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Inhibiting PDE7A Enhances the Protective Effects of Neural Stem

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Inhibiting PDE7A Enhances the Protective Effects of Neural Stem Research Article: New Research | Cognition and Behavior Inhibiting PDE7A enhances the protective effects of neural stem cells on neurodegeneration and memory deficits in sevoflurane-exposed mice https://doi.org/10.1523/ENEURO.0071-21.2021 Cite as: eNeuro 2021; 10.1523/ENEURO.0071-21.2021 Received: 19 February 2021 Revised: 21 May 2021 Accepted: 25 May 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Inhibiting PDE7A enhances the protective effects of neural stem cells on 2 neurodegeneration and memory deficits in sevoflurane-exposed mice 3 Yanfang Huang, Yingle Chen*, Zhenming Kang, Shunyuan Li* 4 Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical 5 University, Quanzhou 362000, Fujian, China 6 7 *Corresponding authors 8 Shunyuan Li and Yingle Chen 9 Department of Anesthesiology, Quanzhou First Hospital Affiliated to Fujian Medical 10 University, Quanzhou 362000, Fujian, China 11 Email: [email protected] (Shunyuan Li); [email protected] (Yingle Chen) 12 Tel: 86-18960333666 13 14 15 Running title: Role of PDE7A in neurodegeneration 16 17 1 18 Abstract 19 Sevoflurane is widely used in general anesthesia, especially for children. However, 20 prolonged exposure to sevoflurane is reported to be associated with adverse effects on 21 the development of brain in infant monkey. Neural stem cells (NSCs), with potent 22 proliferation, differentiation, and renewing ability, provide an encouraging tool for 23 basic research and clinical therapies for neurodegenerative diseases. We aim to explore 24 the functional effects of injecting NSCs with Phosphodiesterase 7A (PDE7A) 25 knockdown in infant mice exposed to sevoflurane. The effects of PDE7A in NSCs 26 proliferation and differentiation were determined by CCK-8 assay and 27 differentiation-related gene expression assay, respectively. The effects of NSCs with 28 modified PDE7A on mice’s long-term memory and learning ability were assessed 29 by behavioral assays. Our data demonstrated that depleting PDE7A promoted, 30 whereas forcing PDE7A suppressed the activation of cAMP/CREB signaling as well as 31 cell proliferation and neuronal differentiation of NSCs. Inhibition of PDE7A in NSCs 32 exhibited profound improved effects on long-term memory and learning ability of mice 33 exposed to sevoflurane. Our results for the first time show that knockdown of PDE7A 34 improves the neurogenesis of NSCs in vitro and in vivo, and is beneficial for alleviating 35 sevoflurane-induced brain damage in infant mice. 36 37 Key words: Sevoflurane; Neural stem cells; Phosphodiesterase 7A (PDE7A); 38 Behavioral assays; cAMP/CREB signaling 2 39 Significance Statement 40 Our results for the first time show that knockdown of PDE7A improves the 41 neurogenesis of NSCs in vitro and in vivo, and is beneficial for alleviating 42 sevoflurane-induced brain damage in infant mice. 43 44 3 45 Introduction 46 Millions of people, including newborns, infants, and children, are subjected to general 47 anesthesia for surgical procedures worldwide. Accumulating evidence has 48 demonstrated that anesthetic reagents administration may have detrimental effects on 49 the development of the brain, causing potential neurodegeneration and deficits in 50 long-term memory and learning ability (Lu, Wu et al. 2010). Sevoflurane, a highly 51 fluorinated methyl isopropyl ether, is commonly used as an anesthetic agent for 52 inducing and maintaining anesthesia. Compared to other intravenous or inhalation 53 anesthetics, sevoflurane is less irritating to the airway, a lower solubility in the blood, 54 and sweeter smell. These features make sevoflurane a favorable choice for use in 55 children (Eger 2004). However, numerous studies have suggested that sevoflurane 56 may cause neuronal apoptosis, resulting in the development of learning disability and 57 deviant behavior (Liang, Ward et al. 2010, Lu, Wu et al. 2010, Wei, Wang et al. 2019). 58 Therefore, it is critical to clarify the detailed effects of sevoflurane on the nervous 59 system and behavior development, and to discover a potential therapeutic treatment to 60 prevent or mitigate the adverse effects of sevoflurane. 61 Neural stem cells (NSCs), abundant in the fetal or adult nervous system, can be 62 dissected from specific brain regions. With appropriate supplements with mitogens 63 (e.g., epidermal growth factor (EGF), nerve growth factor (NGF) and fibroblast 64 growth factor 2 (FGF 2)) in growth media, NSCs are capable of maintaining stable 65 proliferation, and differentiation into astrocytes, oligodendrocytes, and neurons in 66 vitro. These features make NSCs an ideal cell source for regenerative medicine for 67 various brain diseases, including stroke, spinal cord injury, and neurodegenerative 68 diseases (Kim, Lee et al. 2013). Several preclinical studies using mouse, rat, or 69 monkey models demonstrated that transplantation of NSCs into the brain of mice with 4 70 different neurodegenerative diseases exhibited encouraging evidence of improving the 71 functions of the brain (Lunn, Sakowski et al. 2011, Sakthiswary and Raymond 2012). 72 For example, Forotti et al. recently reported that transplantation of human induced 73 pluripotent stem cell-derived NSCs in the ventral horn of the mouse spinal cord 74 ameliorates neuropathological characteristics and improves the neuromuscular 75 function and lifespan (Forotti, Nizzardo et al. 2019). Despite these favorable 76 outcomes of application of NSCs for neurodegenerative disease treatment, the safety 77 and efficacy of NSCs transplantation remain a major challenge for its clinical 78 application in human. 79 Genetic modification is a useful tool to improve the function and avidity of NSCs. For 80 example, ectopic expression of oncogene c-myc actively promotes the proliferative 81 potential of NSCs (Swartling, Cancer et al. 2015). Similarly, overexpression of 82 Shroom Family Member 4 (Shrm4) activates gamma-aminobutyric acid (GABA) 83 pathway in NSCs, resulting in enhanced cell growth, colony formation, anti-apoptosis, 84 and ability to differentiate into neurons (Tian, Guo et al. 2020). The 85 phosphodiesterase 7A (PDE7A) is an enzyme responsible for the regulation of 86 intracellular cAMP in the central nervous system (Morales-Garcia, Alonso-Gil et al. 87 2015). It has been revealed that administration of S14, a PDE7 inhibitor, increased 88 NSCs proliferation, and neuronal differentiation (Chen, Li et al. 2020). In view of 89 those findings, we aim to investigate the functional roles of PDE7A on the NSCs cell 90 proliferation and differentiation in vitro, and long-term memory and learning ability of 91 sevoflurane-treated mice in vivo using genetic modification strategies. 92 93 Materials and Methods 94 Animals 5 95 C57BL/6 mice of either sex were purchased from GemPharmatech (Nanjing, China), 96 and maintained in the standard animal care facility with free access to clean food and 97 water. All animal experiment protocols were approved by the Ethics Committee of 98 XXX. 99 NSCs isolation, culture, and transplantation 100 The pregnant mice were euthanized, and the embryos isolated from uteruses were 101 immersed in D-hank’s solution. The embryos’ brain tissues were carefully separated, 102 followed by the removal of blood vessels and meninges. The hippocampus was 103 carefully dissected, washed, cut into small pieces (0.2 mm × 0.2 mm), and digested in 104 DMEM medium with 0.1% trypsin-EDTA, 0.15% DNAase, and 0.01% hyaluronidase 105 in 37-degree for 15 mins. The NSCs were washed, responded, and seeded into 12-well 106 plate with a density of 4 × 104 cells per well in DMEM/F12 medium supplied with 10 107 ng/ml EGF, 10 ng/ml FGF. 108 Two weeks pups were exposed to 3% sevoflurane for 4 h, and were returned to the 109 original cages for recovery. The main reason for the pups received NSCs injection two 110 weeks post-treatment is that the two-week interval is an ideal period to allow the mice 111 to recover and to familiarize themselves with new environment. We tried to minimize 112 the potential unrelated factors, such as poor health condition or emotion, that may 113 affect the therapeutic effect of NSCs. Thus, two weeks later, the pups were restricted 114 in stereotaxis, and a small hole was drilled in the skull at coordinates AP, +1.7 mm, 115 and LM, -1.0 mm. A total of 5 × 105 NSCs in 100 μl of suspension was gently injected 116 into the frontal cortex's parenchyma with a Hamilton 80300 microsyringe. Each pup 117 only received one-time NSCs injection. 118 Morris water maze test and novel object recognition test 119 For Morris water maze test, a 0.6 m high and 1.6 m diameter circular tank containing 6 120 0.3 m high of water was incorporated in the study. A round platform (0.12 m diameter) 121 was placed in the center of one of the four-quadrant and submerged 1 cm beneath the 122 water surface. The mice were trained for 3 times per day for a consecutive 7 days 123 before the test. The mouse was placed into the water, and its navigation to the 124 platform was recorded by a video camera located above the water tank. The maximum 125 time for a mouse in the water tank was 80 s. If a mouse cannot find the platform with 126 60 s, the mouse was guided to the platform, and the time was recorded as 60 s.
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