Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane‑induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways

  • Authors:
    • Li‑Yan Wang
    • Zhi‑Jun Tang
    • Yu‑Zeng Han
  • View Affiliations

  • Published online on: August 4, 2016     https://doi.org/10.3892/mmr.2016.5586
  • Pages: 3403-3412
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Millions of infants and children are exposed to anesthesia every year during medical care. Sevoflurane is a volatile anesthetic that is frequently used for pediatric anesthesia. However, previous reports have suggested that the administration of sevoflurane promotes neurodegeneration, raising concerns regarding the safety of its usage. The present study aimed to investigate caffeic acid phenethyl ester (CAPE) and its protective effect against sevoflurane‑induced neurotoxicity in neonatal rats. Rat pups were administered with CAPE at 10, 20 or 40 mg/kg body weight from postnatal day 1 (P1) to P15. The P7 rats were exposed to sevoflurane (2.9%) for 6 h. Control group rats received no sevoflurane or CAPE. Neuronal apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick‑end labeling assay. The expression levels of caspases (caspase‑3, ‑8 and ‑9), apoptotic pathway proteins [Bcl‑2‑associated X protein (Bax), B cell CCL/lymphoma 2 (Bcl‑2), Bcl‑2‑like 1 (Bcl‑xL), Bcl‑2‑associated agonist of cell death (Bad) and phosphorylated (p)‑Bad], mitogen‑activated protein kinases (MAPK) signaling pathway proteins [c‑Jun N‑terminal kinase (JNK), p‑JNK, extracellular signal‑regulated kinase (ERK)1/2, p‑ERK1/2, p38, p‑p38 and p‑c‑Jun] and the phosphoinositide 3‑kinase (PI3K)/Akt cascade were evaluated by western blotting following sevoflurane and CAPE treatment. In addition, the expression of cleaved caspase‑3 was analyzed by immunohistochemistry. CAPE significantly reduced sevoflurane‑induced apoptosis, downregulated the expression levels of caspases and pro‑apoptotic proteins (Bax and Bad) and elevated the expression levels of Bcl‑2 and Bcl‑xL when compared with sevoflurane treatment. Furthermore, CAPE appeared to modify the expression levels of MAPKs and activate the PI3K/Akt signaling pathway. Thus, the present study demonstrated that CAPE effectively inhibited sevoflurane‑induced neuroapoptosis by modulating the expression and phosphorylation of apoptotic pathway proteins and MAPKs, and by regulating the PI3K/Akt pathway.

Introduction

Volatile anesthetics are frequently used during pediatric surgery (1). Sevoflurane [2,2,2-trifluoro-1-(trifluoromethyl) ethyl fluoro methyl ether] is widely administered as a general anesthetic in pediatric patients, due to its fast induction and recovery times, and it causes less irritation to the airways compared with other inhaled anesthetics (2). Accumulating evidence indicates that volatile anesthetics induce neuronal apoptosis (36) and affect neurogenesis in vitro and in vivo (7,8). Furthermore, long-term neurocognitive function was observed to be altered in 7 day-old rats (9).

Children aged <4 years that were exposed to general anesthesia more than once have an increased risk of developing learning disabilities (10,11). Although sevoflurane is not as cytotoxic as isoflurane and desflurane, sevoflurane exposure increases the risk of neurodevelopmental impairments and cognitive dysfunction in neonatal animal models (1214).

The various mechanisms that underlie anesthetic-mediated neuronal apoptosis in the evolving brain are yet to be fully determined and numerous potential mechanisms have been proposed, including: i) Disruption of intracellular calcium homeostasis (1517); ii) regulation of the cell cycle (18); iii) inhibition of N-methyl-D-aspartate receptors and activation of gamma-aminobutyric acid receptors; and iv) associated impairment of synaptogenesis (1922).

Mitogen-activated protein kinases (MAPKs) are a group of serine-threonine protein kinases that are important during neurogenesis (23), neurodegeneration (24) and brain inflammation (25). The major members of the MAPK family are c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 MAPK. Previous studies have demonstrated an association between MAPK signaling pathways and neurotoxicity induced by anesthetics. Wang et al (26) reported that N-stearoyl-l-tyrosine protects the developing brain against sevoflurane-induced neurotoxicity by regulating the ERK1/2 signaling pathway. Furthermore, dexmedetomidine was demonstrated to regulate the phosphorylation levels of ERK1/2 in the neonatal rat brain (27) and provided neuroprotection against isoflurane-induced neurodegeneration in the hippocampus of neonatal rats by modulating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway (28). Zhao et al (29) reported that isoflurane causes neurodegeneration via apoptosis through excessive activation of inositol 1,4,5-trisphosphate receptors (InsP3Rs).

Strategies to potentially reduce the anesthetic-induced neurotoxicity require further research. Previous investigations focused on using plant-derived compounds for the therapy of various medical conditions. Resveratrol, a phenolic antioxidant present in grapes and berries, was demonstrated to protect neuronal cells from isoflurane-induced cytotoxicity by regulating the Akt signaling cascade (30). Caffeic acid phenethyl ester (CAPE) is a phenolic chemical compound present in numerous plants and is extracted from honeybee hive propolis (31). It is a strong antioxidant (32), and also exhibits anti-proliferative (33) and anti-inflammatory effects (32,34). Furthermore, the neuroprotective effects of CAPE in in vivo and in vitro experimental models have been demonstrated (3537).

Thus, considering the biological effects of CAPE, the present study aimed to investigate whether CAPE protects against sevoflurane-induced neurotoxicity in a neonatal rat model.

Materials and methods

Study animals

The present study was approved by the animal care and ethical committee of Linyi People's Hospital (Linyi, China) and was performed in accordance with the National Institutes of Health Guide for the Use of Laboratory Animals. A total of 30 pregnant female Sprague-Dawley rats from Guangdong Medical Laboratory Animal Center (Foshan, China), were used in the present study. The animals were housed in individual cages at ~22±1°C, and had access to water and food ad libitum. The rats were observed closely for the day of birth [postnatal day 0 (P0)]. The rat pups had access to water ad libitum and were maintained under a 12-h light/dark cycle at ~22±1°C. The treatment group rat pups received CAPE (10, 20 or 40 mg/kg body weight) orally each day along with standard diet from P1 to P15.

Chemicals and antibodies

Sevoflurane and CAPE were purchased from Sigma-Aldrich (St. Louis, MO, USA). Fluoro-Jade C (0.001%) was obtained from EMD Millipore (Billerica, MA, USA). Primary antibodies against activated caspase-3 (cat. no. sc-7149), -8 (cat. no. sc-56070), -9 (cat. no. sc-7885), B cell CCL/lymphoma 2 (Bcl-2; cat. no. 509), Bcl-2-associated agonist of cell death (Bad; cat. no. sc-8044), Bcl-2-like 1 (Bcl-xL; cat. no. sc-7195), Bcl-2-associated X protein (Bax; cat. no. sc-493), phosphorylated (p)-Bad (cat. no. sc-101640), β-actin (cat. no. sc-69879; Santa Cruz Biotechnology, Inc., Dallas, TX, USA), Akt (cat. no. 2920), p-Akt (cat. no. 4060), glycogen synthase kinase 3β (GSK3β; cat. no. 9315), p-GSK3β (cat. no. 9323), phosphatase and tensin homolog (PTEN; cat. no. 9556), JNK (cat. no. 9252), p-JNK (cat. no. 9255), p-c-Jun (cat. no. 2361), ERK1/2 (cat. no. 4615), p-ERK1/2 (cat. no. 4377), p38 (cat. no. 9228) and p-p38 (cat. no. 9215; Cell Signaling Technology, Inc., Danvers, MA, USA) were used in the current study. All chemicals used in this study were of analytical grade and procured from Sigma-Aldrich unless specified.

Anesthesia exposure

At P7, groups of rat pups were exposed to sevoflurane (2.9%). The pups were retained in a humid chamber with total gas flow 2 l/min, using 25% O2 as the carrier. Anesthetic agent fractions and O2 were measured using a Capnomac Ultima gas analysis system (GE Health-care Life Sciences, Chalfont, UK). During anesthetic exposure, the pups were placed on a warm mat at 38±1°C. Neonatal rats were assigned to receive 2.9% sevoflurane for 6 h in 30% O2 (38). On P7 the rats were administered with CAPE (10, 20 or 40 mg/kg body weight) 1 h prior to sevoflurane exposure. The control group received no anesthesia or CAPE. The anesthetic control group received only anesthesia and were not treated with CAPE. At the end of the study period, the animals (n=6 per group) were anesthetized with sodium thiopenthal (100 mg/kg; Sigma-Aldrich) and were sacrificed after 25–30 min of thiopental injection. Samples of hippocampal tissue were excised for analysis of apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and protein expression by western blotting.

Measurement of plasma S100 calcium binding protein β (S100β) by enzyme-linked immunosorbent assay (ELISA)

The S100 family of dimeric cytosolic calcium binding proteins are expressed in astroglial and Schwann cells. The β isomer of S100 is released into the extracellular space upon tissue injury and enters the serum through the blood brain barrier following mild brain injury, trauma, ischemia, hypoxia and exposure to neurotoxins (39). The levels of plasma S100β in neonatal rats were evaluated using a Sangtec 100 ELISA kit (DiaSorin S.P.A., Gerenzano, Italy) according to the manufacturer's instructions. Briefly, 50 µl plasma from each pup was added to a well of the 96-well plate and mixed with 150 µl tracer from the kit, and incubated for ~2 h. Following incubation, 3,3′,5,5′tetramethylbenzidine substrate and stop solution were added and the solution was mixed well. The optical density was measured at 450 nm using a Bio-Rad iMark microplate absorbance reader (Bio-Rad Laboratories, Inc., Hercules, CA, USA) (40).

Measurement of apoptosis by TUNEL assay

TUNEL assay was performed to assess neuronal apoptosis, as described previously by Li et al (6). Briefly, P7 rat pups exposed to sevoflurane were sacrificed and the brain tissues were excised. The sections were immersed in 10% buffered formalin for 15 min at room temperature. Tissues were post-fixed for 48 h at 4°C, embedded in paraffin and sections (5 µm) were used for the assay. A TUNEL fluorescent assay was performed using the fluorometric TUNEL system kit (Promega Corporation, Madision, WI, USA). The brain tissue slides were protected from direct light and the nuclei were stained using 2 µg/ml Hoechst for 10 min. TUNEL-positive cells in the hippocampal dentate gyrus (DG), CA1 and CA3 regions were analyzed in 10 fields using the NIS-Elements BR image processing and analysis software (Nikon Corporation, Tokyo, Japan).

Immunohistochemical analysis of cleaved caspase-3

Apoptosis was analyzed by immunohistochemical analysis of cleaved caspase-3 levels, as previously described by Li et al (41). Briefly, the brain tissue sections were incubated with anti-cleaved caspase-3 primary antibody at 4°C overnight, followed by biotin-conjugated secondary antibody treatment (1:200; cat. no. sc-2040; Santa Cruz Biotechnology, Inc.) for ~40 min at room temperature. The sections were subsequently incubated with avidin-biotinylated peroxidase complex (Vectastain ABC kit; Vector Laboratories, Inc., Burlingame, CA, USA) for 40 min then stained with 3,3′-diaminobenzidine (Vector Laboratories, Inc.). The sections were observed using an IX70 microscope (Olympus Corporation, Tokyo, Japan) with 6 randomly chosen fields imaged per slide.

Immunoblotting

Hippocampi were isolated from the rat pups immediately following exposure to sevoflurane then used for western blotting as described previously (5,6). The protein concentrations within the samples were determined using bicinchoninic acid protein assay (Bio-Rad Laboratories, Inc.). Protein samples (60 µg) were separated by SDS-PAGE and electrotransferred to nitrocellulose membranes, then incubated with primary antibodies (1:1,000). The positive reactive bands were detected by Amersham ECL enhanced chemiluminescence western blotting detection kit (GE Healthcare Life Sciences). The blots were scanned using Image Master II scanner (GE Healthcare Life Sciences) and densities analyzed using Image Quant TL software (version 2003.03; GE Health-care Life Sciences). The band densities were normalized to those of β-actin using anti-β-actin antibody. Western blotting was repeated six times for quantification.

Statistical analysis

The experimental data are presented as the mean ± standard deviation, obtained from three or six individual experiments. The values were subjected to one-way analysis of variance followed by post-hoc Duncan's multiple range test using SPSS software (version 21.0; IBM SPSS, Armonk, NY, USA). P<0.05 was considered to indicate a statistically significant difference.

Results

CAPE inhibits plasma S100β levels

Previous studies have demonstrated that neuroapoptosis of the neonatal brain increases following exposure to inhaled or intravenous anesthetic agents (7,42,43). S100β, the β isomer of S100, has previously been identified as a valuable biomarker for detecting anesthetic-induced neurodegeneration (40,44). In the present study sevoflurane (2.9%) caused ~4-fold increase in S100β levels, however administration of CAPE caused a significant decrease in the plasma levels of S100β (Fig. 1). Supplementation with 40 mg CAPE exerted a more potent effect on the plasma S100β levels than the lower doses (P<0.05).

CAPE effectively inhibits sevoflurane-induced neurodegeneration

Anesthetics have been shown to induce significant neuronal apoptosis in the developing brain (4,7). In the current study, a 6 h exposure to sevoflurane increased the number of TUNEL-positive cells in the hippocampi of P7 rat pups; the increase was greatest in CA1, followed by DG then CA3 (P<0.05; Fig. 2). Furthermore, CAPE administration significantly decreased the number of TUNEL-positive cells in the hippocampi of the rat pups (P<0.05). The CA1 region of the hippocampus exhibited a higher number of apoptotic cells when compared with the DG and CA3 regions (P<0.05).

Activated caspase-3 is commonly used as a biomarker for anesthesia-induced apoptosis (7,45). Zheng et al (46) demonstrated significant neural degeneration in the hippocampus following exposure to 1% sevoflurane. Thus, the present study examined the number of caspase-positive cells following sevoflurane and CAPE exposure. Consistent with the S100β level results, sevoflurane exposure significantly increased the number of caspase-3-positive cells in the hippocampal regions of the neonatal rats compared with the control. Administration of CAPE (10, 20 or 40 mg) resulted in a significant decrease in the number of caspase-positive cells in a dose-dependent manner (P<0.05; Fig. 3).

Furthermore, after 6 h exposure to inhaled sevoflurane (2.9%), the expression levels of the pro-apoptotic proteins, caspase-3, -8 and -9, were significantly upregulated compared with control levels (P<0.05; Fig. 4), as demonstrated by western blot analysis. Compared with those of the control, the expression levels of Bad and Bax were significantly increased by sevoflurane (P<0.05). Sevoflurane reduced the expression levels of anti-apoptotic proteins, Bcl-2 and Bcl-xL, when compared with control levels (P<0.05; Fig. 4). CAPE treatment significantly downregulated the expression of caspases, and Bax and Bad compared with sevoflurane treatment (P<0.05), whereas the expression levels of Bcl-xL and Bcl-2 were increased (P<0.05). This indicated that CAPE may exert its anti-apoptotic effects by modulating the expression of caspases and apoptotic pathway proteins.

Neuroprotection by CAPE involves the JNK, ERK and p38 signaling pathways

To further investigate the molecular mechanisms associated with neuroprotection by CAPE, the expression of MAPK family proteins (JNK, ERK1/2 and p38 MAPK) were examined. Previous studies have demonstrated that JNK, ERK1/2 and p38 are involved in dexmedetomidine-induced neuroprotection (41,47,48). The present study demonstrated that the levels of p-JNK and p-p38 kinases were significantly upregulated following sevoflurane exposure compared with control (P<0.05; Fig. 5). However, the sevoflurane-increased ERK1/2 levels were not as high as the JNK levels. In addition to the enhanced expression of JNK, the levels of p-c-Jun were increased compared with the control (P<0.05). CAPE significantly downregulated the expression of p-JNK, p-ERK and p-p38, and reduced the expression of p-c-Jun compared with the sevoflurane group (P<0.05). Furthermore, CAPE significantly downregulated the expression levels of total JNK, ERK1/2 and p38 when compared with sevoflurane treatment. However, comparatively, CAPE exhibited a less potent effect on ERK1/2 and p-ERK1/2 levels compared with JNK and p38. These results indicated that the MAPK signaling pathway is involved in CAPE-mediated neuroprotection.

PI3K/Akt signaling pathway is involved in neuroprotection of neonatal brain cells by CAPE

The mechanisms involved in inhalational anesthetic-induced neuronal apoptosis in neonatal brains have been widely investigated. The current study evaluated the affect of sevoflurane on PI3K/Akt signaling pathway proteins. The PI3K/Akt/mechanistic target of rapamycin signaling pathway is important for regulating the cell cycle, and previous reports have demonstrated that InsP3Rs and variations in intracellular calcium homeostasis are involved in anesthesia-induced neurodegeneration (29,49). Sevoflurane exposure significantly reduced the levels of Akt and p-Akt (P<0.05; Fig. 6). Additionally, a significant decrease in the expression levels of GSK3β and p-GSK3β levels were observed following 6 h of exposure to sevoflurane compared with the control (P<0.05; Fig. 6). CAPE supplementation downregulated the PI3K/Akt signaling pathway, as demonstrated by a significant increase in Akt expression levels and enhanced GSK3β expression (P<0.05). Additionally, PTEN expression levels were observed to be enhanced by CAPE treatment compared with groups exposed to sevoflurane only (P<0.05), suggesting that activation of the PI3K/Akt pathway is involved in neuroprotection.

Discussion

Growing experimental data have reported that widespread neuroapoptosis occurs in developing brain cells following early exposure to commonly used general anesthetics (10,11,50,51). Volatile anesthetic, sevoflurane, has previously been demonstrated to induce apoptotic neurodegeneration in the developing rat brain and to cause persistent learning/memory deficits (12,52).

Cell death by apoptosis is a vital aspect of normal brain maturation that leads to the elimination of 50–70% of progenitor cells and neurons during development (53,54). However, neuronal apoptosis exceeding this natural apoptotic rate is triggered by various pathologic conditions, including hypoxia, ischemia or prolonged anesthetic exposure (55,56). Accordingly, the current study examined the level of neuronal apoptosis in the hippocampi of P7 rats exposed to 6 h of sevoflurane anesthesia.

The expression of cleaved caspase-3 expression, a validated marker of cell death, was measured to detect apoptosis. Caspase-3, an aspartate-specific cysteine protease, is an important executioner protein of the apoptosis pathway (57). In the present study, immunohistochemistry and western blot analysis demonstrated that sevoflurane exposure leads to a increase in the protein expression of cleaved caspase-3 in the hippocampus. Neuronal apoptosis was more severe in the CA1 region than the CA3 and DG regions, as detected by immunohistochemistry and TUNEL assay. These findings were consistent with those of previous studies (12,13,38). Furthermore, the expression levels of initiator caspases (caspase-8 and -9) were observed to be enhanced by sevoflurane exposure. Previous studies have demonstrated an association between anesthetic-induced apoptosis and elevated plasma S100β levels, which could potentially be used as a neurodegenerative biomarker for brain damage following various types of stress (40,44). In accordance with previous reports, sevoflurane exposure caused a significant increase in plasma S100β levels. Downregulation of the apoptotic cell counts and the expression of caspases (caspase-3, -8 and -9) by CAPE, suggests that CAPE suppresses sevoflurane-induced apoptosis.

The balance between the anti-apoptotic (Bcl-2 and Bcl-xL) and pro-apoptotic (Bad and Bax) Bcl-2 family proteins regulates cell survival and death (58). Bad is activated through phosphorylation (59) by proto-oncogene proteins c-Akt that subsequently leads to the binding of Bad with 14-3-3, a cytosolic protein, and causes the release of anti-apoptotic protein, Bcl-xL. Bcl-xL binds to Bax and consequently inhibits apoptosis (60,61). Thus, Bcl-xL and Bcl-2 block Bax translocation to the mitochondria and maintain the mitochondrial membrane potential to prevent subsequent apoptosis (61). The enhanced expression of Bad and Bax following sevoflurane exposure observed in the current study suggests that the apoptosis rate is elevated by sevoflurane, which correlates with suppression of Bcl-xl and Bcl-2. Bcl-xL, expressed extensively in the central nervous system (CNS), enriches cell survival by maintaining mitochondrial membrane integrity and reducing cytochrome complex release (58). An anesthesia combination containing nitrous oxide, isoflurane and midazolam has previously been reported to downregulate Bcl-xL, leading to neurotoxicity (62). In the present study, CAPE, at 10-, 20- and 40-mg doses, increased neuronal cell survival, which was demonstrated by the upregulation of anti-apoptotic proteins and significant inhibition of Bax and Bad expression levels.

The PI3K/Akt intracellular signaling pathway is associated with cellular quiescence, proliferation, cell survival and cancer. Activated PI3K phosphorylates and activates Akt, localizing it to the plasma membrane (63). The PI3K/Akt signaling pathway is crucial in the decision between cell proliferation and renewal, as opposed to differentiation and quiescence. The pathway is antagonized by various factors, including PTEN (64) GSK3β (63) and homeobox gene Hb9 (65). Upon activation, Akt inhibits apoptosis via phosphorylation of Bad and GSK3β (66,67). Previous reports suggest a potential link between Akt and JNK signaling, and Akt signaling is reported to be involved in the apoptotic effect of JNK (68). Furthermore, a selective JNK inhibitor, SP600125 (67) was demonstrated to exhibit neuroprotective effects (69,70).

In the present study, sevoflurane exposure inhibited the activation of Akt and upregulated the expression levels of PTEN. In addition, sevoflurane reduced the level of p-GSK3β and p-Akt, which promote the apoptosis of neuronal cells. CAPE potentially activates the PI3K/Akt signaling pathway by significantly increasing the expression and phosphorylation of Akt and GSK3β. Silencing the InsP3R was previously demonstrated to inhibit isoflurane-induced neuroapoptosis (29), potentially contributing to the inhibition of neuroapoptosis by this mechanism. However, this hypothesis requires further validation.

Furthermore, PTEN levels were suppressed by CAPE, contributing to the effect of CAPE on the PI3K/Akt signaling cascade. PTEN inhibition has previously been reported to promote neuroprotection following CNS injury (71). Thus, inhibition of PTEN expression, which was demonstrated in the current study, may also contribute to the neuroprotective effects of CAPE.

JNK signaling is associated with neuronal apoptosis activated by various stimuli that cause brain injury, including ischemia/reperfusion and ethanol (7274). Previous studies have demonstrated that the JNK signaling pathway is activated in isoflurane-induced neuronal apoptosis (6). SP600125, a JNK inhibitor, prevented the phosphorylation of c-Jun, a substrate of JNK, and neuroapoptosis induced by isoflurane (6,75). In the present study, sevoflurane increased the levels of p-JNK and p-c-Jun in the hippocampi of P7 rats, suggesting that the JNK signaling pathway is activated in sevoflurane-induced neuronal apoptosis. Expression of ERK1/2 and its phosphorylated forms, was also enhanced marginally by sevoflurane. CAPE downregulated the expression levels of JNK and ERK1/2 in a dose-dependent manner, indicating that the effects of CAPE may involve the JNK and ERK signaling pathways.

Previous reports have demonstrated that the p38 MAPK signaling pathway is involved in anesthetic-induced neurodegeneration (76) and that p38 is enhanced in isoflurane-induced neuronal apoptosis (75). In the current study, CAPE prevented the sevoflurane-induced increase in p-p38 expression levels, suggesting that the p38 signaling pathway is involved in the neuroprotective effect of CAPE. Treatment with dexmedetomidine and p38 MAPK inhibitor, SB203580 was previously demonstrated to decrease the expression level of p-p38, suggesting that the p38 signaling pathway is also involved in the neuroprotective effects of dexmedetomidine (75).

In conclusion, the observations of the current study indicate that CAPE inhibits sevoflurane-induced neuronal apoptosis in the neonatal rat brain via modulating the expression of caspases and regulating the critical pathways involved in neuronal apoptosis, including the JNK/ERK/p38 MAPK and PI3K/Akt signaling pathways. Thus, CAPE may be a potential candidate for reducing anesthetic-induced neurotoxicity. However, further investigations using specific JNK/ERK and Akt, and studies on the apoptotic pathway inhibitors are required to assess the neuroprotective effects of CAPE.

References

1 

Istaphanous GK and Loepke AW: General anesthetics and the developing brain. Curr Opin Anesthesiol. 22:368–373. 2009. View Article : Google Scholar

2 

Patel SS and Goa KL: Sevoflurane: A review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anaesthesia. Drugs. 51:658–700. 1996. View Article : Google Scholar : PubMed/NCBI

3 

Johnson SA, Young C and Olney JW: Isoflurane-induced neuroapoptosis in the developing brain of nonhypoglycemic mice. J Neurosurg Anesthesiol. 20:21–28. 2008. View Article : Google Scholar

4 

Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, Dissen GA, Creeley CE and Olney JW: Isoflurane-induced neuroapoptosis in theneonatal rhesus macaque brain. Anesthesiology. 112:834–841. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Li Y, Liu C, Zhao Y, Hu K, Zhang J, Zeng M, Luo T, Jiang W and Wang H: Sevoflurane induces short-term changes in proteins in the cerebral cortices of developing rats. Acta Anaesthesiol Scand. 57:380–390. 2013. View Article : Google Scholar

6 

Li Y, Wang F, Liu C, Zeng M, Han X, Luo T, Jiang W, Xu J and Wang H: JNK pathway may be involved in isoflurane-induced apoptosis in the hippocampi of neonatal rats. Neurosci Lett. 545:17–22. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorum-ski CF, Olney JW and Wozniak DF: Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 23:876–882. 2003.PubMed/NCBI

8 

Zhu C, Gao J, Karlsson N, Li Q, Zhang Y, Huang Z, Li H, Kuhn HG and Blomgren K: Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells and reduced neurogenesis in young, but not adult, rodents. J Cereb Blood Flow Metab. 30:1017–1030. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Stratmann G, Sall JW, May LD, Bell JS, Magnusson KR, Rau V, Visrodia KH, Alvi RS, Ku B, Lee MT and Dai R: Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60 day-old and 7 day-old rats. Anesthesiology. 110:834–848. 2009. View Article : Google Scholar : PubMed/NCBI

10 

DiMaggio C, Sun LS and Li G: Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 113:1143–1151. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Ing C, DiMaggio C, Whitehouse A, Hegarty MK, Brady J, von Ungern-Sternberg BS, Davidson A, Wood AJ, Li G and Sun LS: Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 130:e476–e485. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, Ito M and Imaki J: Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology. 110:628–637. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Kodama M, Satoh Y, Otsubo Y, Araki Y, Yonamine R, Masui K and Kazama T: Neonatal desflurane exposure induces more robust neuroapoptosis than do isoflurane and sevoflurane and impairs working memory. Anesthesiology. 115:979–991. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Shih J, May LD, Gonzalez HE, Lee EW, Alvi RS, Sall JW, Rau V, Bickler PE, Lalchandani GR, Yusupova M, et al: Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology. 116:586–602. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Wei HF, Liang G, Yang H, Wang Q, Hawkins B, Madesh M, Wang S and Eckenhoff RG: The common inhalational anesthetic isoflurane induces apoptosis via activation of inositol 1,4,5-trisphosphate receptors. Anesthesiology. 108:251–260. 2008. View Article : Google Scholar : PubMed/NCBI

16 

Lunardi N, Ori C, Erisir A and Jevtovic-Todorovic V: General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats. Neurotox Res. 17:179–188. 2010. View Article : Google Scholar

17 

Zhao X, Yang Z, Liang G, Wu Z, Peng Y, Joseph DJ, Inan S and Wei H: Dual effects of isoflurane on proliferation, differentiation and survival in human neuroprogenitor cells. Anesthesiology. 118:537–549. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Soriano SG, Liu Q, Li J, Liu JR, Han XH, Kanter JL, Bajic D and Ibla JC: Ketamine activates cell cycle signaling and apoptosis in the neonatal rat brain. Anesthesiology. 112:1155–1163. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Sinner B, Friedrich O, Zink W, Zausig Y and Graf BM: The toxic effects of s(+)-ketamine on differentiating neurons in vitro as a consequence of suppressed neuronal Ca2+ oscillations. Anesth Analg. 113:1161–1169. 2011. View Article : Google Scholar : PubMed/NCBI

20 

Zhao YL, Xiang Q, Shi QY, Li SY, Tan L, Wang JT, Jin XG and Luo AL: GABAergic excitotoxicity injury of the immature hippocampal pyramidal neurons' exposure to isoflurane. Anesth Analg. 113:1152–1160. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Brambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Martin LD, Dissen GA, Creeley CE and Olney JW: Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology. 116:372–384. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Istaphanous GK, Ward CG, Nan X, Hughes EA, Mccann JC, McAuliffe JJ, Danzer SC and Loepke AW: Characterization and quantification of isoflurane-induced developmental apoptotic cell death in mouse cerebral cortex. Anesth Analg. 116:845–854. 2013. View Article : Google Scholar : PubMed/NCBI

23 

Mousa A and Bakhiet M: Role of cytokine signaling during nervous system development. Int J Mol Sci. 14:13931–13957. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Harper SJ and Wilkie N: MAPKs: New targets for neurodegeneration. Expert Opin Ther Targets. 7:187–200. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Kaminska B, Gozdz A, Zawadzka M, Ellert-Miklaszewska A and Lipko M: MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target. Anat Rec (Hoboken). 292:1902–1913. 2009. View Article : Google Scholar

26 

Wang WY, Yang R, Hu SF, Wang H, Ma ZW and Lu Y: N-stearoyl-l-tyrosine ameliorates sevoflurane induced neuroapoptosis via MEK/ERK1/2MAPK signaling pathway in the developing brain. Neurosci Lett. 541:167–172. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Sanders RD, Sun P, Patel S, Li M, Maze M and Ma D: Dexmedetomidine provides cortical neuroprotection: Impact on anaesthetic-induced neuroapoptosisin the rat developing brain. Acta Anaesthesiol Scand. 54:710–716. 2010. View Article : Google Scholar

28 

Li Y, Zeng M, Chen W, Liu C, Wang F, Han X, Zuo Z and Peng S: Dexmedetomidine reduces isoflurane-induced neuroapoptosis partly by pre-serving PI3K/Akt pathway in the hippocampus of neonatal rats. PLoS One. 9:e936392014. View Article : Google Scholar

29 

Zhao Y, Liang G, Chen Q, Joseph DJ, Meng Q, Eckenhoff RG, Eckenhoff MF and Wei H: Anesthetic-induced neurodegeneration mediated via inositol 1,4,5-trisphosphate receptors. J Pharmacol Exp Ther. 333:14–22. 2010. View Article : Google Scholar : PubMed/NCBI

30 

Bai T, Dong DS and Pei L: Resveratrol mitigates isoflurane-induced neuroapoptosis by inhibiting the activation of the Akt-regulated mitochondrial apoptotic signaling pathway. Int J Mol Med. 32:819–826. 2013.PubMed/NCBI

31 

Demestre M, Messerli SM, Celli N, Shahhossini M, Kluwe L, Mautner V and Maruta H: CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice. Phytother Res. 23:226–230. 2009. View Article : Google Scholar

32 

Natarajan K, Singh S, Burke TR Jr, Grunberger D and Aggarwal BB: Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappaB. Proc Natl Acad Sci USA. 93:9090–9095. 1996. View Article : Google Scholar

33 

Lin HP, Jiang SS and Chuu CP: Caffeic acid phenethyl ester causes p21 induction, Akt signaling reduction and growth inhibition in PC-3 human prostate cancer cells. PLoS One. 7:e312862012. View Article : Google Scholar

34 

Orban Z, Mitsiades N, Burke TR, Tsokos M and Chrousos GP: Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappaB and suppresses acute inflammation. Neuroimmunomodulation. 7:99–105. 2000. View Article : Google Scholar

35 

Irmak MK, Fadillioglu E, Sogut S, Erdogan H, Gulec M, Ozer M, Yagmurca M and Gozukara ME: Effects of caffeic acid phenethyl ester and alpha-tocopherol on reperfusion injury in rat brain. Cell Biochem Funct. 21:283–289. 2003. View Article : Google Scholar : PubMed/NCBI

36 

Altug ME, Serarslan Y, Bal R, Kontas T, Ekici F, Melek IM, Aslan H and Duman T: Caffeic acid phenethyl ester protects rabbit brains against permanent focal ischemia by antioxidant action: A biochemical and planimetric study. Brain Res. 1201:135–142. 2008. View Article : Google Scholar : PubMed/NCBI

37 

Kurauchi Y, Hisatsune A, Isohama Y, Mishima S and Katsuki H: Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor. Br J Pharmacol. 166:1151–1168. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Istaphanous GK, Howard J, Nan X, Hughes EA, McCann JC, McAuliffe JJ, Danzer SC and Loepke AW: Comparison of the neuroapoptotic properties of equipotent anesthetic concentrations of desflurane, isoflurane, or sevoflurane in neonatal mice. Anesthesiology. 114:578–587. 2011. View Article : Google Scholar : PubMed/NCBI

39 

Bloomfield SM, McKinney J, Smith L and Brisman J: Reliability of S100B in predicting severity of central nervous system injury. Neurocritical Care. 6:121–138. 2007. View Article : Google Scholar : PubMed/NCBI

40 

Wang S, Peretich K, Zhao Y, Liang G, Meng Q and Wei H: Anesthesia induced neurodegeneration in fetal rat brains. Pediatr Res. 66:435–440. 2009. View Article : Google Scholar : PubMed/NCBI

41 

Li B, Du T, Li H, Gu L, Zhang H, Huang J, Hertz L and Peng L: Signaling pathways for transactivation by dexmedetomidine of epidermal growth factor receptors in astrocytes and its paracrine effect on neurons. Br J Pharmacol. 154:191–203. 2008. View Article : Google Scholar : PubMed/NCBI

42 

Pearn ML, Hu Y, Niesman IR, Patel HH, Drummond JC, Roth DM, Akassoglou K, Patel PM and Head BP: Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. Anesthesiology. 116:352–361. 2012. View Article : Google Scholar :

43 

Creeley C, Dikranian K, Dissen G, Martin L, Olney J and Brambrink A: Propofol induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth. 110:i29–i38. 2013. View Article : Google Scholar

44 

Liang G, Ward C, Peng J, Zhao Y, Huang B and Wei H: Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology. 112:1325–1334. 2010. View Article : Google Scholar : PubMed/NCBI

45 

Dong Y, Zhang G, Zhang B, Moir RD, Xia W, Marcantonio ER, Culley DJ, Crosby G, Tanzi RE and Xie Z: The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels. Arch Neurol. 66:620–631. 2009. View Article : Google Scholar : PubMed/NCBI

46 

Zheng SQ, An LX, Cheng1 X and Wang YJ: Sevoflurane causes neuronal apoptosis and adaptability changes of neonatal rats. Acta Anaesthesiol Scand. 57:1167–1174. 2013. View Article : Google Scholar : PubMed/NCBI

47 

Du T, Li B, Liu S, Zang P, Prevot V, Hertz L and Peng L: ERK phosphorylationin intact, adult brain by alpha(2)-adrenergic trans-activation of EGF receptors. Neurochem Int. 55:593–600. 2009. View Article : Google Scholar : PubMed/NCBI

48 

Zhang X, Wang J, Qian W, Zhao J, Sun L, Qian Y and Xiao H: Dexmedetomidine inhibits tumor necrosis factor-alpha and interleukin 6 inlipopolysaccharide-stimulated astrocytes by suppression of c-Jun N-terminalkinases. Inflammation. 37:942–949. 2014. View Article : Google Scholar : PubMed/NCBI

49 

Yang H, Liang G, Hawkins BJ, Madesh M, Pierwola A and Wei H: Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology. 109:243–250. 2008. View Article : Google Scholar : PubMed/NCBI

50 

Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, Sprung J, Weaver AL, Schroeder DR and Warner DO: Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 128:e1053–e1061. 2011. View Article : Google Scholar : PubMed/NCBI

51 

Bong CL, Allen JC and Kim JT: The effects of exposure to general anesthesia in infancy on academic performance at age 12. Anesth Analg. 117:1419–1428. 2013. View Article : Google Scholar : PubMed/NCBI

52 

Fang F, Xue Z and Cang J: Sevoflurane exposure in 7 day-old rats affects neurogenesis, neurodegeneration and neurocognitive function. Neurosci Bull. 28:499–508. 2012. View Article : Google Scholar : PubMed/NCBI

53 

Oppenheim RW: Cell death during development of the nervous system. Annu Rev Neurosci. 14:453–501. 1991. View Article : Google Scholar : PubMed/NCBI

54 

Rakic S and Zecevic N: Programmed cell death in the developing human telencephalon. Eur J Neurosci. 12:2721–2734. 2000. View Article : Google Scholar : PubMed/NCBI

55 

Blomgren K, Leist M and Groc L: Pathological apoptosis in the developing brain. Apoptosis. 12:993–1010. 2007. View Article : Google Scholar : PubMed/NCBI

56 

Loepke AW and Soriano SG: An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 106:1681–1707. 2008. View Article : Google Scholar : PubMed/NCBI

57 

Gown AM and Willingham MC: Improved detection of apoptotic cells in archival paraffin sections: Immunohistochemistry using antibodies to cleaved caspase 3. J Histochem Cytochem. 50:449–454. 2002. View Article : Google Scholar : PubMed/NCBI

58 

Zhao H, Yenari MA, Cheng D, Sapolsky RM and Steinberg GK: Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J Neurochem. 85:1026–1036. 2003. View Article : Google Scholar : PubMed/NCBI

59 

Chong ZZ, Li F and Maiese K: Oxidative stress in the brain: Novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol. 75:207–246. 2005. View Article : Google Scholar : PubMed/NCBI

60 

Hou J, Wang S, Shang YC, Chong ZZ and Maiese K: Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress. Curr Neurovasc Res. 8:220–235. 2011. View Article : Google Scholar : PubMed/NCBI

61 

Koh PO: Nicotinamide attenuates the ischemic brain injury-induced decrease of Akt activation and Bad phosphorylation. Neurosci Lett. 498:105–109. 2011. View Article : Google Scholar : PubMed/NCBI

62 

Yon JH, Daniel-Johnson J, Carter LB and Jevtovic-Todorovic V: Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience. 135:815–827. 2005. View Article : Google Scholar : PubMed/NCBI

63 

Peltier J, O'Neill A and Schaffer DV: PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol. 67:1348–1361. 2007. View Article : Google Scholar : PubMed/NCBI

64 

Wyatt LA, Filbin MT and Keirstead HS: PTEN inhibition enhances neurite outgrowth in human embryonic stem cell-derived neuronal progenitor cells. J Comp Neurol. 522:2741–2755. 2014. View Article : Google Scholar : PubMed/NCBI

65 

Ojeda L, Gao J, Hooten KG, Wang E, Thonhoff JR, Dunn TJ, Gao T and Wu P: Critical role of PI3K/Akt/GSK3β in motoneuron specification from human neural stem cells in response to FGF2 and EGF. PLoS One. 6:e234142011. View Article : Google Scholar

66 

Luo HR, Hattori H, Hossain MA, Hester L, Huang Y, Lee-Kwon W, Donowitz M, Nagata E and Snyder SH: Akt as a mediator of cell death. Proc Natl Acad Sci USA. 100:11712–11717. 2003. View Article : Google Scholar : PubMed/NCBI

67 

Song G, Ouyang G and Bao S: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 9:59–71. 2005. View Article : Google Scholar : PubMed/NCBI

68 

Yeste-Velasco M, Folch J, Casadesús G, Smith MA, Pallàs M and Camins A: Neuroprotection by c-Jun NH2-terminal kinase inhibitor SP600125 against potassium deprivation-induced apoptosis involves the Akt pathway and inhibition of cell cycle reentry. Neuroscience. 159:1135–1147. 2009. View Article : Google Scholar : PubMed/NCBI

69 

Wang W, Shi L, Xie Y, Ma C, Li W, Su X, Huang S, Chen R, Zhu Z, Mao Z, et al: SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson's disease. Neurosci Res. 48:195–202. 2004. View Article : Google Scholar : PubMed/NCBI

70 

Kuan CY and Burke RE: Targeting the JNK signaling pathway for stroke and Parkinson's diseases therapy. Curr Drug Targets CNS Neurol Disord. 4:63–67. 2005. View Article : Google Scholar : PubMed/NCBI

71 

Walker CL, Walker MJ, Liu NK, Risberg EC, Gao X, Chen J and Xu XM: Systemic bisperoxovanadium activates Akt/mTOR, reduces autophagy and enhances recovery following cervical spinal cord injury. PLoS One. 7:e300122012. View Article : Google Scholar

72 

Guan QH, Pei DS, Zhang QG, Hao ZB, Xu TL and Zhang GY: The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways. Brain Res. 1035:51–59. 2005. View Article : Google Scholar : PubMed/NCBI

73 

Han JY, Jeong EY, Kim YS, Roh GS, Kim HJ, Kang SS, Cho GJ and Choi WS: C-jun N-terminal kinase regulates the interaction between 14-3-3 and bad in ethanol-induced cell death. J Neurosci Res. 86:3221–3229. 2008. View Article : Google Scholar : PubMed/NCBI

74 

Fan J, Xu G, Nagel DJ, Hua Z, Zhang N and Yin G: A model of ischemia and reperfusion increases JNK activity, inhibits the association of bad and 14-3-3 and induces apoptosis of rabbit spinal neurocytes. Neurosci Lett. 473:196–201. 2010. View Article : Google Scholar : PubMed/NCBI

75 

Liao Z, Cao D, Han X, Liu C, Peng J, Zuo Z, Wang F and Li Y: Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats. Brain Res Bull. 107:69–78. 2014. View Article : Google Scholar : PubMed/NCBI

76 

Zheng S and Zuo Z: Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases. Mol Pharmacol. 65:1172–1180. 2004. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October-2016
Volume 14 Issue 4

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wang LY, Tang ZJ and Han YZ: Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane‑induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways. Mol Med Rep 14: 3403-3412, 2016
APA
Wang, L., Tang, Z., & Han, Y. (2016). Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane‑induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways. Molecular Medicine Reports, 14, 3403-3412. https://doi.org/10.3892/mmr.2016.5586
MLA
Wang, L., Tang, Z., Han, Y."Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane‑induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways". Molecular Medicine Reports 14.4 (2016): 3403-3412.
Chicago
Wang, L., Tang, Z., Han, Y."Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane‑induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways". Molecular Medicine Reports 14, no. 4 (2016): 3403-3412. https://doi.org/10.3892/mmr.2016.5586