Modulatory effects of Hypericum perforatum extract on sciatic nerve injury-induced peripheral neuropathy: an experimental study on mice
Abstract
Purpose: The effect of Hypericum perforatum (HP), which is a medicinal plant, on sciatic nerve injury-induced peripheral neuropathy has been less studied so far. The current experimental study aimed to investigate the neuroprotective and antinociceptive effects of Hypericum perforatum (HP) extract on sciatic nerve injury-induced peripheral neuropathy in mice.
Materials and Methods: In the present study, 18 Balb/C albino mice were allocated equally into three groups. The first group was determined as controls, and no procedure was performed on these mice. Neuropathy was generated by the partial sciatic nerve ligation method on mice allocated to the second and third groups. Mice in the third group received HP extract at a dose of 70 mg/kg per day for fourteen days. Nociception (cold allodynia) was evaluated using the cold plate test at the end of the experimental period. Tumor necrosis factor –αlpha (TNF-α) and interleukin-6 (IL-6) in plasma; inducible nitric oxide synthase (iNOS), phospholipase A2, cyclooxygenase-2 (COX-2), nuclear factor-kappa B (NF-κB), caspase-3, Bcl-2, and Bax levels in sciatic nerve were measured by enzyme-linked immunosorbent assay test.
Results: Cold plate latencies (sec) of the neuropathy + HP, neuropathy, and control groups were 8.33 ± 0.67, 5.17 ± 0.60, and 13 ± 0.73, respectively. Plasma TNF-α, IL-6 levels, and sciatic nerve iNOS, COX-2, NF-κB, caspase-3, and Bax levels were significantly decreased after HP supplementation. Bcl-2 levels of the neuropathy + HP, neuropathy, and control groups were 9.92 ± 0.71, 5.37 ± 0.53, and 13.65 ± 0.68, respectively.
Conclusion: HP has improved oxidative, inflammatory, and apoptotic responses, as well as cytokine levels in plasma and sciatic nerves of mice. It has been concluded that HP provided neuroprotective, anti-inflammatory, and antinociceptive effects in experimental mice with sciatic nerve injury models, which is suggested to guide future studies on neuropathic pain management.
Supporting Institution
Çukurova University Scientific Research Projects Commission
Project Number
TTU-2017-9518
Thanks
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References
- Jensen TS, Baron R, Haanpää M, Kalso E, Loeser JD, Rice ASC et al. A new definition of neuropathic pain. Pain. 2011;152:2204-5.
- Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002.
- Leung L, Cahill CM. TNF-alpha and neuropathic pain--a review. J Neuroinflammation. 2010;7:27.
- Shih RH, Wang CY, Yang CM. NF-kappaB signaling pathways in neurological inflammation: A Mini Review. Front Mol Neurosci. 2015;8:77.
- Ellis A, Bennett DL. Neuroinflammation and the generation of neuropathic pain. Br J Anaesth. 2013;111:26-37.
- Uslusoy F, Nazıroğlu M, Övey İS, Sönmez TT. Hypericum perforatum L. supplementation protects sciatic nerve injury-induced apoptotic, inflammatory and oxidative damage to muscle, blood and brain in rats. J Pharm Pharmacol. 2019;71:83-92.
- Hung AL, Lim M, Doshi TL. Targeting cytokines for treatment of neuropathic pain. Scand J Pain. 2017;17:287-93.
- Cui YH, Zheng Y. A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults. Neuropsychiatr Dis Treat. 2016;12:1715-23.
- Medina MA, Martínez-Poveda B, Amores-Sánchez MI, Quesada AR. Hyperforin: more than an antidepressant bioactive compound? Life Sci. 2006;79:105-11.
- Raso GM, Meli R, Di Carlo G, Pacilio M, Di Carlo R. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci. 2001;68:921-31.
- Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol. 2002;64:1767-75.
- Hatano T, Sameshima Y, Kawabata M, Yamada S, Shinozuka K, Nakabayashi T et al. St. John's wort promotes adipocyte differentiation and modulates NF-κB activation in 3T3-L1 cells. Biol Pharm Bull. 2014;37:1132-8.
- Genovese T, Mazzon E, Menegazzi M, Di Paola R, Muià C, Crisafulli C et al. Neuroprotection and enhanced recovery with hypericum perforatum extract after experimental spinal cord injury in mice. Shock. 2006;25:608-17.
- You MK, Kim HJ, Kook JH, Kim HA. St. John's wort regulates proliferation and apoptosis in MCF-7 human breast cancer cells by inhibiting AMPK/mTOR and activating the mitochondrial pathway. Int J Mol Sci. 2018;19:966.
- Galeotti N. Hypericum perforatum (St John's wort) beyond depression: A therapeutic perspective for pain conditions. J Ethnopharmacol. 2017;200:136-46.
- National Research Council (US) Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press (US); 1996.
- Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry. 1997;30:129-34.
- Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain. 1990; 43: 205–18.
- Malmberg AB, Basbaum AI. Partial sciatic nevre injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain. 1998;76:215-22.
- Kaplan HM, Doran F. Hypericum perforatum extract inhibits cigarette smoke induced lung inflammation. Biological and Chemical Research. 2017; 4: 35-43.
- Allchorne AJ, Broom DC, Woolf CJ. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats. Mol Pain. 2005;1:36.
- Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54.
- Arifin WN, Zahiruddin WM. Sample size calculation in animal studies using resource equation approach. Malays J Med Sci. 2017;24:101-5.
- Jaggi AS, Jain V, Singh N. Animal models of neuropathic pain. Fundam Clin Pharmacol. 2011;25:1-28.
- Coskun Benlidayi I. Role of inflammation in the pathogenesis and treatment of fibromyalgia. Rheumatol Int. 2019;39:781-91.
- Joseph EK, Levine JD. Caspase signalling in neuropathic and inflammatory pain in the rat. Eur J Neurosci. 2004;20:2896-902.
- Ledeboer A, Gamanos M, Lai W, Martin D, Maier SF, Watkins LR et al. Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci. 2005;22:1977-86.
- Cinelli MA, Do HT, Miley GP, Silverman RB. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med Res Rev. 2020;40:158-89.
- Masiello P, Novelli M, Beffy P, Menegazzi M. Can Hypericum perforatum (SJW) prevent cytokine storm in COVID-19 patients? Phytother Res. 2020;34:1471-3.
- McGarry T, Biniecka M, Veale DJ, Fearon U. Hypoxia, oxidative stress and inflammation. Free Radic Biol Med. 2018;125:15-24.
- Raso GM, Pacilio M, Di Carlo G, Esposito E, Pinto L, Meli R. In-vivo and in-vitro anti-inflammatory effect of Echinacea purpurea and Hypericum perforatum. J Pharm Pharmacol. 2002;54:1379-83.
- Novelli M, Menegazzi M, Beffy P, Porozov S, Gregorelli A, Giacopelli D et al. St. John's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells. Int J Biochem Cell Biol. 2016;81:92-104.
- Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2:725-34.
- Niederberger E, Schmidtko A, Gao W, Kühlein H, Ehnert C, Geisslinger G. Impaired acute and inflammatory nociception in mice lacking the p50 subunit of NF-kappaB. Eur J Pharmacol. 2007;559:55-60.
- Allegra A, Tonacci A, Spagnolo EV, Musolino C, Gangemi S. Antiproliferative effects of St. John's wort, its derivatives, and other Hypericum species in hematologic malignancies. Int J Mol Sci. 2020;22:146.
- Uslusoy F, Nazıroğlu M, Çiğ B. Inhibition of the TRPM2 and TRPV1 channels through Hypericum perforatum in sciatic nerve injury-induced rats demonstrates their key role in apoptosis and mitochondrial oxidative stress of sciatic nerve and dorsal root ganglion. Front Physiol. 2017;8:335.
- Özdemir ÜS, Nazıroğlu M, Şenol N, Ghazizadeh V. Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol. 2016;53:3540-51.
- Galeotti N, Ghelardini C. Reversal of NO-induced nociceptive hypersensitivity by St. John's wort and hypericin: NF-κB, CREB and STAT1 as molecular targets. Psychopharmacology. 2013;227:149-63.
Hypericum perforatum ekstresinin siyatik sinir hasarı ile indüklenen periferik nöropati üzerindeki düzenleyici etkisi: fareler üzerinde deneysel bir çalışma
Abstract
Amaç: Tıbbi bir bitki olan Hypericum perforatum'un (HP) siyatik sinir hasarına bağlı periferik nöropati üzerindeki etkisi şimdiye kadar az oranda çalışılmıştır. Bu çalışmada, Hypericum perforatum (HP), ekstresinin farelerde siyatik sinir hasarına bağlı periferik nöropati üzerindeki nöroprotektif ve antinosiseptif etkilerini araştırmayı amaçlandı.
Gereç ve Yöntem: Bu çalışmada, 18 Balb/C albino fare eşit olarak üç gruba ayrıldı. Birinci grup kontrol olarak belirlendi ve bu farelere herhangi bir işlem yapılmadı. İkinci ve üçüncü gruplara ayrılan farelerde kısmi siyatik sinir ligasyonu yöntemiyle nöropati oluşturuldu. Üçüncü gruptaki farelere, on dört gün boyunca günde 70 mg/kg HP ekstresi verildi. Nosisepsiyon (soğuk allodini), deneysel süreç sonunda soğuk plaka testi kullanılarak değerlendirildi. Plazmada, tümör nekroz faktörü –αlpha (TNF-α) ve interlökin-6 (IL-6); siyatik sinirde ise indüklenebilir nitrik oksit sentaz (iNOS), fosfolipaz A2, siklooksijenaz-2 (COX-2), nükleer faktör-kappa B (NF-κB), kaspaz-3, Bcl-2 ve Bax düzeyleri enzim bağlı immunosorbant testi ile değerlendirildi.
Bulgular: Nöropati + HP, nöropati ve kontrol gruplarının soğuk plaka latansları (sn) sırasıyla 8,33 ± 0,67, 5,17 ± 0,60 ve 13 ± 0,73 idi. Plazma TNF-α, IL-6 seviyeleri ve siyatik sinir iNOS, COX-2, NF-κB, kaspaz-3 ve Bax seviyeleri, HP takviyesinden sonra önemli ölçüde azaldı. Nöropati + HP, nöropati ve kontrol gruplarının Bcl-2 düzeyleri sırasıyla 9,92 ± 0,71, 5,37 ± 0,53 ve 13,65 ± 0,68 idi.
Sonuç: HP, farelerin plazma ve siyatik sinirlerindeki sitokin seviyelerinin yanı sıra oksidatif, inflamatuvar ve apoptotik yanıtları iyileştirmiştir. HP'nin deneysel fare siyatik sinir hasarı modellerinde nöroprotektif, anti-inflamatuvar ve antinosiseptif etkiler sağladığı sonucuna varılmış olup, nöropatik ağrı yönetimiyle ilgili gelecekteki çalışmalara rehberlik edeceği düşünülmektedir.
Project Number
TTU-2017-9518
References
- Jensen TS, Baron R, Haanpää M, Kalso E, Loeser JD, Rice ASC et al. A new definition of neuropathic pain. Pain. 2011;152:2204-5.
- Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002.
- Leung L, Cahill CM. TNF-alpha and neuropathic pain--a review. J Neuroinflammation. 2010;7:27.
- Shih RH, Wang CY, Yang CM. NF-kappaB signaling pathways in neurological inflammation: A Mini Review. Front Mol Neurosci. 2015;8:77.
- Ellis A, Bennett DL. Neuroinflammation and the generation of neuropathic pain. Br J Anaesth. 2013;111:26-37.
- Uslusoy F, Nazıroğlu M, Övey İS, Sönmez TT. Hypericum perforatum L. supplementation protects sciatic nerve injury-induced apoptotic, inflammatory and oxidative damage to muscle, blood and brain in rats. J Pharm Pharmacol. 2019;71:83-92.
- Hung AL, Lim M, Doshi TL. Targeting cytokines for treatment of neuropathic pain. Scand J Pain. 2017;17:287-93.
- Cui YH, Zheng Y. A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults. Neuropsychiatr Dis Treat. 2016;12:1715-23.
- Medina MA, Martínez-Poveda B, Amores-Sánchez MI, Quesada AR. Hyperforin: more than an antidepressant bioactive compound? Life Sci. 2006;79:105-11.
- Raso GM, Meli R, Di Carlo G, Pacilio M, Di Carlo R. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci. 2001;68:921-31.
- Albert D, Zündorf I, Dingermann T, Müller WE, Steinhilber D, Werz O. Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol. 2002;64:1767-75.
- Hatano T, Sameshima Y, Kawabata M, Yamada S, Shinozuka K, Nakabayashi T et al. St. John's wort promotes adipocyte differentiation and modulates NF-κB activation in 3T3-L1 cells. Biol Pharm Bull. 2014;37:1132-8.
- Genovese T, Mazzon E, Menegazzi M, Di Paola R, Muià C, Crisafulli C et al. Neuroprotection and enhanced recovery with hypericum perforatum extract after experimental spinal cord injury in mice. Shock. 2006;25:608-17.
- You MK, Kim HJ, Kook JH, Kim HA. St. John's wort regulates proliferation and apoptosis in MCF-7 human breast cancer cells by inhibiting AMPK/mTOR and activating the mitochondrial pathway. Int J Mol Sci. 2018;19:966.
- Galeotti N. Hypericum perforatum (St John's wort) beyond depression: A therapeutic perspective for pain conditions. J Ethnopharmacol. 2017;200:136-46.
- National Research Council (US) Institute for Laboratory Animal Research. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press (US); 1996.
- Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry. 1997;30:129-34.
- Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain. 1990; 43: 205–18.
- Malmberg AB, Basbaum AI. Partial sciatic nevre injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain. 1998;76:215-22.
- Kaplan HM, Doran F. Hypericum perforatum extract inhibits cigarette smoke induced lung inflammation. Biological and Chemical Research. 2017; 4: 35-43.
- Allchorne AJ, Broom DC, Woolf CJ. Detection of cold pain, cold allodynia and cold hyperalgesia in freely behaving rats. Mol Pain. 2005;1:36.
- Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-54.
- Arifin WN, Zahiruddin WM. Sample size calculation in animal studies using resource equation approach. Malays J Med Sci. 2017;24:101-5.
- Jaggi AS, Jain V, Singh N. Animal models of neuropathic pain. Fundam Clin Pharmacol. 2011;25:1-28.
- Coskun Benlidayi I. Role of inflammation in the pathogenesis and treatment of fibromyalgia. Rheumatol Int. 2019;39:781-91.
- Joseph EK, Levine JD. Caspase signalling in neuropathic and inflammatory pain in the rat. Eur J Neurosci. 2004;20:2896-902.
- Ledeboer A, Gamanos M, Lai W, Martin D, Maier SF, Watkins LR et al. Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci. 2005;22:1977-86.
- Cinelli MA, Do HT, Miley GP, Silverman RB. Inducible nitric oxide synthase: Regulation, structure, and inhibition. Med Res Rev. 2020;40:158-89.
- Masiello P, Novelli M, Beffy P, Menegazzi M. Can Hypericum perforatum (SJW) prevent cytokine storm in COVID-19 patients? Phytother Res. 2020;34:1471-3.
- McGarry T, Biniecka M, Veale DJ, Fearon U. Hypoxia, oxidative stress and inflammation. Free Radic Biol Med. 2018;125:15-24.
- Raso GM, Pacilio M, Di Carlo G, Esposito E, Pinto L, Meli R. In-vivo and in-vitro anti-inflammatory effect of Echinacea purpurea and Hypericum perforatum. J Pharm Pharmacol. 2002;54:1379-83.
- Novelli M, Menegazzi M, Beffy P, Porozov S, Gregorelli A, Giacopelli D et al. St. John's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells. Int J Biochem Cell Biol. 2016;81:92-104.
- Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002;2:725-34.
- Niederberger E, Schmidtko A, Gao W, Kühlein H, Ehnert C, Geisslinger G. Impaired acute and inflammatory nociception in mice lacking the p50 subunit of NF-kappaB. Eur J Pharmacol. 2007;559:55-60.
- Allegra A, Tonacci A, Spagnolo EV, Musolino C, Gangemi S. Antiproliferative effects of St. John's wort, its derivatives, and other Hypericum species in hematologic malignancies. Int J Mol Sci. 2020;22:146.
- Uslusoy F, Nazıroğlu M, Çiğ B. Inhibition of the TRPM2 and TRPV1 channels through Hypericum perforatum in sciatic nerve injury-induced rats demonstrates their key role in apoptosis and mitochondrial oxidative stress of sciatic nerve and dorsal root ganglion. Front Physiol. 2017;8:335.
- Özdemir ÜS, Nazıroğlu M, Şenol N, Ghazizadeh V. Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol. 2016;53:3540-51.
- Galeotti N, Ghelardini C. Reversal of NO-induced nociceptive hypersensitivity by St. John's wort and hypericin: NF-κB, CREB and STAT1 as molecular targets. Psychopharmacology. 2013;227:149-63.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Research |
| Authors | |
| Project Number | TTU-2017-9518 |
| Early Pub Date | July 10, 2023 |
| Publication Date | July 2, 2023 |
| Acceptance Date | May 27, 2023 |
| Published in Issue | Year 2023 Volume: 48 Issue: 2 |
