sica, C. Garlanda, A. Mantovani, Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability, Carcinogenesis 30(7) (2009) 1073-81.
- 8. G. Multhoff, M. Molls, J. Radons, Chronic inflammation in cancer development, Frontiers in Immunology 2 (2012) 98.
- 9. D.W. Edwardson, J. Boudreau, J. Mapletoft, C. Lanner, A.T. Kovala, A.M. Parissenti, Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance, PLoS One 12(9) (2017) e0183662.
- 10. L. Arendt-Nielsen, J.B. Frøkjær, C. Staahl, T. Graven-Nielsen, J.P. Huggins, T.S. Smart, et al., Effects of gabapentin on experimental somatic pain and temporal summation, Regional Anesthesia and Pain Medicine 32(5) (2007) 382-8.
- 11. T.V. de Brito, G.J.D. Júnior, J.S. da Cruz Júnior, R.O. Silva, C.E. da Silva Monteiro, A.X. Franco, et al., Gabapentin attenuates intestinal inflammation: role of PPAR-gamma receptor, European Journal of Pharmacology 873 (2020) 172974.
- 12. C.E. Hamm, R.D. Gary, I.M. McIntyre, Gabapentin concentrations and postmortem distribution, Forensic Science International 262 (2016) 201-3.
- 13. G.C. Quintero, Review about gabapentin misuse, interactions, contraindications and side effects, Journal of Experimental Pharmacology (2017) 13-21.
- 14. O.M. Abdel-Salam, A.A. Sleem, Study of the analgesic, anti-inflammatory, and gastric effects of gabapentin, Drug Discovery and Therapeutics 3(1) (2009) 1-10.
- 15. J.M. Dias, T.V. de Brito, D. de Aguiar Magalhães, P.W. da Silva Santos, J.A. Batista, E.G. do Nascimento Dias, et al., Gabapentin, a synthetic analogue of gamma aminobutyric acid, reverses systemic acute inflammation and oxidative stress in mice, Inflammation 37 (2014) 1826-36.
- 16. X. Li, B. Wang, N. Yu, L. Yang, C. Nan, Z. Sun, et al., Gabapentin alleviates brain injury in intracerebral hemorrhage through suppressing neuroinflammation and apoptosis, Neurochemical Research 47(10) (2022) 3063-75.
- 17. Y. Ong, E. Yong, Panax (ginseng)--panacea or placebo? Molecular and cellular basis of its pharmacological activity, Annals of the Academy of Medicine, Singapore 29(1) (2000) 42-6.
- 18. L.O. Dragsted, M. Strube, J. Larsen, Cancer‐protective factors in fruits and vegetables: biochemical and biological background, Pharmacology & Toxicology 72 (1993) 116-35.
- 19. F. Marks, K. Müller-Decker, G. Fürstenberger, A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism, Toxicology 153(1-3) (2000) 11-26.
- 20. F.V. DeFeudis, Ginkgo biloba extract (EGb 761): from chemistry to the clinic, Ullstein Med., Wiesbaden (1998).
- 21. F.V. DeFeudis, V. Papadopoulos, K. Drieu, Ginkgo biloba extracts and cancer: a research area in its infancy, Fundamental & Clinical Pharmacology 17(4) (2003) 405-17.
- 22. C.Y. Lee, H.Y. Lai, A. Chiu, S.H. Chan, L.P. Hsiao, S.T. Lee, The effects of antiepileptic drugs on the growth of glioblastoma cell lines, Journal of Neuro-Oncology 127(3) (2016) 445-453.
- 23. S.H. Hsu, C.J. Chang, C.M. Tang, F.T. Lin, In vitro and in vivo effects of Ginkgo biloba extract EGb 761 on seeded Schwann cells within poly(DL-lactic acid-co-glycolic acid) conduits for peripheral nerve regeneration, Journal of Biomaterials Applications 19(2) (2004) 163-182.
- 24. N. Chen, C. Peng, D. Li, Epigenetic underpinnings of inflammation: a key to unlock the tumor microenvironment in glioblastoma, Frontiers in Immunology 13 (2022) 869307.
- 25. R. Roesler, S.A. Dini, G.R. Isolan, Neuroinflammation and immunoregulation in glioblastoma and brain metastases: recent developments in imaging approaches, Clinical & Experimental Immunology 206(3) (2021) 314-324.
- 26. S.M. Allan, P.J. Tyrrell, N.J. Rothwell, Interleukin-1 and neuronal injury, Nature Reviews Immunology 5(8) (2005) 629-640.
- 27. K. Tanabe, R. Matsushima-Nishiwaki, S. Dohi, O. Kozawa, Phosphorylation status of heat shock protein 27 regulates the interleukin-1β-induced interleukin-6 synthesis in C6 glioma cells, Neuroscience 170(4) (2010) 1028-1034.
- 28. N. Simi, N. Tsakiri, P. Wang, N. Rothwell, Interleukin-1 and inflammatory neurodegeneration, Biochemical Society Transactions 35(5) (2007) 1122-1126.
- 29. K. Tanabe, O. Kozawa, H. Iida, Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells, Journal of Neuroinflammation 8 (2011) 1-8.
- 30. J. Weissenberger, S. Loeffler, A. Kappeler, M. Kopf, A. Lukes, T.A. Afanasieva, et al., IL-6 is required for glioma development in a mouse model, Oncogene 23(19) (2004) 3308-3316.
- 31. C. Rolhion, F. Penault-Llorca, J.L. Kémény, J.J. Lemaire, C. Jullien, C. Labit-Bouvier, et al., Interleukin-6 overexpression as a marker of malignancy in human gliomas, Journal of Neurosurgery 94(1) (2001) 97-101.
- 32. T. Tchirkov, T. Khalil, E. Chautard, K. Mokhtari, L. Veronese, B. Irthum, et al., Interleukin-6 gene amplification and shortened survival in glioblastoma patients, British Journal of Cancer 96(3) (2007) 474-476.
- 33. Y. Yeung, K. McDonald, T. Grewal, L. Munoz, Interleukins in glioblastoma pathophysiology: implications for therapy, British Journal of Pharmacology 168(3) (2013) 591-606.
- 34. Z. Zhang, D. Peng, H. Zhu, X. Wang, Experimental evidence of Ginkgo biloba extract EGB as a neuroprotective agent in ischemia stroke rats, Brain Research Bulletin 87(2-3) (2012) 193-198.
- 35. J. Tulsulkar, Z.A. Shah, Ginkgo biloba prevents transient global ischemia-induced delayed hippocampal neuronal death through antioxidant and anti-inflammatory mechanism, Neurochemistry International 62(2) (2013) 189-197.
- 36. M.S. Tan, J.T. Yu, C.C. Tan, H.F. Wang, X.F. Meng, C. Wang, et al., Efficacy and adverse effects of Ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis, Journal of Alzheimer’s Disease 43(2) (2015) 589-603.
- 37. F. Leng, P. Edison, Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?, Nature Reviews Neurology 17(3) (2021) 157-172.
- 38. B. Gargouri, J. Carstensen, H.S. Bhatia, M. Huell, G.P. Dietz, B.L. Fiebich, Anti-neuroinflammatory effects of Ginkgo biloba extract EGb761 in LPS-activated primary microglial cells, Phytomedicine 44 (2018) 45-55.
GBM ve nöron ko-kültür modelinde gabapentin ve ginkgo biloba'nın nöroinflamatuar süreçteki etkinliğinin değerlendirilmesi
Year 2025,
Volume: 53 Issue: 2, 39 - 48, 01.04.2025
Çiğdem Sevim
,
Ali Taghizadehghalehjoughi
Abstract
Bu çalışma, Ginkgo Biloba ekstresi ve Gabapentin'in nöron-Glioblastoma hücre hattı üzerindeki anti-inflamatuar etkilerini araştırmayı amaçladı. Gelişmiş ko-kültür teknikleri kullanarak in vivo koşulları yakından taklit eden bir tümör ortamı simüle ettik ve sitokin ekspresyonunun detaylı genetik analizini gerçekleştirdik. 20 ila 80 µg/ml aralığında farklı dozları test ettik ve Gabapentin (80 µg/ml) ile Ginkgo Biloba ekstresinin (80 µg/ml) kombinasyonunun, IL1β, IL6, IL8 ve TNF-α gibi proinflamatuar sitokin seviyelerini değiştirmediğini, ancak diğer gruplara kıyasla anti-inflamatuar sitokin IL10 seviyelerini önemli ölçüde artırdığını bulduk. Bu bulgular, Gabapentin ve Ginkgo Biloba'nın birlikte uygulanmasının inflamatuar yanıtı düzenleyebileceğini ve bunu kontrol grubuna benzer seviyelerde tutabileceğini göstermektedir. Kesin etkili doz aralığının belirlenmesi ve nöroinflamasyonun durdurulma mekanizmalarının anlaşılması, glioblastoma multiforme için terapötik seçeneklerin ilerletilmesi açısından kritik olacaktır. Bu araştırma, glioblastoma hastalarında inflamasyonu azaltmayı hedefleyen yeni tedavi stratejilerinin geliştirilmesi için umut verici bir temel sağlamaktadır.
Ethical Statement
Bu çalışma, etik kurul onayı gerektiren hayvan veya insan denekleri içermemektedir. Bu nedenle, etik kurul onayına ihtiyaç duyulmamıştır. Çalışma sırasında etik ilkelere ve ilgili kurallara tamamen uyulmuştur.
Supporting Institution
Bu çalışma herhangi bir finansal ya da kurumsal destek almamıştır.
References
- 1. D. Laug, S.M. Glasgow, B. Deneen, A glial blueprint for gliomagenesis, Nature Reviews Neuroscience 19 (2018) 393-403.
- 2. S. Nasir, S. Nazir, R. Hanif, A. Javed, Glioblastoma Multiforme: Probing Solutions to Systemic Toxicity towards High-Dose Chemotherapy and Inflammatory Influence in Resistance against Temozolomide, Pharmaceutics 15 (2023) 687.
- 3. A.F. Tamimi, M. Juweid, Epidemiology and outcome of glioblastoma, Exon Publications (2017) 143-153.
- 4. N.T. Cini, M. Pennisi, S. Genc, D.A. Spandidos, L. Falzone, P.D. Mitsias, A. Tsatsakis, A. Taghizadehghalehjoughi, Glioma lateralization: Focus on the anatomical localization and the distribution of molecular alterations (Review), Oncology Reports 52(4) (2024) 139.
- 5. A. Seidlitz, T. Siepmann, S. Löck, T. Juratli, M. Baumann, M. Krause, Impact of waiting time after surgery and overall time of postoperative radiochemotherapy on treatment outcome in glioblastoma multiforme, Radiation Oncology 10 (2015) 1-10.
- 6. Z. Tan, H. Xue, Y. Sun, C. Zhang, Y. Song, Y. Qi, The role of tumor inflammatory microenvironment in lung cancer, Frontiers in Pharmacology 12 (2021) 688625.
- 7. F. Colotta, P. Allavena, A. Sica, C. Garlanda, A. Mantovani, Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability, Carcinogenesis 30(7) (2009) 1073-81.
- 8. G. Multhoff, M. Molls, J. Radons, Chronic inflammation in cancer development, Frontiers in Immunology 2 (2012) 98.
- 9. D.W. Edwardson, J. Boudreau, J. Mapletoft, C. Lanner, A.T. Kovala, A.M. Parissenti, Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance, PLoS One 12(9) (2017) e0183662.
- 10. L. Arendt-Nielsen, J.B. Frøkjær, C. Staahl, T. Graven-Nielsen, J.P. Huggins, T.S. Smart, et al., Effects of gabapentin on experimental somatic pain and temporal summation, Regional Anesthesia and Pain Medicine 32(5) (2007) 382-8.
- 11. T.V. de Brito, G.J.D. Júnior, J.S. da Cruz Júnior, R.O. Silva, C.E. da Silva Monteiro, A.X. Franco, et al., Gabapentin attenuates intestinal inflammation: role of PPAR-gamma receptor, European Journal of Pharmacology 873 (2020) 172974.
- 12. C.E. Hamm, R.D. Gary, I.M. McIntyre, Gabapentin concentrations and postmortem distribution, Forensic Science International 262 (2016) 201-3.
- 13. G.C. Quintero, Review about gabapentin misuse, interactions, contraindications and side effects, Journal of Experimental Pharmacology (2017) 13-21.
- 14. O.M. Abdel-Salam, A.A. Sleem, Study of the analgesic, anti-inflammatory, and gastric effects of gabapentin, Drug Discovery and Therapeutics 3(1) (2009) 1-10.
- 15. J.M. Dias, T.V. de Brito, D. de Aguiar Magalhães, P.W. da Silva Santos, J.A. Batista, E.G. do Nascimento Dias, et al., Gabapentin, a synthetic analogue of gamma aminobutyric acid, reverses systemic acute inflammation and oxidative stress in mice, Inflammation 37 (2014) 1826-36.
- 16. X. Li, B. Wang, N. Yu, L. Yang, C. Nan, Z. Sun, et al., Gabapentin alleviates brain injury in intracerebral hemorrhage through suppressing neuroinflammation and apoptosis, Neurochemical Research 47(10) (2022) 3063-75.
- 17. Y. Ong, E. Yong, Panax (ginseng)--panacea or placebo? Molecular and cellular basis of its pharmacological activity, Annals of the Academy of Medicine, Singapore 29(1) (2000) 42-6.
- 18. L.O. Dragsted, M. Strube, J. Larsen, Cancer‐protective factors in fruits and vegetables: biochemical and biological background, Pharmacology & Toxicology 72 (1993) 116-35.
- 19. F. Marks, K. Müller-Decker, G. Fürstenberger, A causal relationship between unscheduled eicosanoid signaling and tumor development: cancer chemoprevention by inhibitors of arachidonic acid metabolism, Toxicology 153(1-3) (2000) 11-26.
- 20. F.V. DeFeudis, Ginkgo biloba extract (EGb 761): from chemistry to the clinic, Ullstein Med., Wiesbaden (1998).
- 21. F.V. DeFeudis, V. Papadopoulos, K. Drieu, Ginkgo biloba extracts and cancer: a research area in its infancy, Fundamental & Clinical Pharmacology 17(4) (2003) 405-17.
- 22. C.Y. Lee, H.Y. Lai, A. Chiu, S.H. Chan, L.P. Hsiao, S.T. Lee, The effects of antiepileptic drugs on the growth of glioblastoma cell lines, Journal of Neuro-Oncology 127(3) (2016) 445-453.
- 23. S.H. Hsu, C.J. Chang, C.M. Tang, F.T. Lin, In vitro and in vivo effects of Ginkgo biloba extract EGb 761 on seeded Schwann cells within poly(DL-lactic acid-co-glycolic acid) conduits for peripheral nerve regeneration, Journal of Biomaterials Applications 19(2) (2004) 163-182.
- 24. N. Chen, C. Peng, D. Li, Epigenetic underpinnings of inflammation: a key to unlock the tumor microenvironment in glioblastoma, Frontiers in Immunology 13 (2022) 869307.
- 25. R. Roesler, S.A. Dini, G.R. Isolan, Neuroinflammation and immunoregulation in glioblastoma and brain metastases: recent developments in imaging approaches, Clinical & Experimental Immunology 206(3) (2021) 314-324.
- 26. S.M. Allan, P.J. Tyrrell, N.J. Rothwell, Interleukin-1 and neuronal injury, Nature Reviews Immunology 5(8) (2005) 629-640.
- 27. K. Tanabe, R. Matsushima-Nishiwaki, S. Dohi, O. Kozawa, Phosphorylation status of heat shock protein 27 regulates the interleukin-1β-induced interleukin-6 synthesis in C6 glioma cells, Neuroscience 170(4) (2010) 1028-1034.
- 28. N. Simi, N. Tsakiri, P. Wang, N. Rothwell, Interleukin-1 and inflammatory neurodegeneration, Biochemical Society Transactions 35(5) (2007) 1122-1126.
- 29. K. Tanabe, O. Kozawa, H. Iida, Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells, Journal of Neuroinflammation 8 (2011) 1-8.
- 30. J. Weissenberger, S. Loeffler, A. Kappeler, M. Kopf, A. Lukes, T.A. Afanasieva, et al., IL-6 is required for glioma development in a mouse model, Oncogene 23(19) (2004) 3308-3316.
- 31. C. Rolhion, F. Penault-Llorca, J.L. Kémény, J.J. Lemaire, C. Jullien, C. Labit-Bouvier, et al., Interleukin-6 overexpression as a marker of malignancy in human gliomas, Journal of Neurosurgery 94(1) (2001) 97-101.
- 32. T. Tchirkov, T. Khalil, E. Chautard, K. Mokhtari, L. Veronese, B. Irthum, et al., Interleukin-6 gene amplification and shortened survival in glioblastoma patients, British Journal of Cancer 96(3) (2007) 474-476.
- 33. Y. Yeung, K. McDonald, T. Grewal, L. Munoz, Interleukins in glioblastoma pathophysiology: implications for therapy, British Journal of Pharmacology 168(3) (2013) 591-606.
- 34. Z. Zhang, D. Peng, H. Zhu, X. Wang, Experimental evidence of Ginkgo biloba extract EGB as a neuroprotective agent in ischemia stroke rats, Brain Research Bulletin 87(2-3) (2012) 193-198.
- 35. J. Tulsulkar, Z.A. Shah, Ginkgo biloba prevents transient global ischemia-induced delayed hippocampal neuronal death through antioxidant and anti-inflammatory mechanism, Neurochemistry International 62(2) (2013) 189-197.
- 36. M.S. Tan, J.T. Yu, C.C. Tan, H.F. Wang, X.F. Meng, C. Wang, et al., Efficacy and adverse effects of Ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis, Journal of Alzheimer’s Disease 43(2) (2015) 589-603.
- 37. F. Leng, P. Edison, Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?, Nature Reviews Neurology 17(3) (2021) 157-172.
- 38. B. Gargouri, J. Carstensen, H.S. Bhatia, M. Huell, G.P. Dietz, B.L. Fiebich, Anti-neuroinflammatory effects of Ginkgo biloba extract EGb761 in LPS-activated primary microglial cells, Phytomedicine 44 (2018) 45-55.