14 research outputs found
High-Dose Cannabidiol Induced Hypotension after Global Hypoxia-Ischemia in Piglets
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
DHA and therapeutic hypothermia in a short-term follow-up piglet model of hypoxia-ischemia: Effects on H+MRS biomarkers
<div><p>Background</p><p>Therapeutic hypothermia has become the standard of care for newborns with hypoxic-ischemic encephalopathy in high and middle income countries. Docosahexaenoic acid (DHA) has neuroprotective properties of reducing excitotoxicity, neuroinflammation and apoptosis in rodent models. We aim to study whether post hypoxic administration of i.v. DHA will reduce H<sup>+</sup>MRS biomarkers and gene expression of inflammation and apoptosis both with and without hypothermia in a large animal model.</p><p>Methods</p><p>Fifty-five piglets were randomized to severe global hypoxia (N = 48) or not (Sham, N = 7). Hypoxic piglets were further randomized by factorial design: Vehicle (VEH), DHA, VEH + Hypothermia (HT), or DHA + HT. 5 mg/kg DHA was given intravenously 210 min after end of hypoxia. Two-way ANOVA analyses were performed with DHA and hypothermia as main effects.</p><p>Results</p><p>Cortical lactate/N-acetylaspartate (Lac/NAA) was significantly reduced in DHA + HT compared to HT. DHA had significant main effects on increasing N-acetylaspartate and glutathione in hippocampus. Therapeutic hypothermia significantly reduced the Lac/NAA ratio and protein expression of IL-1β and TNFα in hippocampus and reduced Troponin T in serum. Neuropathology showed significant differences between sham and hypoxia, but no differences between intervention groups.</p><p>Conclusion</p><p>DHA and therapeutic hypothermia significantly improve specific H<sup>+</sup>MRS biomarkers in this short-term follow up model of hypoxia-ischemia. Longer recovery periods are needed to evaluate whether DHA can offer translational neuroprotection.</p></div
The Cannabinoid Receptor Agonist Win 55,212-2 Reduces the Initial Cerebral Damage After Hypoxic-Ischemic Injury in Fetal Lambs
The aim of the present work was to evaluate in an early time point the effect of the cannabinoid agonist WIN 55,212-2 after hypoxic–ischemic (HI) brain injury induced by partial occlusion of the umbilical cord of premature fetal lambs. Lambs were assigned to three experimental groups: one SHAM group: non-injured animals, and two hypoxic–ischemic groups that received a dose of 0.01 μg/kg WIN 55,212-2 (HI + WIN group) or not (HI +VEH) after 60 min of a hypoxic–ischemic event. All animals were managed on mechanical ventilation for 3 h and then sacrificed. Brains were perfusion-fixed and different regions separated for regional cerebral blood flow measurement, apoptosis quantification by TUNEL method and S-100 protein analysis by flow cytometry. The number of apoptotic cells was lower in the HI + WIN group in all regions studied. Moreover, animals treated with the cannabinoid agonist showed higher values in the percentage of S-100 positive cells in all regions, except in the cortex. In both studies we obtained similar values between SHAM group and HI + WIN group. Our results suggest that the administration of the cannabinoid agonist WIN 55,212-2 after hypoxic–ischemic brain injury in preterm lambs decreases brain injury reducing the delayed cell death and glial damage
Experimental design.
<p>Fifty-five piglets underwent anesthesia and instrumentation for continuous monitoring of blood pressure, saturation, heart rate and rectal temperature. 48 piglets were subjected to hypoxia-ischemia (HI) by 8% O<sub>2</sub> on the endotracheal tube until severe acidosis (arterial base excess (BE) -20 mmol/l) and/or hypotension (mean arterial blood pressure <20 mm Hg). After reoxygenation with room air, piglets were randomized to one out of four intervention groups by factorial design: i) Vehicle (VEH) (N = 12), ii) DHA (N = 12), iii) VEH + Hypothermia (HT) (N = 12) and iiii) DHA + HT (N = 12). Hypothermia was started immediately after this second randomization. DHA was given 210 minutes after the end of hypoxia and piglets were euthanized 9.5 hours after the end of hypoxia.</p
The Cannabinoid Receptor Agonist Win 55,212-2 Reduces the Initial Cerebral Damage After Hypoxic-Ischemic Injury in Fetal Lambs
The aim of the present work was to evaluate in an early time point the effect of the cannabinoid agonist WIN 55,212-2 after hypoxic–ischemic (HI) brain injury induced by partial occlusion of the umbilical cord of premature fetal lambs. Lambs were assigned to three experimental groups: one SHAM group: non-injured animals, and two hypoxic–ischemic groups that received a dose of 0.01 μg/kg WIN 55,212-2 (HI + WIN group) or not (HI +VEH) after 60 min of a hypoxic–ischemic event. All animals were managed on mechanical ventilation for 3 h and then sacrificed. Brains were perfusion-fixed and different regions separated for regional cerebral blood flow measurement, apoptosis quantification by TUNEL method and S-100 protein analysis by flow cytometry. The number of apoptotic cells was lower in the HI + WIN group in all regions studied. Moreover, animals treated with the cannabinoid agonist showed higher values in the percentage of S-100 positive cells in all regions, except in the cortex. In both studies we obtained similar values between SHAM group and HI + WIN group. Our results suggest that the administration of the cannabinoid agonist WIN 55,212-2 after hypoxic–ischemic brain injury in preterm lambs decreases brain injury reducing the delayed cell death and glial damage
Physiology of the intervention groups throughout the experiment.
<p>Physiology of the intervention groups throughout the experiment.</p
Biomarkers in CSF and blood.
<p>S100B in CSF was significantly increased in VEH + HT compared to VEH (p = 0.035). In serum, Troponin T was significantly decreased in groups treated with therapeutic hypothermia compared to normothermia (p = 0.018, two-way ANOVA). Dotted line representing mean value in sham piglets.</p
DHA and therapeutic hypothermia in a short-term follow-up piglet model of hypoxia-ischemia: Effects on H+MRS biomarkers - Fig 5
<p><b>Protein expression from a) prefrontal cortex and b) hippocampus</b>. In cortex, DHA significantly increased IL-1β. In hippocampus, IL-1β was significantly reduced in both DHA and VEH + HT compared to VEH. Dotted line representing mean value in sham piglets. * p<0.05.</p
H<sup>+</sup>MRS biomarkers in hippocampus.
<p>N-acetylaspartate (NAA) was significantly increased in the DHA treated groups. Lac/NAA and Glu/NAA were significantly reduced in the hypothermia treated piglets. Dotted line representing mean value in sham piglets.</p