Isoflurane Post-Treatment Ameliorates GMH-Induced Brain Injury in Neonatal Rats

Leitzke, Arthur; Rolland, William; Krafft, Paul R.; Lekic, Tim; Klebe, Damon; Flores, Jerry; Allen, Nicole R. Van; Zhang, Junyi

doi:10.1161/strokeaha.113.001988

Cited by 14 publications

(12 citation statements)

References 15 publications

(15 reference statements)

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“…General anesthesia is associated with metabolic changes in various organs, including both upregulation and suppression of apoptosis [ 24 – 27 ]. In addition, general anesthetics typically protect many organs [ 28 ], but are neurotoxic in some cases [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Propofol elicits autophagy via endoplasmic reticulum stress and calcium exchange in C2C12 myoblast cell line

Chen

Jiang

et al. 2018

PLoS ONE

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In this study, we investigated the relationship between propofol and autophagy and examined whether this relationship depends on ER stress, production of ROS (reactive oxygen species), and disruption of calcium (Ca2+) homeostasis. To this end, we measured C2C12 cell apoptosis in vitro, along with Ca2+ levels; ROS production; and expression of proteins and genes associated with autophagy, Ca2+ homeostasis, and ER stress, including LC3 (microtubule-associate protein 1 light chain 3), p62, AMPK (adenosine 5’-monophosphate (AMP)-activated protein kinase), phosphorylated AMPK, mTOR (the mammalian target of rapamycin), phosphorylated mTOR, CHOP (C/BEP homologous protein), and Grp78/Bip (78 kDa glucose-regulated protein). We found that propofol treatment induced autophagy, ER stress, and Ca2+ release. The ratio of phosphorylated AMPK to AMPK increased, whereas the ratio of phosphorylated mTOR to mTOR decreased. Collectively, the data suggested that propofol induced autophagy in vitro through ER stress, resulting in elevated ROS and Ca2+. Additionally, co-administration of an ER stress inhibitor blunted the effect of propofol.

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Section: Resultsmentioning

confidence: 99%

Propofol elicits autophagy via endoplasmic reticulum stress and calcium exchange in C2C12 myoblast cell line

Chen

Jiang

et al. 2018

PLoS ONE

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“…Both male and female pups were used, as previously reported (Leitzke et al . ; Klebe et al . ; Manaenko et al .…”

Section: Discussionmentioning

confidence: 99%

“… reported GMH was associated with reduced cerebral expression of sphingosine kinases 1 and 2 (Leitzke et al . ), the enzymes responsible for phosphorylating sphingosine to S1P (Spiegel and Milstien ). While, S1PR1 is expressed ubiquitously in the body, S1PR1 is enriched in the germinal matrix of fetuses and premature infants (Braun et al .…”

Section: Discussionmentioning

confidence: 99%

Fingolimod confers neuroprotection through activation of Rac1 after experimental germinal matrix hemorrhage in rat pups

Rolland

Krafft

Lekic

et al. 2017

Journal of Neurochemistry

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Fingolimod, a sphingosine-1-phosphate receptor (S1PR) agonist, is clinically available to treat multiple sclerosis and is showing promise in treating stroke. We investigated if fingolimod provides long-term protection from experimental neonatal germinal matrix hemorrhage (GMH), aiming to support a potential mechanism of acute fingolimod-induced protection. GMH was induced in P7 rats by infusion of collagenase (0.3 U) into the right ganglionic eminence. Animals euthanized at four weeks post-GMH received low or high dose fingolimod (0.25 or 1.0 mg/kg) or vehicle, and underwent neurocognitive testing before histopathological evaluation. Subsequently, a cohort of animals euthanized at 72 hours post-GMH received 1.0 mg/kg fingolimod; the specific S1PR1 agonist, SEW2871; or fingolimod co-administered with the S1PR1/3/4 inhibitor, VPC23019, or the Rac1 inhibitor, EHT1864. All drugs were injected intraperitoneally 1, 24, and 48 hours post-surgery. At 72 hours post-GMH, brain water content, extravasated Evans blue dye, and hemoglobin were measured as well as the expression levels of phospho-Akt, Akt, GTP-Rac1, Total-Rac1, ZO1, occludin, and claudin-3 determined. Fingolimod significantly improved long-term neurocognitive performance and ameliorated brain tissue loss. At 72 hours post-GMH, fingolimod reduced brain water content and Evans blue dye extravasation as well as reversed GMH-induced loss of tight junctional proteins. S1PR1 agonism showed similar protection, whereas S1PR or Rac1 inhibition abolished the protective effect of fingolimod. Fingolimod treatment improved functional and morphological outcomes after GMH, in part, by tempering acute post-hemorrhagic blood-brain barrier disruption via the activation of the S1PR1/Akt/Rac1 pathway.

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“…General anesthesia is associated with metabolic changes in various organs with reports documenting both upregulation and suppression of apoptosis. 8–10 While many general anesthetics exert protective effect on many organs, 11 it shows neurotoxic effect in some cases. 12 Given that autophagy pathway interacts with apoptotic and cytoprotective signaling, it seems important to examine the role of anesthesia on autophagy.…”

Section: Introductionmentioning

confidence: 99%

Anesthesia with Disuse Leads to Autophagy Up-regulation in the Skeletal Muscle

Kashiwagi

Hosokawa

Maeyama³

et al. 2015

Anesthesiology

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Background It has been known that skeletal muscles show atrophic changes after prolonged sedation or general anesthesia. Whether these effects are due to anesthesia itself or to disuse during anesthesia has not been fully clarified. Autophagy dysregulation has been implicated in muscle wasting conditions. This study tested the hypothesis that the magnitude of skeletal muscle autophagy is affected by both anesthesia and immobility. Methods The extent of autophagy was analyzed chronologically during general anesthesia. In vivo microscopy was performed using green fluorescent protein-tagged LC3 for detection of autophagy using sternomastoid muscles of live mice during pentobarbital anesthesia (n = 6 to 7). Western blotting and histological analyses were also conducted on tibialis anterior muscles (n = 3 to 5). To distinguish the effect of anesthesia from that due to disuse, autophagy was compared between animals anesthetized with pentobarbital and those immobilized by short-term denervation without continuation of anesthesia. Conversely, tibialis anterior and sternomastoid muscles were electrically stimulated during anesthesia. Results Western blots and microscopy showed time-dependent autophagy upregulation during pentobarbital anesthesia, peaking at 3 h (728.6+/− 93.5% of basal level, mean +/−SE). Disuse by denervation without sustaining anesthesia did not lead to equivalent autophagy, suggesting that anesthesia is essential to causes autophagy. In contrast, contractile stimulation of the tibialis anterior and sternomastoid muscles significantly reduced the autophagy upregulation during anesthesia (85% at 300 min). Ketamine, Ketamine plus xylazine, isoflurane, and propofol also upregulated autophagy. Conclusions Short-term disuse without anesthesia does not lead to autophagy, but anesthesia with disuse leads to marked upregulation of autophagy.

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Isoflurane Post-Treatment Ameliorates GMH-Induced Brain Injury in Neonatal Rats

Cited by 14 publications

References 15 publications

Propofol elicits autophagy via endoplasmic reticulum stress and calcium exchange in C2C12 myoblast cell line

Propofol elicits autophagy via endoplasmic reticulum stress and calcium exchange in C2C12 myoblast cell line

Fingolimod confers neuroprotection through activation of Rac1 after experimental germinal matrix hemorrhage in rat pups

Anesthesia with Disuse Leads to Autophagy Up-regulation in the Skeletal Muscle

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