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Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia.

Lafuente H, Pazos MR, Alvarez A, Mohammed N, Santos M, Arizti M, Alvarez FJ, Martinez-Orgado JA - Front Neurosci (2016)

Bottom Line: Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult.Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio.The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult.

View Article: PubMed Central - PubMed

Affiliation: Neonatology Research Group, Biocruces Health Research Institute Bizkaia, Spain.

ABSTRACT
Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl-aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFα (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult.

No MeSH data available.


Related in: MedlinePlus

Mean arterial blood pressure and amplitude-integrated electroencephalography (aEEG) in experimental groups of piglets. Line draws represent the mean arterial blood pressure (A) and the mean aEEG (B), obtained from 1- to 2-day-old piglets after hypoxic-ischemic insult, treated with normothermia (shaded symbol) or hypothermia (empty symbol) and administered with either vehicle (square) or cannabidiol (triangle). Data are represented as mean ± SEM. (*) P < 0.05 vs. NV group by Kruskall-Wallis one-factorial analysis of variance; (**) P < 0.05 vs. both normothermic groups (NV and NC) by Kruskall-Wallis one-factorial analysis of variance; (***) P < 0.05 vs. all groups by Kruskall-Wallis one-factorial analysis of variance.
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Figure 1: Mean arterial blood pressure and amplitude-integrated electroencephalography (aEEG) in experimental groups of piglets. Line draws represent the mean arterial blood pressure (A) and the mean aEEG (B), obtained from 1- to 2-day-old piglets after hypoxic-ischemic insult, treated with normothermia (shaded symbol) or hypothermia (empty symbol) and administered with either vehicle (square) or cannabidiol (triangle). Data are represented as mean ± SEM. (*) P < 0.05 vs. NV group by Kruskall-Wallis one-factorial analysis of variance; (**) P < 0.05 vs. both normothermic groups (NV and NC) by Kruskall-Wallis one-factorial analysis of variance; (***) P < 0.05 vs. all groups by Kruskall-Wallis one-factorial analysis of variance.

Mentions: Normothermic and hypothermic sham operated groups of animals without HI are included in the Supplementary Materials. Piglets from all experimental groups were similar in terms of age, weight and physiological parameters (Table 1), except for mean arterial blood pressure and aEEG (Figure 1). The hypoxic-ischemic insult induced a decrease in pH in all injured animals (H interval, Table 1). After hypothermic therapy begins, pH levels significantly recovered toward baseline levels at the drug treatment (D interval, Table 1) in both HV and HC groups. At the end of experiment (E interval, Table 1), mean pH level in HC group was significantly higher than in the other groups. In normothermia-treated animals, the hypoxic-ischemic insult led to a decrease in mean arterial blood pressure that spontaneously recovered in the following 30 min.


Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia.

Lafuente H, Pazos MR, Alvarez A, Mohammed N, Santos M, Arizti M, Alvarez FJ, Martinez-Orgado JA - Front Neurosci (2016)

Mean arterial blood pressure and amplitude-integrated electroencephalography (aEEG) in experimental groups of piglets. Line draws represent the mean arterial blood pressure (A) and the mean aEEG (B), obtained from 1- to 2-day-old piglets after hypoxic-ischemic insult, treated with normothermia (shaded symbol) or hypothermia (empty symbol) and administered with either vehicle (square) or cannabidiol (triangle). Data are represented as mean ± SEM. (*) P < 0.05 vs. NV group by Kruskall-Wallis one-factorial analysis of variance; (**) P < 0.05 vs. both normothermic groups (NV and NC) by Kruskall-Wallis one-factorial analysis of variance; (***) P < 0.05 vs. all groups by Kruskall-Wallis one-factorial analysis of variance.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940392&req=5

Figure 1: Mean arterial blood pressure and amplitude-integrated electroencephalography (aEEG) in experimental groups of piglets. Line draws represent the mean arterial blood pressure (A) and the mean aEEG (B), obtained from 1- to 2-day-old piglets after hypoxic-ischemic insult, treated with normothermia (shaded symbol) or hypothermia (empty symbol) and administered with either vehicle (square) or cannabidiol (triangle). Data are represented as mean ± SEM. (*) P < 0.05 vs. NV group by Kruskall-Wallis one-factorial analysis of variance; (**) P < 0.05 vs. both normothermic groups (NV and NC) by Kruskall-Wallis one-factorial analysis of variance; (***) P < 0.05 vs. all groups by Kruskall-Wallis one-factorial analysis of variance.
Mentions: Normothermic and hypothermic sham operated groups of animals without HI are included in the Supplementary Materials. Piglets from all experimental groups were similar in terms of age, weight and physiological parameters (Table 1), except for mean arterial blood pressure and aEEG (Figure 1). The hypoxic-ischemic insult induced a decrease in pH in all injured animals (H interval, Table 1). After hypothermic therapy begins, pH levels significantly recovered toward baseline levels at the drug treatment (D interval, Table 1) in both HV and HC groups. At the end of experiment (E interval, Table 1), mean pH level in HC group was significantly higher than in the other groups. In normothermia-treated animals, the hypoxic-ischemic insult led to a decrease in mean arterial blood pressure that spontaneously recovered in the following 30 min.

Bottom Line: Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult.Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio.The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult.

View Article: PubMed Central - PubMed

Affiliation: Neonatology Research Group, Biocruces Health Research Institute Bizkaia, Spain.

ABSTRACT
Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl-aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFα (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult.

No MeSH data available.


Related in: MedlinePlus