Sport Physiology

Sport Physiology

The Effects of High-Intensity Interval Training on Inflammation and Oxidative Stress in Hippocampal Tissue of Rats with Heart Failure

Document Type : Research Paper

Authors
Fahimeh Fatahi 1
Abasali Gaeini 1
reza nuri 2
Alireza Ghardashi afoosi 1
Soheila Adeli 3
1 Department of Exercise Physiology, Faculty of Sport and Health Sciences, University of Tehran, Tehran, Iran
2 faculty of sports and sciences، university of Tehran ، Iran
3 Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Science, Tehran, Iran
10.22089/spj.2025.18371.2390
Abstract
Background and Purpose
Heart failure (HF) is a progressive condition characterized by systemic inflammation, neuroinflammation, and oxidative stress. Persistent inflammatory responses contribute to cognitive decline and impaired brain function in cardiovascular patients. Contributory factors include cerebral hypoperfusion, neurohumoral activation, systemic inflammation, hypertension, atherosclerosis, aging, and genetic predispositions. Chronic cerebral hypoperfusion leads to neuroinflammation, oxidative stress, and disruption of the blood-brain barrier (BBB). Loss of BBB integrity activates further inflammatory and oxidative stress pathways, exacerbating cognitive impairment. Sustained neuroinflammation is marked by elevated cytokines which impair the BBB and promote infiltration of peripheral macrophages into brain tissue, perpetuating inflammation. In HF animal models, increased expression of pro-inflammatory genes such as TLR-4, TNF-α, IL-1β, and IL-6 in the cerebral cortex and hippocampus compromises BBB structure and facilitates neuroinflammation. While physiological cytokine levels support synaptic plasticity and memory consolidation, excessive TNF-α and IL-1β stimulate microglial activation and apoptosis. Additionally, HF decreases hippocampal and cortical superoxide dismutase (SOD) activity, while elevating malondialdehyde (MDA) levels, indicating oxidative neuronal damage associated with cognitive impairments, depression, and anxiety.Exercise has emerged as a promising non-pharmacological strategy to mitigate cardiovascular and neuroinflammatory complications. Mechanistically, exercise attenuates neuroinflammation through modulation of microglial activation, NF-κB signaling, proinflammatory cytokines, mitochondrial function, and reactive oxygen species (ROS). Treadmill exercise enhances brain function by modifying gene expression, promoting neuroplasticity, increasing metabolic efficiency, and boosting antioxidant capacity. It maintains cerebral homeostasis by regulating microglial activity, proinflammatory cytokines, and neuroinflammation, thereby reducing risk of neurodegeneration. Zhang et al. demonstrated that exercise downregulated pro-inflammatory markers and upregulated anti-inflammatory factors in Alzheimer’s disease models, also reducing oxidative stress markers like MDA and enhancing SOD activity. Similarly, treadmill running in aged mice increased microglial activation while suppressing pro-inflammatory cytokine production, conferring neuroprotection. This study investigated the neuroprotective capacity of high-intensity interval training (HIIT) against neuroinflammation in HF rats. Due to its characteristics—brief, intense energy stimulation, recovery periods, and increased cerebral blood flow—HIIT may simultaneously enhance antioxidant defenses and reduce inflammatory responses.
Materials and Methods
Twenty-four male Wistar rats (8 weeks old, mean weight 250 ± 50 g) were housed under controlled conditions (22 ± 2°C, 12-hour light/dark cycle) with ad libitum access to food and water at the Faculty of Sport Sciences and Health animal facility. After one week of acclimatization, rats were allocated randomly into three groups: healthy control (H, n=8), sedentary HF (HF, n=8), and HF + HIIT (HFT, n=8). HF was induced by subcutaneous administration of isoproterenol (130 mg/kg) daily for four days. Cardiac function was confirmed by echocardiography performed by a veterinary specialist; rats with ejection fraction <45% and fractional shortening <35% were included. After a 25-day recovery period, HFT rats underwent an 8-week HIIT protocol (three 60-minute sessions weekly). Each session comprised a 5-minute warm-up at 40–50% VO₂max, followed by interval running on a zero-degree incline: four minutes at 85–90% VO₂max alternating with two minutes at 50–60% VO₂max, repeated for 30 minutes, concluding with a 5-minute cool-down at 40–50% VO₂max. Training intensity progressively increased by 0.02 m/s weekly, based on prior literature.Forty-eight hours after completing the last session and following a 12-hour fast, rats were anesthetized (ketamine/xylazine), and hippocampal tissues were harvested, snap-frozen in liquid nitrogen, and stored at −80°C. Levels of IL-1β, IL-10, SOD, and MDA were quantified by ELISA kits following manufacturer protocols. Data analysis employed SPSS 25. Normality was assessed by Shapiro-Wilk test; intergroup differences were examined using one-way ANOVA and Tukey’s post hoc test at P<0.05. Data are presented as mean ± standard error. GraphPad Prism was utilized for figure generation.
Results
HF significantly elevated hippocampal IL-1β and MDA while decreasing IL-10 and SOD compared to healthy controls (P<0.01). Following eight weeks of HIIT, the HFT group exhibited marked reductions in IL-1β and MDA alongside significant increases in IL-10 and SOD compared to the sedentary HF group (P<0.05). These findings indicate that HIIT effectively restores inflammatory balance and antioxidant capacity in HF-affected hippocampal tissue.
Conclusion
An eight-week HIIT regimen improves hippocampal inflammatory status by decreasing pro-inflammatory markers, enhancing anti-inflammatory cytokines, and augmenting antioxidant enzymes in rats with HF. Modulating neuroinflammation and oxidative stress through HIIT offers a potential non-pharmacological intervention to protect neural integrity in HF.
Article Message
HIIT represents an effective therapeutic modality to mitigate neuroinflammation and oxidative damage in the brain, particularly the hippocampus, in HF. By regulating cytokine expression and antioxidant defense, HIIT may attenuate HF-induced neural injury and improve cognitive resilience.
Ethical Considerations
This study was approved by the Research Ethics Committee of the Faculty of Sport and Health Sciences, University of Tehran (ethical code: IR.UT.SPORT.REC.1403.014). All experimental procedures conformed to national guidelines for laboratory animal care, with efforts to minimize pain and distress.
Authors’ Contributions
Conceptualization: Abbasali Gaeini, Alireza Ghardashi Afousi
Data Collection: Fahime Fatahi, Soheila Adeli
Data Analysis: Reza Nouri, Fahimeh Fatahi
Manuscript Writing: Fahimeh Fatahi, Alireza Ghardashi Afousi
Review and Editing: Fahimeh Fatahi, Abbasali Gaeini, Alireza Ghardashi Afousi
Funding Responsibility: Soheila Adeli, Fahimeh Fatahi
Literature Review: Reza Nouri, Fahimeh Fatahi
Project Management: Abbasali Gaeini, Alireza Ghardashi Afousi
Additional Contributions: Soheila Adeli
Conflict of Interest
The authors declare no conflicts of interest regarding this study.
Acknowledgments
We gratefully acknowledge Ms. Aida Sabouri for her valuable assistance with animal modeling.
 
Keywords
HIIT, Heart Failure, Neuroinflammation

Subjects

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Sport Physiology
Volume 17, Issue 68
Winter 2026
Pages 55-73

  • Receive Date 11 August 2025
  • Revise Date 25 August 2025
  • Accept Date 04 September 2025