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Cannabidiol Protects the Neonatal Mouse Heart from Hyperoxia-Induced Injury
Teresa Hellberg1, Thomas Schmitz1, Christoph Bührer1
1Department of Neonatology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Insights
Cannabidiol (CBD) may protect preterm infants' hearts from oxygen-induced damage. Low-dose CBD (10 mg/kg) improved heart cell growth and structure, but higher doses were less effective. Sex differences influenced outcomes.
Area of Science:
- Neonatal physiology and cardiovascular development
- Pharmacology and therapeutic interventions
- Oxidative stress and inflammation research
Background:
- Neonatal hyperoxia causes oxidative stress, inflammation, and disrupts cardiac maturation, leading to long-term cardiovascular issues in preterm infants.
- Cannabidiol (CBD), a non-psychoactive compound, has shown organ protection in neonatal hyperoxia, but its cardiac effects are unknown.
- Understanding CBD's impact on the developing heart is crucial for potential therapeutic applications in preterm neonates.
Purpose of the Study:
- To investigate the cardioprotective effects of Cannabidiol (CBD) against hyperoxia-induced cardiac injury in a neonatal mouse model.
- To determine if CBD can mitigate oxidative stress, inflammation, apoptosis, and adverse cardiac remodeling caused by neonatal hyperoxia.
- To explore the dose-dependency and sex-specific effects of CBD in this neonatal injury model.
Main Methods:
- Neonatal mice were exposed to 80% oxygen from postnatal day 5-7, receiving vehicle or CBD (10 or 30 mg/kg) or kept in room air.
- Cardiac function, oxidative stress markers (Nrf2), inflammatory markers (IL1β, TNFα, IL6, CXCL1), apoptosis (Casp3, AIF), autophagy (Atg5, Atg12), and cardiomyocyte proliferation (Ki67) were assessed.
- Histological analysis evaluated cardiac remodeling, including hypertrophy and fibrosis, at postnatal day 7 and 14.
Main Results:
- Hyperoxia induced significant oxidative stress, inflammation, dysregulated apoptosis/autophagy, reduced cardiomyocyte proliferation, and adverse cardiac remodeling (hypertrophy, fibrosis).
- CBD treatment attenuated hyperoxia-induced inflammation and normalized autophagy. The 10 mg/kg dose preserved cardiomyocyte proliferation and reduced heart wall thickness.
- Both CBD doses reduced collagen deposition and apoptosis. Male mice showed more severe long-term impairments and responded better to low-dose CBD, indicating sex-specific effects.
Conclusions:
- Cannabidiol (CBD) demonstrates potential cardioprotective effects against neonatal hyperoxia-induced cardiac injury.
- A low dose of CBD (10 mg/kg) appears most effective, suggesting a narrow therapeutic window and highlighting dose-specific mechanisms.
- Sex-dependent responses to CBD underscore the complexity of early cardiac maturation and the need for personalized therapeutic strategies.
Abstract:
Neonatal hyperoxia induces oxidative and inflammatory stress that disrupts cardiac maturation and contributes to long-term cardiovascular morbidity in individuals born preterm. Cannabidiol (CBD), a non-psychoactive phytocannabinoid with antioxidant and anti-inflammatory properties, has demonstrated protective effects in neonatal hyperoxic injury in other organs; however, its impact on the developing heart remains unclear. This study investigated whether CBD mitigates hyperoxia-induced cardiac injury in a neonatal mouse model. Newborn mice were exposed to 80% O2 for 48 h from postnatal day (P)5 to P7 and received vehicle, 10 mg/kg CBD, or 30 mg/kg CBD intraperitoneally, while controls remained in room air. Hearts were collected at P7 or after recovery until P14. Hyperoxia triggered oxidative stress (Nrf2), inflammation (IL1β, TNFα, IL6, CXCL1; p < 0.05), and dysregulated apoptosis/autophagy, leading to reduced cardiomyocyte proliferation (Ki67+ -50% at P14; p < 0.01) and adverse remodeling (hypertrophy, fibrosis; p < 0.01). CBD attenuated these responses and normalized autophagy (Atg5, Atg12; p < 0.05). Notably, 10 mg/kg CBD, but not 30 mg/kg, preserved proliferative capacity and reduced wall thickness, suggesting a narrow therapeutic window, while both doses limited collagen deposition and apoptosis (Casp3, AIF; p < 0.05). Several effects were sex-dependent, with males exhibiting more pronounced long-term structural and proliferative impairments and greater responsiveness to low-dose CBD. These findings identify CBD as a potential cardioprotective modulator of neonatal hyperoxia-induced injury and highlight the importance of dose- and sex-specific mechanisms in early cardiac maturation.
