2023 Advances in clinical and experimental medicine : official organ Wroclaw Medical University Mechanism / Preclinical Saline / IV

2023 · Guo — Hydrogen suppresses oxidative stress by inhibiting the p38 MAPK signaling pathway in preeclampsia

Original title: Hydrogen suppresses oxidative stress by inhibiting the p38 MAPK signaling pathway in preeclampsia.

Super-Abstract

In a rat model of preeclampsia, hydrogen-rich saline significantly reduced inflammation markers, oxidative stress, and blood pressure-related damage — and the protective effect appears to work via inhibiting the p38 MAPK signaling pathway. This is an animal study in pregnant rats; the findings are mechanistically informative but cannot be directly applied to pregnant humans.

Classified as a Mechanism / Preclinical study using Saline / IV. See Methodology for how we grade evidence.

Commentary

Preeclampsia — a serious hypertensive complication of pregnancy characterized by high blood pressure and proteinuria — remains a major cause of maternal and fetal mortality worldwide, with limited therapeutic options. This study uses the well-established L-NAME rat model to induce preeclampsia-like conditions and tests hydrogen-rich saline (HRS) as a protective agent. The p38 MAPK pathway is a known mediator of inflammatory and oxidative stress responses, and the study elegantly dissects its role by comparing HRS treatment alone to HRS plus the p38 MAPK inhibitor SB203580. The results are coherent: HRS reduces TNF-α, IL-1β, MDA (a lipid peroxidation marker), systolic blood pressure, and proteinuria — effects partially overlapping with direct p38 inhibition. This mechanistic clarity is a strength. However, this is an animal model study, and preeclampsia in humans is considerably more complex than the L-NAME model captures; clinical translation would require human safety and efficacy data.

Key quotes

„hydrogen-rich saline (LH group) decreased placental MDA, proteinuria, TNF-α, and IL-1β levels in the placental tissues compared with the L group (all p < 0.05)“ — the main anti-inflammatory and antioxidant findings in the preeclampsia rat model
„hydrogen-rich saline (LH group) treatment significantly decreased the p38 MAPK mRNA expression and p-p38 MAPK protein levels compared with the L group (p < 0.05)“ — evidence that H₂ exerts its effect specifically via the p38 MAPK pathway
„The protective effect of hydrogen may be associated with the inhibition of the p38 MAPK signaling pathway.“ — the authors' mechanistic conclusion

Our assessment

This is an animal study (rat preeclampsia model) — its findings are mechanistically valuable but do not constitute evidence that hydrogen-rich saline is safe or effective in pregnant humans. The L-NAME rat model is a useful research tool but does not fully replicate human preeclampsia. The p38 MAPK mechanism identified is biologically plausible and consistent with H₂'s known anti-inflammatory properties. Any consideration of HRS in human pregnancy would require rigorous clinical safety evaluation — pregnant women are a highly protected population and the absence of human data here is a major limitation.

Study design

Type: animal study · Model: Sprague Dawley rats, L-NAME-induced preeclampsia · n: 5 groups (non-pregnant; normal pregnancy; L-NAME; L-NAME + HRS; L-NAME + HRS + SB203580) · H₂ delivery: hydrogen-rich saline (intravenous)
Result: HRS reduced placental MDA, TNF-α, IL-1β, proteinuria vs. L-NAME group (all p < 0.05); HRS decreased p38 MAPK mRNA and p-p38 protein; p38 inhibitor SB203580 further amplified this reduction; mechanism: H₂ protective effect linked to p38 MAPK pathway inhibition

Abstract

BACKGROUND: Hypertensive disorders complicating pregnancy (HDCP) are one of the most serious medical disorders during pregnancy. OBJECTIVES: To investigate the effects of hydrogen on the mitogen-activated protein kinase (MAPK) signaling pathway in preeclampsia (PE). MATERIAL AND METHODS: The N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced PE model with Sprague Dawley (SD) rats was employed. An inhibitor of MAPK signaling pathways (SB203580) was used as a p38 MAPK inhibitor. The SD rats were randomized into 5 groups: non-pregnant (NP); normal pregnancy (P); pregnancy + L-NAME (L); pregnancy + L-NAME + hydrogen-rich saline (LH); and pregnancy + L-NAME + hydrogen-rich saline + SB203580 (LHS). The pregnancies were terminated on day 22 of gestation, and the placentas and kidneys were microscopically inspected. Tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β) and malondialdehyde (MDA) levels were assessed. The mean systolic blood pressure (SBP) and level of proteinuria were recorded. The p38 MAPK mRNA expression and p-p38 MAPK protein levels were measured using real-time polymerase chain reaction (RT-PCR) and western blot, respectively. RESULTS: It was found that hydrogen-rich saline (LH group) decreased placental MDA, proteinuria, TNF-α, and IL-1β levels in the placental tissues compared with the L group (all p < 0.05). Additionally, hydrogen-rich saline (LH group) treatment significantly decreased the p38 MAPK mRNA expression and p-p38 MAPK protein levels compared with the L group (p < 0.05). The p38 MAPK inhibitor SB203580 (LHS group) further decreased the p38 MAPK mRNA expression and p-p38 MAPK protein levels compared with the LH group (p < 0.05). CONCLUSIONS: Hydrogen can decrease the reactive oxygen species (ROS) content and inhibit the MAPK pathway. The protective effect of hydrogen may be associated with the inhibition of the p38 MAPK signaling pathway.

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