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The Protective Effects of Apremilast Against Oxygen–Glucose Deprivation/Reperfusion (OGD/R)-Induced Inflammation and Apoptosis in Astroglia Mediated by CREB/BDNF

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Abstract

Oxygen–glucose deprivation and reoxygenation (OGD/R)-induced impairment of astrocytes may lead to neuronal dysfunction in the central nervous system (CNS). Apremilast is a phosphodiesterase 4 (PDE4) inhibitor primarily used for the treatment of psoriasis and psoriatic arthritis that has demonstrated certain neuroprotective properties. PDE4 is an isoenzyme that degrades 3′-5′-cyclic adenosine monophosphate (cAMP), which serves as a neuroprotective agent by promoting neuronal recovery through protein kinase (PKA)-mediated phosphorylation of cAMP response element-binding protein (CREB) and subsequent expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF) and anti-apoptotic B cell lymphoma (Bcl-2). However, the effects of apremilast in astrocytes have not been elucidated. In the present study, we employed an in vitro model of ischemic stroke using oxygen–glucose deprivation and reoxygenation (OGD/R)-challenged astrocytes to investigate the effects of apremilast against apoptosis (the flow cytometry assay), cell death (the lactate dehydrogenase release assay), oxidative stress (2′, 7′ dichlorofluorescin diacetate staining), and the expression of the key neuroprotective factors CREB and BDNF (Western blot analysis). Our findings show that treatment with apremilast could significantly reduce astrocyte apoptosis and cell death induced by OGD/R as evidenced by reduced release of glial fibrillary acidic protein (GFAP) and improvement of the Bax/Bcl-2 ratio. The results of MTT assay, measurement of lactate dehydrogenase (LDH) release, and flow cytometry confirmed the improvement in cell viability mediated by apremilast. Importantly, we found that CREB phosphorylation was required for the increases in BDNF and Bcl-2 induced by apremilast as well as the decrease in astrocyte apoptosis. These preliminary findings indicate that apremilast may have the potential to prevent astrocyte cell death and promote neuronal healing in cerebral ischemic injury. Further in vivo research will expand our understanding of these promising results.

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Authors and Affiliations

  1. Department of Neurosurgery, Zaozhuang Municipal Hospital, Zaozhuang, 277100, Shandong, China

    Hang Yin, Hao Qin & Qiang Zhuang

  2. Department of Dermatology, Zaozhuang Municipal Hospital, Zaozhuang, 277100, Shandong, China

    Tiantian Wang

  3. Department of Pharmacy, Zaozhuang Municipal Hospital, Zaozhuang, 277100, Shandong, China

    Qixia Yang

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  1. Hang Yin
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  2. Hao Qin
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  3. Tiantian Wang
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  4. Qiang Zhuang
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  5. Qixia Yang
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Correspondence to Qixia Yang.

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Yin, H., Qin, H., Wang, T. et al. The Protective Effects of Apremilast Against Oxygen–Glucose Deprivation/Reperfusion (OGD/R)-Induced Inflammation and Apoptosis in Astroglia Mediated by CREB/BDNF. Neurotox Res 39, 754–763 (2021). https://doi.org/10.1007/s12640-021-00340-2

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