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PDE‑7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long- Term Memory Deficits in Mice Following Sevoflurane Exposure Yingle Chen, Shunyuan Li,* Xianmei Zhong, Zhenming Kang, and Rulei Chen

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ABSTRACT: Sevoflurane, one of the most commonly used anesthetic agents, has been demonstrated to induce widespread neurodegeneration in the developing brain. We aimed to evaluate the protective effects of a PDE-7 inhibitor (BRL-50481) against the neurotoxic effects of sevoflurane on the developing nervous system. Spatial learning and memory in sevoflurane-treated mice were examined using the Morris water maze test, and neuroprotective effects of PDE-7 inhibitor (BRL-50481) against sevoflurane- induced impairments were evaluated. Our results showed that sevoflurane treatment markedly induced neurodegeneration and impaired long-term memory in neonatal mice. Notably, BRL-50481 coadministration could significantly attenuate sevoflurane- induced learning and memory defects, prevent deterioration of recognition memory, and protect against neuron apoptosis. Mechanistically, BRL-50481 administration suppressed sevoflurane-induced neurodegenerative disorders through restoring cAMP and activating cAMP/CREB signaling in the hippocampus. PDE7 inhibitor may be a potential therapeutic agent for sevoflurane- induced neurodegeneration and long-term memory deficits. KEYWORDS: Sevoflurane, neurodegeneration, long-term memory deficits, PDE-7 inhibitor, cAMP/CREB signaling

■ INTRODUCTION

rats exhibited significantly dose- and duration-dependent neurodegeneration with various doses and durations of sevoflurane treatments.12 Amrock et al. evaluated the neuro- degenerative effects of single or multiple doses of 2.5% sevoflurane administration using neonatal rats and found that 2 h exposure resulted in severe synaptic loss and dramatic apoptotic cell death in many brain regions.11

Pregnant women, newborns, and infants are often exposed to anesthetic agents during childbirth or for surgical procedures. It has been demonstrated that the administration of anesthetic reagents is toxic to the developing brain and causes widespread neurodegeneration and long-term deficits in learning and behavior.1−5 Hence, it is of crucial importance to study the effects of anesthetics on the developing nervous system and discover effective therapeutic treatments. Sevoflurane, also called fluoromethyl,

The cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) has been extensively implicated in neurogenesis, survival, proliferation, and differ- entiation.13−16 As a transcriptional factor, CREB is activated by

is one of the most commonly used volatile anesthetic agents for the induction and maintenance of general anesthesia.6 It is useful for infants and children due to its rapid induction, fast recovery, and less irritation to the airway.6,7 However, numerous studies have reported that neonatal administration of sevoflurane induced widespread neurological disorders, including neurodegenera- tion, deficits learning tasks, and long-term potentiation inhibition.8−12 Zheng et al. found that neonatal

Received: February 25, 2020 Accepted: March 25, 2020 Published: April 9, 2020

in spatial

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Figure 1. Sevoflurane does not affect learning and memory of neonatal mouse at early stages. Two weeks after sevoflurane exposure, spatial learning and memory were examined by Morris water maze test on Day1 (P21), Day 2 (P22), and Day 3 (P23). (A) Delay time to reach the platform of indicated groups. (B) Swimming path length before reaching the platform of indicated groups. (C) Percent of time spent in the target quadrant in a probe test of indicated groups. n = 8 for each time point. Data represent mean ± SD.

Figure 2. BRL-50481 attenuates sevoflurane induced learning and memory defects. Eight weeks after sevoflurane exposure, spatial learning and memory were examined by Morris water maze test on Day 1 (P63), Day 2 (P64), and Day 3 (P65). (A) Delay time to reach the platform of indicated groups. (B) Swimming path length before reaching the platform of indicated groups. (C) Percent of time spent in the target quadrant in a probe test of indicated groups. n = 8 for each time point. Data represent mean ± SD, *P < 0.05, #P < 0.001 compared with sham group.

cAMP-dependent phosphorylation on Ser 133, which triggers the transcription of downstream targets including BDNF, TrkB, and c-Fos, and eventually regulates neurogenesis.16−18 Recently, Xiong et al. reported that sevoflurane-nitrous oxide learning and memory deficiencies anesthesia-induced spatial were associated with the cAMP/CREB signaling inhibition in rats.10

The phosphodiesterase 7 (PDE-7) is a cAMP-specific metallophosphohydrolase enzyme, which suppresses the cAMP/CREB signaling pathway though catalyzing cAMP to the inactive form 5′AMP.4,19,20 Accumulating evidence have showed that PDE-7 inhibitors emerge as promising candidates for promoting neuron survival, improving cognitive symptoms, and treating memory deficits.21−24 BRL-50481 is a PDE-7 specific inhibitor, which can decrease animals’ anxiety levels, promote oligodendrocyte precursor differentiation, inhibit neuroinflammation, and protect against spinal cord in- jury.21,22,24,25 However, the roles of BRL-50481 on sevoflur- ane-induced neurodegenerative disorders remain unknown. In the present study, we demonstrated the neuroprotective effects of PDE7 inhibitor, BRL-50481, against sevoflurane-induced neurodegeneration and long-term memory deficits. Noticeably, BRL-50481 attenuated sevoflurane-induced learning and memory defects, prevented deterioration of recognition memory, and protected against neuron apoptosis through activating the cAMP/CREB signaling, suggesting a potential

therapeutic role of PDE7 inhibitors in the treatment of sevoflurane-induced neurodegenerative disorders.

■ RESULTS AND DISCUSSION

Sevoflurane is a commonly used volatile anesthetic agent due to it exhibiting rapid induction, fast recovery, and less irritation to the airway.6,7 However, accumulative research and clinical data have demonstrated that neonatal administration of sevoflurane may cause widespread neurological disor- ders.8−12,16 Recently, PDE-7 inhibitors have emerged as promising candidates for promoting neuron survival, improv- ing cognitive symptoms, and treating memory deficits.4,19−27 However, little is known about whether PDE-7 inhibitors can attenuate sevoflurane-induced neurodegenerative disorders. Here, we utilized a PDE-7 specific inhibitor, BRL-50481, to demonstrate the preventive effect of PDE-7 inhibitors on sevoflurane-induced neurodegeneration and long-term memo- ry deficits.

Neither Sevoflurane nor the BRL-50481 Affects the Spatial Learning and Memory Ability of Neonatal Mice at Early Stage. P7 neonatal pups undergo extensive neurogenesis to develop episodic memory and establish hippocampal learning. Therefore, they are very sensitive to neurotoxic influences at this stage.8,11,12,16 Based on this, we used P7 mouse pups to perform anesthesia administration to evaluate the neurotoxic effects of sevoflurane exposure. We first

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investigated the spatial learning and memory ability in P7 pups after 4 h sevoflurane exposure and then evaluated the neuroprotective effects of PDE-7 inhibitor (BRL-50481) through coadministration with sevoflurane (Figure 1). As shown in Figure 1A, the time of delay to find the platform was measured on postnatal days 21, 22, and 23 (Day 1, Day 2, and Day 3) after 4 h sevoflurane exposure on P7 pups, which was comparable to that of the sham group. Moreover, the low or high dose PDE-7 inhibitor (BRL-50481) injected groups showed the same pattern compared to sham and control group. Similarly, there was no difference in the swimming path length and percentage of time stay in the target quadrant (Figure 1B and C). These data suggested that neither sevoflurane nor the PDE-7 inhibitor affected the spatial learning and memory ability of mice at the early developmental stage.

BRL-50481 Attenuates Sevoflurane-Induced Learn- ing and Memory Defects in Neonatal Mouse. We next monitored the spatial learning and memory ability of 9 week postnatal mice (P63−P65) using the Morris water maze test. As shown in Figure 2, 4 h sevoflurane exposure (B0 group) induced marked neurocognitive deficiency compared to the sham and control groups. The delay time to find the platform and swimming path length were significantly prolonged for th B0 group (Figure 2A and B). The sevoflurane-induced memory retention defect was observed using the probe test, where the B0 group spent the least amount of time in the target quadrant (Figure 2C). Although the PDE-7 inhibitor BRL-50481 alone (control group) did not exhibit enhanced neurocognition and memory retention compared to sham the sevoflurane-induced learning and (control vs sham), memory defects were significantly attenuated by a high-dose (5 mg/kg) BRL-50481 injection (B5 vs B0), which was not rescued by the low-dose (1 mg/kg) BRL-50481 administration (B1 vs B0). We observed improved escape latency (Figure 2A and C) and shorter swimming length (Figure 2B) in the control and B5 groups, which indicted that a higher dose of PDE-7 inhibitor could significantly attenuate sevoflurane- induced learning and memory defects.

Interestingly, we found that the spatial learning and memory ability of the pups receiving 4 h sevoflurane exposure was similar to that of the sham group at an early stage (P21−P23). However, 8 weeks after sevoflurane exposure, these mice exhibited significant neurodegenerative disorders compared to the sham group (P63−P65). We speculated that this phenotypic trait might be caused by progressive neuro- degeneration. There was no or less deficit observed at the early stage (2 weeks), but the deficits were evident at 8 weeks after sevoflurane exposure. In line with our findings, other groups observed similar results. Keith et al. demonstrated that cell-death-induced hippocampal DG deficit was improved over 6 weeks.28 Fang et al. treated the 7 day old rats with sevoflurane exposure and found altered neurodegeneration, neurocognitive function, and neurogenesis at 6 weeks instead of 2 weeks after exposure.9 Further studies need to be performed to address the cause of this delay in the onset of cognitive deficit.

BRL-50481 Prevents Sevoflurane-Induced Deteriora- tion of Recognition Memory in Neonatal Mouse. To further investigate the recognition memory defects induced by sevoflurane, we performed the novel object recognition test, which utilizes the natural tendency of rodents to spend more time to explore a novel object than a familiar one. The results the sevoflurane-treated group (B0) and showed that

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sevoflurane plus low-dose BRL-50481 injected group (B1) indeed exhibited a malfunction in the memory of the mice, they barely remembered the object that they were supposed to be familiar (Figure 3). In contrast, the high-dose BRL-50481

Figure 3. BRL-50481 prevents sevoflurane induced deterioration of recognition memory. (A) Exploration time of indicated group spent with an old object and new object. (B) Discrimination index of recognizing the new vs old object of an indicated group. n = 8 for each group. Data represent mean ± SD, *P < 0.05 compared with sham.

injected group (B5) prevented this malfunction and displayed the recognition ability similar to that of the sham and control groups (Figure 3). The above results suggested that a higher dose of PDE-7 inhibitor prevented sevoflurane-induced deterioration of recognition memory.

BRL-50481 Protects against Sevoflurane-Induced Apoptosis in Hippocampus. To further evaluate the neurocognitive deficits after 4 h of sevoflurane exposure, we performed caspase-3 (CA3) IHC staining in the hippocampal CA1 and dentate gyrus (DG) regions. The degenerated neurons were labeled by CV3 and are shown in Figure 4A.

Figure 4. BRL-50481 protects against sevoflurane induced apoptosis in hippocampus. (A) Representative images of cleaved caspase-3 immunohistochemical staining in the hippocampal CA1 region. Arrows indicate the cleaved caspase-3 positive cells. (B, C) Auantitative statistic of degenerated neurons of indicated groups in hippocampal CA1 (B) and (C) DG regions. n = 8 for each group. Data represent mean ± SD, *P < 0.05, #P < 0.001 compared with Sham.

Apoptotic cell density (AC-3 cells mm−2) increased about 10- fold in CA1 and DG regions in the sevoflurane-treated group (B0) compared to the sham group (Figure 4B and C). Notably, coadministration of high-dose BRL-50481 with sevoflurane (B5) strikingly reduced sevoflurane-induced apoptosis (Figure 4B and C).

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BRL-50481 Suppresses Sevoflurane-Induced Neuro- degeneration through Restoring Hippocampal cAMP/ CREB Signaling. We next measured the pCREB and total CREB protein levels in each group. Although there was no significant difference in total CREB protein levels after sevoflurane exposure (Figure 5A and B), pCREB protein

Figure 5. BRL-50481 administration rescues sevoflurane induced pCREB downregulation. (A) Immunoblots of lysates from indicated hippocampus to show the protein levels of total CREB, pCREB, and β-actin. (B, C) Relative protein levels of total (B) CREB and (C) pCREB normalized by β-actin. n = 8 for each group. Data represent mean ± SD, *P < 0.05 compared with sham.

expression in the B0 group was significantly decreased (Figure 5A and C). Accordingly, coadministration of high-dose PDE-7 inhibitor BRL-50481 with sevoflurane (B5) could restore pCREB to the sham group’s level. These results indicated that sevoflurane impaired the cycle of pCREB and decreased the pCREB level and the PDE-7 inhibitor might be involved in this cycle to block the inhibitory effect of sevoflurane.

CREB phosphorylation can be triggered by cAMP accumulation. We observed decreased pCREB expression after sevoflurane exposure in the above results; next, we asked whether cAMP was involved in the sevoflurane-induced neurodegeneration and long-term memory deficits. The ELISA the cAMP levels were significantly results showed that the sevoflurane-treated decreased in the hippocampus of group (B0 in Figure 6). Accordingly, coadministration of high-dose PDE-7 inhibitor BRL-50481 with sevoflurane (B5) could restore cAMP to the sham group’s level. Thus, the results suggested that sevoflurane exposure suppressed the

Figure 6. BRL-50481 administration facilitates cAMP accumulation after sevoflurane exposure. The hippocampal cAMP levels of indicated groups were determined by using a mouse cAMP ELISA kit. Data represent mean ± SD, *P < 0.05 compared with sham.

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cAMP accumulation and in turn inhibited the cAMP/CREB signaling, whereas BRL-50481 prevented this inhibitory effect and restored cAMP/CREB signaling in the hippocampus.

Increasing the intracellular cAMP levels appears to favor the survival and differentiation of neurons, such as oligodendroglial and Schwann cells.13−15,18,25,29,30 PDE-7 catalyzes cAMP to the inactive form and then suppresses the cAMP/CREB signaling pathway. study, we demonstrated the neuroprotective effects of PDE7 inhibitor against sevoflurane- induced neurotoxicity through activating the cAMP/CREB signaling pathway. Notably, the rescued neurodegenerative disorders were observed in the high-dose BRL-50481-treated improve- including prevention of neurodegeneration, group, ment in learning and memory, reduction of apoptosis in the hippocampus, restoration of cAMP, and activation of the cAMP/CREB signaling pathway. In agreement with the neuroprotective function of PDE7 inhibitors, Valdes-Moreno et al. found that PDE7 inhibitors improved feeding and anxiety behaviors of rats through increasing the accumbal and hypothalamic thyrotropin-releasing hormone expression.24 Medina-Rodriguez et al. revealed that PDE7 inhibitor treatment could accelerate human oligodendrocyte precursor differentiation and survival.25 Paterniti et al. demonstrated that PDE7 inhibitor administration could significantly reduce the degree of spinal cord inflammation, tissue injury, and levels of TNF-α, IL-6, COX-2, and iNOS.21 Collectively, these results strongly suggested that PDE7 inhibitors could promote neurogenesis and improve neurodegenerative disorders. Specifically, the PDE7 inhibitor BRL-50481 is a potential drug candidate to be further studied for the treatment of sevoflurane-induced neurodegeneration.

In this

This study demonstrated the neuroprotective effects of PDE7 inhibitor, BRL-50481, on sevoflurane-induced neuro- degeneration. Mechanistically, BRL-50481 administration significantly attenuated sevoflurane-induced learning and memory defects, deterioration of recognition memory, and neuron apoptosis through activating the cAMP/CREB signal- ing in the hippocampus. These findings suggested that PDE7 inhibitor BRL-50481 is a potential drug candidate for the treatment of sevoflurane-induced neurodegenerative disorders.

■ MATERIALS AND METHODS

Animals and Treatments. Seven day old C57BL/6 male mice (Beijing Vital River Company, Beijing, China) were used in this study. The mice were bred and maintained in the animal care facility following the standard rearing conditions of 12 h light and 12 h dark. All mouse studies were performed following the guidelines established by the Institutional Animal Care and Use Committee in Quanzhou First Hospital Affiliated to Fujian Medical University (QFH2017jb43i).

BRL-50481 (Tocris Bioscience, Bristol, United Kingdom) was dissolved in 2.5% dimethyl sulfoxide (Sigma, St. Louis, MO) with 0.9% NaCl and injected intraperitoneally into pups before subjecting them to sevoflurane, with a vehicle injection as control. Thirty minutes later, the injected pups were put into a semiclosed chamber and exposed to 3% sevoflurane for 4 h. After exposure, pups were returned to the parents’ cages and monitored for health status until the following tests.

The pups were randomly divided into five groups as follows:

Sham: vehicle intraperitoneal injection; Control: 5 mg/kg BRL-50481 intraperitoneal injection; B0: Sevoflurane anesthesia, vehicle intraperitoneal injection; B1: Sevoflurane anesthesia, 1 mg/kg BRL-50481 intra- peritoneal injection;

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B5: Sevoflurane anesthesia, 5 mg/kg BRL-50481 intra- peritoneal injection.

Each group contained 10 pups.

Morris Water Maze Test and Analysis. The spatial memory ability of control and treated mice was determined using the Morris water maze test developed by Richard Morris.31 In brief, a 160 cm diameter and 60 cm high circular tank was filled with water at 30 cm high. The water temperature was maintained at 22 °C. A 12 cm diameter circular platform was submerged 1 cm below the water surface in the center of one of the four virtual quadrants.32

The control and treated mice were trained four times per day for 6 days. The mouse was released into the water, and it navigated to reach the platform. The maximum swimming time of the tested mouse was 80 s. If the mouse could escape to the refuge within 60 s, the delay to find the platform time was recorded as 60 s. Mice were allowed to stay on the platform for 15 s, and then they were sent to their cages under a heat lamp to maintain their core temperature. The escape latency was recorded by a tracking system, and data were analyzed using ViewPoint video tracking system (ViewPoint Behavior Technology, Civrieux, France). Three daily trials were averaged for each animal.32 Immunohistochemistry (IHC) Analyses. Mice were euthanized and perfused with cold phosphate-buffered saline and 4% paraformaldehyde immediately. The brains were fixed with 4% paraformaldehyde overnight and then cryoprotected by immersion in 30% sucrose at 4 °C for 48 h. Coronal sections (25 μm) were cut using a manual rotary microtome (Leica, Wetzlar, Germany).

The caspase-3 IHC staining was performed as previously described.33 The cleaved caspase-3 antibody (ab13847) was purchased from Abcam (Cambridge, MA).

Immunoblotting Analyses. Frozen hippocampus homogenates were lysed using radioimmunoprecipitation buffer (Bioequip, Shanghai, China). The samples were subjected to immunoblotting analysis as described previously.33 The pCREB (Ser133, #9198, 1:1000 dilution) and CREB (#9197, 1:2000 dilution) primary antibodies were ordered from Cell Signaling Technology (Danvers, MA), and the internal control β-actin antibody was ordered from Abcam (ab8226, 1:2000 dilution).

cAMP Concentration Assay. cAMP levels were measured using the mouse cAMP ELISA kit (ab133051, Biocompare, South San Francisco, CA) following the manufacturer’s instructions.

Statistical Analysis. Statistical analyses were carried out by using the SPSS 11.0 package. Differences between groups were analyzed using analysis of variance (ANOVA) or two-sample t test with Bonferroni correction. All data represent mean ± standard deviation (SD). Statistical significance thresholds were set at *P < 0.05.

■ AUTHOR INFORMATION

Corresponding Author

Shunyuan Li − Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China; Email: cylfj@126.com

orcid.org/0000-0003-1778-8386;

Authors

Yingle Chen − Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China

Xianmei Zhong − Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China

Zhenming Kang − Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China

Rulei Chen − Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou 362000, Fujian, China

Complete contact information is available at:

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Author Contributions Did the experiments and analyzed the data: Y.C., S.L., X.Z., Z.K., R.C. Designed the study and wrote the manuscript: S.L. All authors approved the final submission. Funding This work was supported by the Natural Science Foundation Project of Fujian Province (#2018J01200). Notes The authors declare no competing financial interest.

■ REFERENCES

(1) Warner, D. O., Zaccariello, M. J., Katusic, S. K., Schroeder, D. R., Hanson, A. C., Schulte, P. J., Buenvenida, S. L., Gleich, S. J., Wilder, R. T., Sprung, J., Hu, D., Voigt, R. G., Paule, M. G., Chelonis, J. J., and Flick, R. P. (2018) Neuropsychological and Behavioral Outcomes after Exposure of Young Children to Procedures Requiring General Anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology 129, 89−105. (2) Andropoulos, D. B. (2018) Effect of Anesthesia on the Developing Brain: Infant and Fetus. Fetal Diagn Ther 43, 1−11. (3) Glatz, P., Sandin, R. H., Pedersen, N. L., Bonamy, A. K., Eriksson, L. I., and Granath, F. (2017) Association of Anesthesia and Surgery During Childhood With Long-term Academic Performance. JAMA Pediatr 171, e163470. (4) Bollen, E., and Prickaerts, J. (2012) Phosphodiesterases in neurodegenerative disorders. IUBMB Life 64, 965−970. (5) Ing, C., Wall, M. M., DiMaggio, C. J., Whitehouse, A. J. O., Hegarty, M. K., Sun, M., von Ungern-Sternberg, B. S., Li, G., and Sun, L. S. (2017) Latent Class Analysis of Neurodevelopmental Deficit After Exposure to Anesthesia in Early Childhood. J. Neurosurg Anesthesiol 29, 264−273. (6) De Hert, S., and Moerman, A. (2015) Sevoflurane. F1000Research 4, 626. (7) Goa, K. L., Noble, S., and Spencer, C. M. (1999) Sevoflurane in paediatric anaesthesia: a review. Paediatr Drugs 1, 127−153. (8) Satomoto, M., Satoh, Y., Terui, K., Miyao, H., Takishima, K., Ito, M., and Imaki, J. (2009) Neonatal Exposure to Sevoflurane Induces Abnormal Social Behaviors and Deficits in Fear Conditioning in Mice. Anesthesiology 110, 628−637. (9) Fang, F., Xue, Z., and Cang, J. (2012) Sevoflurane exposure in 7- day-old rats affects neurogenesis, neurodegeneration and neuro- cognitive function. Neurosci. Bull. 28, 499−508. (10) Xiong, W.-X., Zhou, G.-X., Wang, B., Xue, Z.-G., Wang, L., Sun, H.-C., and Ge, S.-J. (2013) Impaired spatial learning and memory after sevoflurane-nitrous oxide anesthesia in aged rats is associated with down-regulated cAMP/CREB signaling. PLoS One 8, e79408− e79408. (11) Amrock, L. G., Starner, M. L., Murphy, K. L., and Baxter, M. G. (2015) Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure. Anesthesiology 122, 87− 95. (12) Zheng, S. Q., An, L. X., Cheng, X., and Wang, Y. J. (2013) Sevoflurane causes neuronal apoptosis and adaptability changes of neonatal rats. Acta Anaesthesiol. Scand. 57, 1167−1174. (13) Nakagawa, S., Kim, J. E., Lee, R., Chen, J., Fujioka, T., Malberg, J., Tsuji, S., and Duman, R. S. (2002) Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. J. Neurosci. 22, 9868−9876. (14) Fujioka, T., Fujioka, A., and Duman, R. S. (2004) Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus. J. Neurosci. 24, 319−328. (15) Ao, H., Ko, S. W., and Zhuo, M. (2006) CREB activity maintains the survival of cingulate cortical pyramidal neurons in the adult mouse brain. Mol. Pain 2, 15.

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(16) Ding, M.-l., Ma, H., Man, Y.-g., and Lv, H.-y. (2017) Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/ BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can. J. Physiol. Pharmacol. 95, 1396−1405. (17) Chrivia, J. C., Kwok, R. P., Lamb, N., Hagiwara, M., Montminy, M. R., and Goodman, R. H. (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365, 855−859. (18) Kida, S., and Serita, T. (2014) Functional roles of CREB as a positive regulator in the formation and enhancement of memory. Brain Res. Bull. 105, 17−24. (19) Chevalier, E., Lagente, V., Dupont, M., Fargeau, H., Palazzi, X., Richard, V., Dassaud, M., Fric, M., Coupe, M., Carre, C., Leduc, S., Bernardelli, P., Vergne, F., Berna, P., and Bertrand, C. P. (2012) Lack of involvement of type 7 phosphodiesterase in an experimental model of asthma. Eur. Respir. J. 39, 582−588. (20) Morales-Garcia, J. A., Echeverry-Alzate, V., Alonso-Gil, S., Sanz- SanCristobal, M., Lopez-Moreno, J. A., Gil, C., Martinez, A., Santos, A., and Perez-Castillo, A. (2017) Phosphodiesterase7 Inhibition Activates Adult Neurogenesis in Hippocampus and Subventricular Zone In Vitro and In Vivo. Stem Cells 35, 458−472. (21) Paterniti, I., Mazzon, E., Gil, C., Impellizzeri, D., Palomo, V., Redondo, M., Perez, D. I., Esposito, E., Martinez, A., and Cuzzocrea, S. (2011) PDE 7 inhibitors: new potential drugs for the therapy of spinal cord injury. PLoS One 6, e15937. (22) Redondo, M., Zarruk, J. G., Ceballos, P., Pérez, D. I., Pérez, C., Perez-Castillo, A., Moro, M. A., Brea, J., Val, C., Cadavid, M. I., Loza, M. I., Campillo, N. E., Martínez, A., and Gil, C. (2012) Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model. Eur. J. Med. Chem. 47, 175−185. (23) Morales-Garcia, J. A., Alonso-Gil, S., Gil, C., Martinez, A., Santos, A., and Perez-Castillo, A. (2015) Phosphodiesterase 7 inhibition induces dopaminergic neurogenesis in hemiparkinsonian rats. Stem Cells Transl. Med. 4, 564−575. (24) Valdes-Moreno, M. I., Alcantara-Alonso, V., Estrada-Camarena, E., Mengod, G., Amaya, M. I., Matamoros-Trejo, G., and de Gortari, P. (2017) Phosphodiesterase-7 inhibition affects accumbal and hypothalamic thyrotropin-releasing hormone expression, feeding and anxiety behavior of rats. Behav. Brain Res. 319, 165−173. (25) Medina-Rodriguez, E. M., Arenzana, F. J., Pastor, J., Redondo, M., Palomo, V., Garcia de Sola, R., Gil, C., Martinez, A., Bribian, A., and de Castro, F. (2013) Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival. Cell. Mol. Life Sci. 70, 3449−3462. (26) Pekkinen, M., Ahlstrom, M. E. B., Riehle, U., Huttunen, M. M., and Lamberg-Allardt, C. J. E. (2008) Effects of phosphodiesterase 7 inhibition by RNA interference on the gene expression and differentiation of human mesenchymal stem cell-derived osteoblasts. Bone 43, 84−91. (27) Safavi, M., Baeeri, M., and Abdollahi, M. (2013) New methods for the discovery and synthesis of PDE7 inhibitors as new drugs for neurological and inflammatory disorders. Expert Opin. Drug Discovery 8, 733−751. (28) Keith, J. R., Wu, Y., Epp, J. R., and Sutherland, R. J. (2007) Fluoxetine and the dentate gyrus: memory, recovery of function, and electrophysiology. Behav. Pharmacol. 18, 521−531. (29) Li, Q. Q., Shi, G. X., Yang, J. W., Li, Z. X., Zhang, Z. H., He, T., Wang, J., Liu, L. Y., and Liu, C. Z. (2015) Hippocampal cAMP/PKA/ CREB is required for neuroprotective effect of acupuncture. Physiol. Behav. 139, 482−490. (30) Wang, H., Xu, J., Lazarovici, P., Quirion, R., and Zheng, W. (2018) cAMP Response Element-Binding Protein (CREB): A Possible Signaling Molecule Link in the Pathophysiology of Schizophrenia. Front. Mol. Neurosci. 11, 255. (31) Morris, R. (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods 11, 47−60.

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Research Article

(32) Vorhees, C. V., and Williams, M. T. (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848−858. (33) Guo, L., Zhang, P., Chen, Z., Xia, H., Li, S., Zhang, Y., Kobberup, S., Zou, W., and Lin, J. D. (2017) Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J. Clin. Invest. 127, 4449−4461.

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