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Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets.

Wang Z, Ma N, Riley J, Armstead WM, Liu R - PLoS ONE (2012)

Bottom Line: If occurring, it can result in severe neurologic disabilities that persist throughout life.After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group.Salvinorin A administration 0 and 30 min after HI preserves autoregulation of pial artery to hypercapnia and hypotension via kappa opioid receptor and ERK pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT

Background: Cerebral hypoxia/ischemia (HI) is not uncommon during the perinatal period. If occurring, it can result in severe neurologic disabilities that persist throughout life. Salvinorin A, a non-opioid Kappa opioid receptors (KOR) selective agonist, has the potential to address this devastating situation. We have demonstrated that salvinorin A administration before HI, preserves pial artery autoregulative function through both the KOR and extracellular signal-regulated kinases (ERK) pathways. In the present study, we tested the hypothesis that administration of salvinorin A after HI could preserve cerebral autoregulation via KOR and ERK pathway.

Methodology/principal findings: The response of the pial artery to hypercapnia, hypotension and isoproterenol were monitored before and 1 hour after HI in piglets equipped with a cranial window. Four groups of drug administration were performed after HI. The control group had DMSO (1 µl/kg, i.v.) administrated immediately after HI. Two salvinorin A treated groups had salvinorin A (10 µg/kg, i.v.) administrated 0 and 30 min after HI, respectively. The 4(th) group had salvinorin A and the KOR antagonist norbinaltorphimine (Nor-BIN, 1 µM topical) co-administrated 0 min after HI (n = 5). The dilation responses of the pial artery to hypercapnia and hypotension were impaired after global HI and were preserved with salvinorin A administration immediately or 30 min after HI. The preservation of autoregulation was abolished when nor-BIN was administered. Levels of phosphor-ERK(pERK)/ERK in the cerebrospinal fluid (CSF) were measured before and 1 hour after HI. After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group. The elevated levels of pERK/ERK were not observed with salvinorin A only groups.

Conclusions: Salvinorin A administration 0 and 30 min after HI preserves autoregulation of pial artery to hypercapnia and hypotension via kappa opioid receptor and ERK pathway.

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Related in: MedlinePlus

Isoproterenol induced artery dilation was independent of KOR or ERK signaling.Effects of isoproterenol (10 nM, 1 µM) on pial artery diameter before (baseline) and after HI did not change significantly in the presence and absence of various interventions, compared to baseline p>0.05. N = 5 in each group. Percentage change =  (diameter after isoproterenol−diameter before isoproterenol)/diameter before isoproterenol)*100; SA: Salvinorin A; Norbin: norbinaltorphimine.
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pone-0041724-g003: Isoproterenol induced artery dilation was independent of KOR or ERK signaling.Effects of isoproterenol (10 nM, 1 µM) on pial artery diameter before (baseline) and after HI did not change significantly in the presence and absence of various interventions, compared to baseline p>0.05. N = 5 in each group. Percentage change =  (diameter after isoproterenol−diameter before isoproterenol)/diameter before isoproterenol)*100; SA: Salvinorin A; Norbin: norbinaltorphimine.

Mentions: As a positive control, pial artery responses to isoproterenol (indicated in figure 3) were measured and no change was observed among all groups before and after HI.


Salvinorin A administration after global cerebral hypoxia/ischemia preserves cerebrovascular autoregulation via kappa opioid receptor in piglets.

Wang Z, Ma N, Riley J, Armstead WM, Liu R - PLoS ONE (2012)

Isoproterenol induced artery dilation was independent of KOR or ERK signaling.Effects of isoproterenol (10 nM, 1 µM) on pial artery diameter before (baseline) and after HI did not change significantly in the presence and absence of various interventions, compared to baseline p>0.05. N = 5 in each group. Percentage change =  (diameter after isoproterenol−diameter before isoproterenol)/diameter before isoproterenol)*100; SA: Salvinorin A; Norbin: norbinaltorphimine.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3404042&req=5

pone-0041724-g003: Isoproterenol induced artery dilation was independent of KOR or ERK signaling.Effects of isoproterenol (10 nM, 1 µM) on pial artery diameter before (baseline) and after HI did not change significantly in the presence and absence of various interventions, compared to baseline p>0.05. N = 5 in each group. Percentage change =  (diameter after isoproterenol−diameter before isoproterenol)/diameter before isoproterenol)*100; SA: Salvinorin A; Norbin: norbinaltorphimine.
Mentions: As a positive control, pial artery responses to isoproterenol (indicated in figure 3) were measured and no change was observed among all groups before and after HI.

Bottom Line: If occurring, it can result in severe neurologic disabilities that persist throughout life.After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group.Salvinorin A administration 0 and 30 min after HI preserves autoregulation of pial artery to hypercapnia and hypotension via kappa opioid receptor and ERK pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Critical Care, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT

Background: Cerebral hypoxia/ischemia (HI) is not uncommon during the perinatal period. If occurring, it can result in severe neurologic disabilities that persist throughout life. Salvinorin A, a non-opioid Kappa opioid receptors (KOR) selective agonist, has the potential to address this devastating situation. We have demonstrated that salvinorin A administration before HI, preserves pial artery autoregulative function through both the KOR and extracellular signal-regulated kinases (ERK) pathways. In the present study, we tested the hypothesis that administration of salvinorin A after HI could preserve cerebral autoregulation via KOR and ERK pathway.

Methodology/principal findings: The response of the pial artery to hypercapnia, hypotension and isoproterenol were monitored before and 1 hour after HI in piglets equipped with a cranial window. Four groups of drug administration were performed after HI. The control group had DMSO (1 µl/kg, i.v.) administrated immediately after HI. Two salvinorin A treated groups had salvinorin A (10 µg/kg, i.v.) administrated 0 and 30 min after HI, respectively. The 4(th) group had salvinorin A and the KOR antagonist norbinaltorphimine (Nor-BIN, 1 µM topical) co-administrated 0 min after HI (n = 5). The dilation responses of the pial artery to hypercapnia and hypotension were impaired after global HI and were preserved with salvinorin A administration immediately or 30 min after HI. The preservation of autoregulation was abolished when nor-BIN was administered. Levels of phosphor-ERK(pERK)/ERK in the cerebrospinal fluid (CSF) were measured before and 1 hour after HI. After HI, the pERK/ERK levels significantly increased in both DMSO control group and salvinorin A and nor-BIN co-administration group. The elevated levels of pERK/ERK were not observed with salvinorin A only groups.

Conclusions: Salvinorin A administration 0 and 30 min after HI preserves autoregulation of pial artery to hypercapnia and hypotension via kappa opioid receptor and ERK pathway.

Show MeSH
Related in: MedlinePlus