Short-term effects of cannabidiol after global hypoxia-ischemia in newborn piglets

Garberg, Håvard Tetlie; Huun, Marianne Ullestad; Escobar, Javier; Martı́nez-Orgado, José; Løberg, E. M.; Solberg, Rønnaug; Saugstad, Ola Didrik

doi:10.1038/pr.2016.149

Cited by 33 publications

(40 citation statements)

References 39 publications

(61 reference statements)

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“…We recently studied the effects of CBD 1 mg/kg i.v. in a piglet model of global HI [10], and in contrast to previous studies in piglets [2,3,4,5] no neuroprotective effects were found in the early phase after HI. The hypoxic-ischemic insult in our model produces more severe multiorgan damage compared to these studies [2,3,4,5].…”

Section: Introductioncontrasting

confidence: 85%

“…However, these models did not induce severe global HI. Cardiovascular dysfunction in the current animal model is demonstrated by severe hypotension during HI, and in the recovery phase a degree of persistent hypotension and tachycardia, as well as significantly elevated plasma troponin T [10]. High-dose CBD did not induce cardiac arrhythmias or significant alterations in heart rate.…”

Section: Discussionmentioning

confidence: 99%

“…The animal model used has been extensively described previously [10]. Briefly, 22 newborn Noroc (LyxLD) pigs were exposed to HI by ventilation with a gas mixture of 8% O 2 in N 2 until either the mean arterial blood pressure (MABP) decreased to 20 mm Hg or the base excess reached −20 mmol/L.…”

Section: Methodsmentioning

confidence: 99%

“…After resuscitation, the piglets were randomized, by sealed envelopes, to treatment with high-dose CBD ( n = 13) or vehicle (VEH) ( n = 9). We have previously demonstrated a significant effect of HI on the parameters assessed in this study [10] and thus a nonhypoxic control group was not included in the current experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Even though intravenous CBD up to 100 mg/kg in animal models [16] and 30 mg/kg in humans [16,17] have been well tolerated, these studies did not involve global HI, which is known to induce cardiovascular dysfunction [18]. In piglets exposed to HI, the highest dose of CBD yet to be tested is 1 mg/kg i.v., and it did not produce unwanted cardiovascular effects [3,4,10]. …”

Section: Introductionmentioning

confidence: 99%

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High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets

Garberg

Solberg²,

Barlinn³

et al. 2017

Neonatology

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Background: Cannabidiol (CBD) is considered a promising neuroprotectant after perinatal hypoxia-ischemia (HI). We have previously studied the effects of CBD 1 mg/kg in the early phase after global HI in piglets. In contrast to prior studies, we found no evidence of neuroprotection and hypothesized that higher doses might be required to demonstrate efficacy in this animal model. Objective: To assess the safety and potential neuroprotective effects of high-dose CBD. Methods: Anesthetized newborn piglets underwent global HI by ventilation with 8% O₂ until the point of severe metabolic acidosis (base excess -20 mmol/L) and/or hypotension (mean arterial blood pressure ≤20 mm Hg). Piglets were randomized to intravenous treatment with vehicle (n = 9) or CBD (n = 13). The starting dose, CBD 50 mg/kg, was reduced if adverse effects occurred. The piglets were euthanized 9.5 h after HI and tissue was collected for analysis. Results: CBD 50 mg/kg (n = 4) induced significant hypotension in 2 out of 4 piglets, and 1 out of 4 piglets suffered a fatal cardiac arrest. CBD 25 mg/kg (n = 4) induced significant hypotension in 1 out of 4 piglets, while 10 mg/kg (n = 5) was well tolerated. A significant negative correlation between the plasma concentration of CBD and hypotension during drug infusion was observed (p < 0.005). Neuroprotective effects were evaluated in piglets that did not display significant hypotension (n = 9) and CBD did not alter the degree of neuronal damage as measured by a neuropathology score, levels of the astrocytic marker S100B in CSF, magnetic resonance spectroscopy markers (Lac/NAA and Glu/NAA ratios), or plasma troponin T. Conclusions: High-dose CBD can induce severe hypotension and did not offer neuroprotection in the early phase after global HI in piglets.

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Section: Introductioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets

Garberg

Solberg²,

Barlinn³

et al. 2017

Neonatology

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New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

et al. 2021

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Around 0.75 million babies worldwide suffer from moderate or severe hypoxic-ischemic encephalopathy (HIE) each year resulting in around 400,000 babies with neurodevelopmental impairment. In 2010, neonatal HIE was associated with 2.4% of the total Global Burden of Disease. Therapeutic hypothermia (TH), a treatment that is now standard of care in high-income countries, provides proof of concept that strategies that aim to improve neurodevelopment are not only possible but can also be implemented to clinical practice. While TH is beneficial, neonates with moderate or severe HIE treated with TH still experience devastating complications: 48% (range: 44–53) combined death or moderate/severe disability. There is a concern that TH may not be effective in low- and middle-income countries. Therapies that further improve outcomes are desperately needed, and in high-income countries, they must be tested in conjunction with TH. We have in this review focussed on pharmacological treatment options (e.g. erythropoietin, allopurinol, melatonin, cannabidiol, exendin-4/exenatide). Erythropoietin and allopurinol show promise and are progressing towards the clinic with ongoing definitive phase 3 randomised placebo-controlled trials. However, there remain global challenges for the next decade. Conclusion: There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials to avoid exposure to harmful medications or abandoning putative treatments. What is Known:• Therapeutic hypothermia is beneficial in neonatal hypoxic-ischemic encephalopathy.• Neonates with moderate or severe hypoxic-ischemic encephalopathy treated with therapeutic hypothermia still experience severe sequelae. What is New:• Erythropoietin, allopurinol, melatonin, cannabidiol, and exendin-4/exenatide show promise in conjunction with therapeutic hypothermia.• There is a need for more optimal animal models, greater industry support/sponsorship, increased use of juvenile toxicology, dose-ranging studies with pharmacokinetic-pharmacodynamic modelling, and well-designed clinical trials.

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Cannabinoid Analogue WIN 55212–2 Protects Paraquat-Induced Lung Injury and Enhances Macrophage M2 Polarization

Zhang

et al. 2022

Inflammation

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WIN 55212–2 is an endocannabinoids analogue that has been reported to have anti-inflammatory and anti-fibrosis effects on different models. In this study, we investigated the protective effects of WIN 55212–2 on paraquat (PQ)-induced poison on mice especially on lung injury. Mice were administrated with different dose of PQ and thereafter treated with 0.2 mg/kg or 1 mg/kg WIN 55212–2. The survival of mice was recorded during 4 weeks of observation. Twenty-eight days after PQ treatment, the cell population and inflammatory factors IL-6, IL-10, and TNF-α were measured in bronchoalveolar lavage fluid (BALF). Pulmonary fibrosis was evaluated by Masson staining. Our results showed that WIN 55212–2 treatment reduced PQ-induced mortality of mice in a dose dependent manner. It decreased the number of inflammation-associated cells, as well as the level of pro-inflammatory factors in BALF ( P < 0.05). WIN 55212–2 increased M2 cells in BALF ( P < 0.05), improved the lung histology, reduced fibrosis formation, and decreased TGF-β, α-SMA and PDGFRa expression. The protective effects of WIN 55212–2 on PQ-induced lung injury and fibrosis were associated with an increase inM2 cells and increased expressions of IL-10, CD163, and CD206, suggesting that polarization of M2 macrophages may be involved in WIN 55212–2 protective effects on PQ-induced lung injury.

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Short-term effects of cannabidiol after global hypoxia-ischemia in newborn piglets

Abstract: In contrast to previous studies, we do not find significant protective effects of CBD after HI in piglets. Evaluation of CBD in higher doses might be warranted.

Cited by 33 publications

References 39 publications

High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets

High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets

New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy

Cannabinoid Analogue WIN 55212–2 Protects Paraquat-Induced Lung Injury and Enhances Macrophage M2 Polarization

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