Neuroprotective effects of intermittent hypobaric hypoxia in rats: caspase-3, NT-3, SOD, and carbonyl profiles
DOI:
https://doi.org/10.25170/djm.v25i1.6554Keywords:
carbonyl, caspase-3, intermittent hypobaric hypoxia, NT-3, SODAbstract
Introduction: The brain is the largest energy-consuming organ in the body and is highly vulnerable to damage under hypoxic conditions. However, certain periods of hypoxia can be tolerated and provide protective effects. This study aimed to investigate the protective effects of intermittent hypobaric hypoxia (IHH) on the expression of caspase-3, neurotrophin-3, carbonyl, and superoxide dismutase (SOD) levels in rat brain tissues.
Methods: A total of 25 male Wistar rats were divided into five groups: a control group (normoxic conditions) and four treatment groups exposed to hypobaric hypoxia in a chamber simulating 25,000 feet altitude for 5 minutes at intervals of 7 days for each exposure. Group 1 was exposed to a one-time hypoxia condition (IHH 1), group 2 was exposed two times (IHH 2), group 3 was exposed three times (IHH 3), and group four were exposed four times (IHH 4).
Results: Caspase-3 levels significantly decreased in the treatment groups compared to the control group (p<0.05), indicating a positive response to IHH. In contrast, neurotrophin-3 and carbonyl levels showed no significant changes across the groups, maintaining a stable trend. Additionally, a significant increase in SOD levels was observed between group 1 and group 3 (p<0.05), suggesting enhanced antioxidant defense with repeated IHH exposure.
Conclusion: Intermittent hypobaric hypoxia can suggest a protective effect against hypoxic damage by suppressing caspase-3 expression. Repeated IHH exposure enhances antioxidant defense by elevating SOD levels. In contrast, neurotrophin-3 and carbonyl levels remain unchanged, suggesting these markers are unresponsive to short-term IHH.
Downloads
References
1. Tibbetts P. Fundamental neuroscience. Third edi-tion. Edited by Larry R Squire, Darwin Berg, Floyd E Bloom, Sascha du Lac, Anirvan Ghosh, and Nicholas C Spitzer. Q Rev Biol. 2009;84(1).
2. Semenov M. Proliferative capacity of adult mouse brain. Int J Mol Sci. 2021;22(7):3449.
3. Shi Q, Li S, Lyu Q, Zhang S, Bai Y, Ma J. Hypoxia inhibits cell cycle progression and cell proliferation in brain microvascular endothelial cells via the miR-212-3p/MCM2 axis. Int J Mol Sci. 2023;24(3):2788.
4. Dunn JF, Isaacs AM. The impact of hypoxia on blood-brain, blood-CSF, and CSF-brain barriers. J Appl Physiol (1985). 2021;131(3):977-85.
5. Kane AD, Kothmann E, Giussani DA. Detection and response to acute systemic hypoxia. BJA Educ. 2020;20(2):58-64.
6. Li G, Guan Y, Gu Y, Guo M, Ma W, Shao Q, et al. Intermittent hypoxic conditioning restores neurological dysfunction of mice induced by long-term hypoxia. CNS Neurosci Ther. 2023;29(1):202-15.
7. Coimbra-Costa D, Garzón F, Alva N, Pinto TCC, Aguado F, Torrella JR, et al. Intermittent hypobaric hypoxic preconditioning provides neuroprotection by increasing antioxidant activity, erythropoietin expression and preventing apoptosis and astrogliosis in the brain of adult rats exposed to acute severe hypoxia. Int J Mol Sci. 2021;22(10):5272.
8. Costa DC, Alva N, Trigueros L, Gámez A, Carbonell T, Rama R. Intermittent hypobaric hypoxia induces neuroprotection in kainate-induced oxidative stress in rats. J Mol Neurosci. 2013;50(3):402-10.
9. Wang H, Shi X, Schenck H, Hall JR, Ross SE, Kline GP, et al. Intermittent hypoxia training for treating mild cognitive impairment: A pilot study. Am J Alzheimers Dis Other Demen. 2020;35: 1533317519896725.
10. Coimbra-Costa D, Alva N, Duran M, Carbonell T, Rama R. Oxidative stress and apoptosis after acute respiratory hypoxia and reoxygenation in rat brain. Redox Biol. 2017;12:216-25.
11. Liu DB, Yang JS, Lu QB, Zhu ZF, Fang Q. Effect of NT-3 on infection-induced memory impairment of neonatal rats. Eur Rev Med Pharmacol Sci. 2019 Mar;23(5):2182-7.
12. Barh D, García-Solano ME, Tiwari S, Bhattacharya A, Jain N, Torres-Moreno D, et al. BARHL1 is downregulated in Alzheimer’s disease and may regulate cognitive functions through ESR1 and multiple pathways. Genes (Basel). 2017;8(10):245.
13. Lee KH, Cha M, Lee BH. Neuroprotective effect of antioxidants in the brain. Int J Mol Sci. 2020; 21(19):7152.
14. Martínez-Orgado J, Martínez-Vega M, Silva L, Romero A, de Hoz-Rivera M, Villa M, et al. Protein carbonylation as a biomarker of oxidative stress and a therapeutic target in neonatal brain damage. Antioxidants (Basel). 2023;12(10):1839.
15. Mudjihartini N, Paramita R, Siregar AMK, Filzadiyanti E, Sarsanti PAN, Purwaningsih E. Comparing the effect of Centella asiatica L. and Acalypha indica L. treatment to carbonyl and glutathione level in the brains of old rats. Acta Biochim Indones. 2022;5(1):79.
16. Reinhart RO. Basic flight physiology. 3rd ed. New York: McGraw-Hill Professional; 2007.
17. Triweda RH. Perubahan vaskularisasi otot jantung secara kuantitatif pada tikus Wistar yang mengalami hipoksia hipobarik intermiten = Quantitative vascularization changes of cardiac muscle in Wistar rats with intermittent hypobaric hypoxia [tugas akhir]. Jakarta: Fakultas Kedokteran Universitas Indonesia; 2018.
18. El-Khoury R, Bradford A, O’Halloran KD. Chronic hypobaric hypoxia increases isolated rat fast-twitch and slow-twitch limb muscle force and fatigue. Physiol Res. 2012;61(2):195-201.
19. Hidayat A, Wiradisastra K, Hernowo BS, Achmad TH. Effects of IHH exposures towards the heart by measuring LDH, caspase-3 expressions and lactic acid level. Maranatha J Med Health. 2010;10:61-8.
20. Imbriani P, Tassone A, Meringolo M, Ponterio G, Madeo G, Pisani A, et al. Loss of non-apoptotic role of caspase-3 in the PINK1 mouse model of Par-kinson’s disease. Int J Mol Sci. 2019;20(14):3407.
21. Mudjihartini N, Paramita R, Prijanti AR, Sarsanti PAN, Fadilah F, Purwaningsih EH. The effects of Centella asiatica and Acalypha indica L. extracts on aging process. Res J Pharm Technol. 2020;13(2):787-90.
22. Hollville E, Deshmukh M. Physiological functions of non-apoptotic caspase activity in the nervous system. Semin Cell Dev Biol. 2018;82:127-36.
23. Nakajima YI, Kuranaga E. Caspase-dependent non-apoptotic processes in development. Cell Death Differ. 2017;24(8):1422-30.
24. Dewi S, Mulyawan W, Wanandi SI, Sadikin M. The effect of intermittent hypobaric hypoxia on oxidative stress status and antioxidant enzymes activity in rat brain. Acta Biochim Indones. 2018;1(2):46-51.
25. Wardaya W, Sukmawati D, Ibrahim N, Ferdinal F, Mudjihartini N, Sadikin M, et al. Intermittent exposure to hypobaric hypoxia increases VEGF, HIF-1α, and Nrf-2 expressions in brain tissue. Indones Biomed J. 2025;17(2):197-206.
26. Dewi S, Wanandi SI, Jusman SW. Manganese superoxide dismutase gene expression in rats’ heart, brain, and blood induced by systemic hypoxia [thesis]. Jakarta: Fakultas Kedokteran Universitas Indonesia; 2008.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Damianus Journal of Medicine

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.








