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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

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https://dx.doi.org/10.1021/acschemneuro.0c00106 ACS Chem. Neurosci. 2020, 11, 1353−1358