Oxidant–antioxidant system alterations in LPS-induced sepsis: Modulatory effects of pregabalin

Öz

Objective: This study aimed to investigate the effects of pregabalin (PRG) on the oxidant–antioxidant system in brain, pancreas, spleen, and testicular tissues using a lipopolysaccharide (LPS)-induced sepsis model. Methods: Rats were randomly assigned to three groups: control, LPS, and LPS+PRG. The control group received equivalent volumes of saline intraperitoneally (i.p.) and orally. Sepsis was induced in the LPS group by administering LPS (5 mg/kg, i.p.). In the LPS+PRG group, PRG was administered orally at a dose of 30 mg/kg 1 hour before LPS injection; subsequently, LPS (5 mg/kg, i.p.) was administered. All rats were sacrificed 6 hours after LPS administration. Malondialdehyde (MDA), catalase (CAT), and su-peroxide dismutase (SOD) levels were measured in brain, pancreas, spleen, and testicular tissues to eval-uate the oxidant–antioxidant status. Results: In brain tissue, no statistically significant differences in MDA, CAT, or SOD levels were ob-served between the control and LPS groups (p > 0.05). MDA levels were significantly decreased in the PRG-treated group compared with both the control (p < 0.001) and LPS (p = 0.029) groups. CAT levels were also significantly reduced in the PRG-treated group compared with the control group (p = 0.040), whereas no statistically significant difference was observed compared to the LPS group (p = 0.240). In contrast, SOD levels were significantly increased in the PRG-treated group compared with both the con-trol (p < 0.001) and LPS (p < 0.001) groups. No statistically significant differences were observed in pancreas, spleen, or testicular tissues. Conclusion: PRG may modulate the oxidant–antioxidant system in brain tissue during LPS-induced systemic inflammation. Further studies are required to clarify its effects on the pancreas, spleen, and testicular tissues.

Anahtar Kelimeler

• Sepsis
• Pregabalin
• Oksidant-Antioksidant System

Destekleyen Kurum

Süleyman Demirel University Scientific Research Projects Coordination Unit

Proje Numarası

Project number: TM-2019-7407

Etik Beyan

Burdur Mehmet Akif Ersoy University Animal Experiments Local Ethics Committee (29.11.2023/1211)

Teşekkür

None

LPS kaynaklı sepsiste oksidan-antioksidan sistem değişiklikleri: Pregabalinin modülatör etkileri

Öz

Amaç: Bu çalışmanın amacı, lipopolisakkarit (LPS) ile indüklenen sepsis modelinde pregabalinin (PRG) oksidan–antioksidan sistem üzerindeki etkilerini beyin, pankreas, dalak ve testis dokularında araştırmaktır. Yöntem: Sıçanlar rastgele kontrol, LPS ve LPS+PRG olmak üzere üç gruba ayrıldı. Kontrol grubuna in-traperitoneal (i.p.) ve oral yolla eşdeğer hacimlerde salin uygulandı. LPS grubunda sepsis, 5 mg/kg dozunda i.p. LPS uygulanarak oluşturuldu. LPS+PRG grubuna, LPS uygulamasından 1 saat önce oral yolla 30 mg/kg pregabalin verildi; bunu takiben 1 saat sonra 5 mg/kg dozunda i.p. LPS uygulandı. Tüm hayvanlar, LPS uygulamasından 6 saat sonra sakrifiye edildi. Oksidan–antioksidan durumun değer-lendirilmesi amacıyla beyin, pankreas, dalak ve testis dokularında malondialdehit (MDA), katalaz (CAT) ve süperoksit dismutaz (SOD) düzeyleri ölçüldü. Bulgular: Beyin dokusunda PRG uygulanan grupta MDA düzeylerinin kontrol (p < 0.001) ve LPS (p = 0.029) gruplarına kıyasla istatistiksel olarak anlamlı derecede azaldığı saptandı. Kontrol grubuna kıyasla PRG uygulanan grupta CAT düzeyleri de anlamlı ölçüde azalırken (p = 0.040), LPS grubuna kıyasla istatistiksel açıdan anlamlı bir fark gözlenmedi (p = 0.240). Buna karşılık, SOD düzeyleri PRG uygulanan grupta hem kontrol hem de LPS gruplarına kıyasla istatistiksel olarak anlamlı düzeyde arttı (her iki karşılaştırma için p < 0.001). Pankreas, dalak ve testis dokularında ise istatistiksel olarak anlam-lı bir farklılık saptanmadı. Sonuç: PRG, LPS ile indüklenen sistemik inflamasyon sırasında beyin dokusundaki oksidan-antioksidan sistemini modüle edebilir. Pankreas, dalak ve testis dokuları üzerindeki olası etkilerinin aydınlatılabilmesi için daha ileri çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

• Sepsis
• Pregabalin
• Oksidan-Antioksidan Sistem

Destekleyen Kurum

Süleyman Demirel Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi

Proje Numarası

Project number: TM-2019-7407

Etik Beyan

Burdur Mehmet Akif Ersoy Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu (29.11.2023/1211)

Teşekkür

Yok

Kaynakça

1. Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci. 2019;20(21):5376. doi: 10.3390/ijms20215376.
2. Srzić I, Nesek Adam V, Tunjić Pejak D. Sepsis defini-tion: what's new in the treatment guidelines. Acta Clin Croat. 2022;61(Suppl 1):67-72. doi: 10.20471/acc.2022.61.s1.11.
3. Fleischmann C, Scherag A, Adhikari NK, et al. Interna-tional Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259-72. doi: 10.1164/rccm.201504-0781OC.
4. Rudd KE, Johnson SC, Agesa KM, et al. Global, region-al, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study. Lancet. 2020;395(10219):200-211. doi: 10.1016/S0140-6736(19)32989-7.
5. Mantzarlis K, Tsolaki V, Zakynthinos E. Role of oxida-tive stress and mitochondrial dysfunction in sepsis and potential therapies. Oxid Med Cell Longev. 2017;2017:5985209. doi: 10.1155/2017/5985209.
6. Kumar S, Gupta E, Kaushik S, et al. Evaluation of oxi-dative stress and antioxidant status: Correlation with the severity of sepsis. Scand J Immunol. 2018;87(4):e12653. doi: 10.1111/sji.12653.
7. Pan S, Lv Z, Wang R, et al. Sepsis-induced brain dys-function: pathogenesis, diagnosis, and treatment. Ox-id Med Cell Longev. 2022;2022:1328729. doi: 10.1155/2022/1328729.
8. Sekino N, Selim M, Shehadah A. Sepsis-associated brain injury: underlying mechanisms and potential therapeutic strategies for acute and long-term cogni-tive impairments. J Neuroinflammation. 2022;19(1):101. doi: 10.1186/s12974-022-02464-4.

9. Chaari A, Abdel Hakim K, Bousselmi K, et al. Pancreatic injury in patients with septic shock: A literature re-view. World J Gastrointest Oncol. 2016;8(7):526-31. doi: 10.4251/wjgo.v8.i7.526.
10. Hoover DB, Poston MD, Brown S, et al. Cholinergic leukocytes in sepsis and at the neuroimmune junction in the spleen. Int Immunopharmacol. 2020;81:106359. doi: 10.1016/j.intimp.2020.106359.
11. Wang H, Yang Y, Zhang X, et al. Liensinine attenuates inflammation and oxidative stress in spleen tissue in an LPS-induced mouse sepsis model. J Zhejiang Univ Sci B. 2023;24(2):185-190. doi: 10.1631/jzus.B2200340.
12. Doğanay S, Budak Ö, Toprak V, et al. Protective role of melatonin against testicular damage caused by polymicrobial sepsis in adult rats. Ulus Travma Acil Cerrahi Derg. 2022;28(6):723-729. doi: 10.14744/tjtes.2021.90575.
13. Pourmirzaei F, Ranjbaran M, Kadkhodaee M, et al. Sperm and testicular dysfunction during cecal ligation and puncture-induced sepsis in male rats and effects of tannic acid through reducing testicular oxidative stress and inflammation. Iran J Basic Med Sci. 2021;24(11):1554-1560. doi: 10.22038/IJBMS.2021.59375.13183.
14. Hong JSW, Atkinson LZ, Al-Juffali N, et al. Gabapen-tin and pregabalin in bipolar disorder, anxiety states, and insomnia: Systematic review, meta-analysis, and rationale. Mol Psychiatry. 2022;27(3):1339-1349. doi: 10.1038/s41380-021-01386-6.
15. Zhang Z, Jiang J, He Y, et al. Pregabalin mitigates microglial activation and neuronal injury by inhibit-ing HMGB1 signaling pathway in radiation-induced brain injury. J Neuroinflammation. 2022;19(1):231. doi: 10.1186/s12974-022-02596-7.
16. Ha KY, Carragee E, Cheng I, et al. Pregabalin as a neu-roprotector after spinal cord injury in rats: biochemi-cal analysis and effect on glial cells. J Korean Med Sci. 2011;26(3):404-11. doi: 10.3346/jkms.2011.26.3.404.
17. Zhang Y, Zhang C, Yi X, et al. Gabapentinoids for the treatment of stroke. Neural Regen Res. 2024;19(7):1509-1516. doi: 10.4103/1673-5374.387968.
18. Wu Y, Guo X, Zhang J. Calcium channel α2δ ligands mirogabalin, pregabalin, and gabapentin: Advance-ments in diabetic peripheral neuropathic pain thera-peutics. Pain Ther. 2025;14(6):1647-1686. doi: 10.1007/s40122-025-00771-1.
19. Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009;30(4):379-87. doi: 10.1038/aps.2009.24.
20. Ayaz G, Halici Z, Albayrak A, et al. Evaluation of 5-HT7 receptor trafficking on in vivo and in vitro model of lipopolysaccharide (LPS)- induced inflammatory cell injury in rats and LPS-treated A549 cells. Biochem Genet. 2017;55(1):34–47. doi: 10.1007/s10528-016-9769-2.
21. Meymandi MS, Sepehri G, Abdolsamadi M, et al. The effects of co-administration of pregabalin and vitamin E on neuropathic pain induced by partial sciatic nerve ligation in male rats. Inflammopharmacology. 2017;25(2):237–246. doi: 10.1007/s10787-017-0325-4.
22. Ben‐Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45(Suppl 6):13–18. doi: 10.1111/j.0013-9580.2004.455003.x.
23. Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 1990;186:421–431. doi: 10.1016/0076-6879(90)86135-I.
24. Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121-6. doi: 10.1016/S0076-6879(84)05016-3.
25. Woolliams JA, Wiener G, Anderson PH, et al. Varia-tion in the activities of glutathione peroxidase and superoxide dismutase and in the concentration of copper in the blood in various breed crosses of sheep. Res Vet Sci. 1983;34(3):253-6. doi: 10.1016/S0034-5288(18)32219-7.
26. Özdemir-Kumral ZN, Cumhur A, Oluk AI, et al. Nesfat-in-1 ameliorates sepsis-induced remote organ injury: The role of oxidant-antioxidant status and neutro-phils. Clin Exp Health Sci. 2018;8(3):175-181. doi: 10.5152/clinexphealthsci.2017.606.
27. Catalão CHR, Santos-Júnior NN, da Costa LHA, et al. Brain oxidative stress during experimental sepsis is attenuated by simvastatin administration. Mol Neuro-biol. 2017;54(9):7008-7018. doi: 10.1007/s12035-016-0218-3.
28. Aşcı S, Demirci S, Aşcı H, et al. Neuroprotective ef-fects of pregabalin on cerebral ischemia and reperfu-sion. Balkan Med J. 2016;33(2):221-7. doi: 10.5152/balkanmedj.2015.15742.
29. Evans JA, Mendonca P, Soliman KFA. Involvement of Nrf2 activation and NF-kB pathway inhibition in the antioxidant and anti-inflammatory effects of hes-peretin in activated BV-2 microglial cells. Brain Sci. 2023;13(8):1144. doi: 10.3390/brainsci13081144.
30. Abdelnaser M, Alaaeldin R, Attya ME, et al. Modulat-ing Nrf-2/HO-1, apoptosis and oxidative stress signal-ing pathways by gabapentin ameliorates sepsis-induced acute kidney injury. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(2):947-958. doi: 10.1007/s00210-023-02650-y.
31. Muñoz-Casares FC, Padillo FJ, Briceño J, et al. Mela-tonin reduces apoptosis and necrosis induced by is-chemia/reperfusion injury of the pancreas. J Pineal Res. 2006;40(3):195-203. doi: 10.1111/j.1600-079X.2005.00291.x.
32. Kar E, Alataş İÖ, Şahintürk V, et al. Early treatment with metformin decreases pancreatic damage in rats with LPS induced sepsis. Turkish Journal of Life Sci-ences. 2018;3(1):194-199.
33. Shi J, Wang Y, Zhang X, et al. Ameliorative effect of malvidin on spleen injury in LPS-induced sepsis. Chem Biodivers. 2023;20(8):e202201161. doi: 10.1002/cbdv.202201161.
34. Kumar J, Haldar C, Verma R. Melatonin ameliorates LPS-induced testicular nitro-oxidative stress (iN-OS/TNFα) and inflammation (NF-kB/COX-2) via mod-ulation of SIRT-1. Reprod Sci. 2021;28(12):3417-3430. doi: 10.1007/s43032-021-00597-0.
35. Alles SRA, Cain SM, Snutch TP. Pregabalin as a pain therapeutic: Beyond calcium channels. Front Cell Neu-rosci. 2020;14:83. doi: 10.3389/fncel.2020.00083.
36. Takahashi Y, Nishimura T, Higuchi K, et al. Transport of pregabalin via L-type amino acid transporter 1 (SLC7A5) in human brain capillary endothelial cell line. Pharm Res. 2018;35(12):246. doi: 10.1007/s11095-018-2532-0.
37. Walters GC, Usachev YM. Mitochondrial calcium cycling in neuronal function and neurodegeneration. Front Cell Dev Biol. 2023;11:1094356. doi: 10.3389/fcell.2023.1094356.