EFFECTS OF NF-ΚB AND NRF2 MODULATORS ON REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCTION IN RAT HEARTS FOLLOWING SURGICAL TRAUMA UNDER PROLONGED STRESS
R.M. Ryabushko, V.O. Kostenko
- Poltava State Medical University, Ukraine
DOI: https://doi.org/10.15407/fz71.02.051

Abstract
This study is of great relevance due to the growing interest
in understanding the mechanisms underlying cardiovascular
complications following surgery and trauma, particularly in
the context of posttraumatic stress disorder. A commonly used
experimental model for the latter is single prolonged stress
(SPS). This study investigated the effects of transcription
factor modulators – specifically, ammonium pyrrolidinium
dithiocarbamate, an inhibitor of NF-κB activation, and sul-
foraphane, an Nrf2 inducer, on the production of reactive
oxygen species (ROS) and nitrogen species (RNS) in the rat
heart following surgical trauma under the influence of SPS.
Experimental design: twenty-eight adult male Wistar rats were
divided into four groups, group 1 was the control group (intact
animals), while the others were subjected to laparotomy and
SPS. The rats were administered isotonic sodium chloride
solution (control II), ammonium pyrrolidine dithiocarbamate
(76 mg/kg), and sulforaphane (10 mg/kg) via gavage for 7
days. The results demonstrated that surgical trauma under SPS
resulted in a significant increase in superoxide anion radical
(O₂⁻•) production in the heart driven by microsomal mono-
oxygenases, nitric oxide synthase (NOS), the mitochondrial
respiratory chain, and NADPH oxidase of leukocyte. There
was also an increase in both total and inducible NOS activ-
ity, a disruption in the coupling of its constitutive isoforms
(cNOS), and a rise in peroxynitrite concentration. Ammonium
pyrrolidinium dithiocarbamate and sulforaphane reduced O ₂⁻•
generation by 41.7% and 37.2%, respectively, mitochondrial
respiratory chain activity by 27.6% and 18.7%, and leukocyte
NADPH oxidase activity by 32.3% and 24.1%. Inducible NOS
activity also decreased by 30.6% and 51.9%. Sulforaphane
significantly increased the cNOS coupling index by 130%,
while ammonium pyrrolidinium dithiocarbamate showed no
significant effect. In conclusion, both compounds reduce ROS
and RNS production in the heart, with sulforaphane enhancing
cNOS coupling, thereby preventing the enzyme from shifting
towards O₂⁻• formation.
Keywords:
transcription factors NF-κB and Nrf2; ammonium pyrrolidinium dithiocarbamate; sulforaphane; prolonged stress; post-traumatic stress disorder; reactive oxygen and nitrogen species; NO synthase; heart.
References
- Karatzias T, Shevlin M, Ben-Ezra M, McElroy E, Redican E, Vang ML, Cloitre M, Ho GWK, Lorberg B, Martsenkovskyi D, Hyland P. War exposure, posttrauma tic stress disorder, and complex posttraumatic stress disorder among parents living in Ukraine during the Russian war. Acta Psychiatr Scand. 2023 Mar;147(3):276-85.
CrossRef
PubMed
- Ben-Ezra M, Mor-Ben-Ishai S, Hamama-Raz Y , Bachem R, Leshem E, Levin Y . The association between negative war-related beliefs and probable PTSD and complex PTSD among Ukrainians during the 2022 Russian invasion. Psychiatr Res. 2024 Sep;339:116051.
CrossRef
PubMed
- Mellon SH, Gautam A, Hammamieh R, Jett M, Wolkowitz OM. Metabolism, metabolomics, and inflammation in posttraumatic stress disorder. Biol Psychiatr. 2018 May 15;83(10):866-75.
CrossRef
PubMed
- Hori H, Kim Y . Inflammation and post-traumatic stress disorder. Psychiatr Clin Neurosci. 2019 Apr;73(4):143-53.
CrossRef
PubMed
Al-Makhamreh H, Alkhulaifat D, Al-Ani A, Mafrachi B, Saadeh A, Al-Ani H, Bani Hani A, AlRyalat SA. The impact of war-related stress on coronary artery disease severity in war survivors: A SYNTAX study. Int J Environ Res Publ Health. 2021 Mar 21;18(6):3233. Вплив модуляторів транскрипційних факторів NF-κB і Nrf2 на продукцію активних форм кисню та азоту в серці щурів 57
CrossRef
PubMed PubMedCentral
- Sun Y , Qu Y , Zhu J. The relationship between inflammation and post-traumatic stress disorder. Front Psychiatr. 2021 Aug 11;12:707543.
CrossRef
PubMed PubMedCentral
- Kozaeva R, Klymenko MO, Katrushov OV, Kostenko VO. Bioflavonoids as agents for correcting nitrooxidative stress and salivary gland functions in rats exposed to alcohol during modeled lipopolysaccharideinduced systemic inflammatory response. Wiad Lek. 2022;75(3):685-90.
CrossRef
PubMed
- Frenkel Y , Cherno V , Kostenko H, Chopra H, Gautam RK, Kostenko V . Dietary supplementation with resveratrol attenuates serum melatonin level, pro-inflammatory response and metabolic disorder in rats fed high-fructose high-lipid diet under round-the-clock lighting. Pathophysiology. 2023 Feb;30(1):37-47.
CrossRef
PubMed PubMedCentral
- Ryabushko RM, Boyarska ZO, Kostenko VO. Laparotomy enhances reactive nitrogen species production in rat heart after reproduction of single prolonged stress. Probl Ekol Med. 2023;27(5-6):26-30.
CrossRef
- Jomova K, Raptova R, Alomar SY , Alwasel SH, Nepovi-mova E, Kuca K, Valko M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol. 2023 Oct;97(10):2499-574.
CrossRef
PubMed PubMedCentral
- Akimov OY , Kostenko VO. Role of NF-κB transcriptional factor activation during chronic fluoride intoxication in development of oxidative-nitrosative stress in rat's gastric mucosa. J Trace Elem Med Biol. 2020 Apr 19;61:126535.
CrossRef
PubMed
- Redondo A, Chamorro PAF, Riego G, Leánez S, Pol O. Treatment with sulforaphane produces antinociception and improves morphine effects during inflammatory pain in mice. J Pharmacol Exp Ther. 2017 Dec;363(3):293-302.
CrossRef
PubMed
- Serova LI, Tillinger A, Alaluf LG, Laukova M, Keegan K, Sabban EL. Single intranasal neuropeptide Y infusion attenuates development of PTSD-like symptoms to traumatic stress in rats. Neuroscience. 2013 Apr 16;236:298-312.
CrossRef
PubMed
- Souza RR, Noble LJ, McIntyre CK. Using the single prolonged stress model to examine the pathophysiology of PTSD. Front Pharmacol. 2017 Sep 11;8:615.
CrossRef
PubMed PubMedCentral
- Taran OV, Solovyova NV, Kostenko VO. Effect of laparotomy and lipopolysaccharide-induced systemic inflammatory response on metabolic disorders in rats. Fiziol Zh. 2022;68(3):35-43. [Ukrainian].
CrossRef
- Kostenko VO, Tsebrzhins'kii OI. Production of super-oxide anion radical and nitric oxide in renal tissues sutured with different surgical suture material. Fiziol Zh. 2000;46(5):56-62. [Ukrainian].
- Dell'Oste V , Fantasia S, Gravina D, Palego L, Betti L, Dell'Osso L, Giannaccini G, Carmassi C. Metabolic and inflammatory response in post-traumatic stress disorder (PTSD): A systematic review on peripheral neuroimmune biomarkers. Int J Environ Res Publ Health. 2023 Feb 8;20(4):2937.
CrossRef
PubMed PubMedCentral
- Cusack B, Buggy DJ. Anaesthesia, analgesia, and the surgical stress response. BJA Educ. 2020 Sep;20(9):321-8.
CrossRef
PubMed PubMedCentral
- Dmytriv TR, Tsiumpala SA, Semchyshyn HM, Storey KB, Lushchak VI. Mitochondrial dysfunction as a possible trigger of neuroinflammation at post-traumatic stress disorder (PTSD). Front Physiol. 2023 Oct 24;14:1222826.
CrossRef
PubMed PubMedCentral
- V ourc'h M, Roquilly A, Asehnoune K. Trauma-induced damage-associated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient. Front Immunol. 2018 Jun 15;9:1330.
CrossRef
PubMed PubMedCentral
- Li W, Jin K, Luo J, Xu W, Wu Y , Zhou J, Wang Y , Xu R, Jiao L, Wang T, Yang G. NF-κB and its crosstalk with endoplasmic reticulum stress in atherosclerosis. Front Cardiovascul Med. 2022 Sep 20;9:988266.
CrossRef
PubMed PubMedCentral
- Rezaee A, Rahmanian P, Nemati A, Sohrabifard F, Karimi F, Elahinia A, et al. NF-ĸB axis in diabetic neuropathy, cardiomyopathy and nephropathy: A roadmap from molecular intervention to therapeutic strategies. Heliyon. 2024 Apr 18;10(9):e29871.
CrossRef
PubMed PubMedCentral
- Sadek KM, Mahmoud SFE, Zeweil MF, Abouzed TK. Proanthocyanidin alleviates doxorubicin-induced cardiac injury by inhibiting NF-kB pathway and modulating oxidative stress, cell cycle, and fibrogenesis. J Biochem Mol Toxicol. 2021 Apr;35(4):e22716.
CrossRef
PubMed
- Adoga JO, Channa ML, Nadar A. Type-2 diabetic rat heart: The effect of kolaviron on mTOR-1, P70S60K, PKC-α, NF-kB, SOD-2, NRF-2, eNOS, AKT-1, ACE, and P38 MAPK gene expression profile. Biomed Pharmacother. 2022 Apr;148:112736.
CrossRef
PubMed
- Frenkel YD, Cherno VS, Kostenko VO. Nrf2 induction alleviates metabolic disorder and systemic inflammatory response in rats under a round-the-clock lighting and high-carbohydrate-lipid diet. Rom J Diabet Nutr Metab Dis. 2022;29(2):194-201.
- Frenkel' YuD, Cherno VS, Kostenko VO. Effect of NF-κB and Nrf2 transcription factor modulators on indicators of oxidative-nitrosative stress in skeletal muscles of rats under chronic hypomelatoninemia and carbohydrate-lipid diet. Fiziol Zh. 2023;69(2):11-8. [Ukrainian].
CrossRef
- Ibrahim Fouad G. Sulforaphane, an Nrf-2 Agonist, modulates oxidative stress and inflammation in a rat model of cuprizone-induced cardiotoxicity and hepatotoxicity. Cardiovascul Toxicol. 2023 Jan;23(1):46-60.
CrossRef
PubMed PubMedCentral
- Gebhart V, Reiß K, Kollau A, Mayer B, Gorren ACF. Site and mechanism of uncoupling of nitric-oxide synthase: Uncoupling by monomerization and other misconceptions. Nitric Oxide. 2019 Aug 1;89:14-21.
CrossRef
PubMed
- Stachon T, Latta L, Seitz B, Szentmáry N. Hypoxic stress increases NF-κB and iNOS mRNA expression in normal, but not in keratoconus corneal fibroblasts. Graefes Arch Clin Exp Ophthalmol. 2021 Feb;259(2):449-58.
CrossRef
PubMed PubMedCentral
- Ignarro LJ, Freeman B, eds. Nitric Oxide: Biology and Pathobiology; 3rd ed. Academic Press; 2017.
|