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Inhibition of Epac2 Attenuates Neural Cell Apoptosis and Improves Neurological Deficits in a Rat Model of Traumatic Brain Injury.

ABSTRACT: Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. TBI-induced neuronal apoptosis is one of the main contributors to the secondary injury process. The aim of this study is to investigate the involvement of Exchange protein directly activated by cAMP 2 (Epac2) on TBI. We found that the expression level of Epac2 surrounding the injured area of brain in rats of TBI model was significantly increased at 12 h after TBI. The role of Epac2 in TBI was further explored by using a selective Epac2 antagonist ESI-05 to decrease the Epac2 expression. We discovered that inhibition of Epac2 could improve the neurological impairment and attenuate brain edema following TBI. The Epac2 inhibition effectively reduced neuronal cell death and P38 MAPK signaling pathway may be involved in this process. Our results suggest that inhibition of Epac2 may be a potential therapy for TBI by reducing the neural cell death, alleviating brain edema and improving neurologic deficits.

SUBMITTER: Zhang L

PROVIDER: S-EPMC5924794 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Inhibition of Epac2 Attenuates Neural Cell Apoptosis and Improves Neurological Deficits in a Rat Model of Traumatic Brain Injury.

Zhang Ling L Zhang Li L Liu Huixiang H Jiang Feng F Wang Huanjing H Li Di D Gao Rong R

Frontiers in neuroscience 20180423

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. TBI-induced neuronal apoptosis is one of the main contributors to the secondary injury process. The aim of this study is to investigate the involvement of Exchange protein directly activated by cAMP 2 (Epac2) on TBI. We found that the expression level of Epac2 surrounding the injured area of brain in rats of TBI model was significantly increased at 12 h after TBI. The role of Epac2 in TBI was further explored by ...[more]

PMID: 29740274

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Project description:BackgroundDespite previous evidence for a potent inflammatory response after a traumatic brain injury (TBI), it is unknown whether exercise preconditioning (EP) improves outcomes after a TBI by modulating inflammatory responses.MethodsWe performed quantitative real-time PCR (qPCR) to quantify the genes encoding 84 cytokines and chemokines in the peripheral blood and used ELISA to determine both the cerebral and blood levels of interleukin-6 (IL-6). We also performed the chromatin immunoprecipitation (ChIP) assay to evaluate the extent of nuclear factor kappa-B (NF-κB) binding to the DNA elements in the IL-6 promoter regions. Also, we adopted the Western blotting assay to measure the cerebral levels of heat shock protein (HSP) 70, synapsin I, and β-actin. Finally, we performed both histoimmunological and behavioral assessment to measure brain injury and neurological deficits, respectively.ResultsWe first demonstrated that TBI upregulated nine pro-inflammatory and/or neurodegenerative messenger RNAs (mRNAs) in the peripheral blood such as CXCL10, IL-18, IL-16, Cd-70, Mif, Ppbp, Ltd, Tnfrsf 11b, and Faslg. In addition to causing neurological injuries, TBI also upregulated the following 14 anti-inflammatory and/or neuroregenerative mRNAs in the peripheral blood such as Ccl19, Ccl3, Cxcl19, IL-10, IL-22, IL-6, Bmp6, Ccl22, IL-7, Bmp7, Ccl2, Ccl17, IL-1rn, and Gpi. Second, we observed that EP inhibited both neurological injuries and six pro-inflammatory and/or neurodegenerative genes (Cxcl10, IL-18, IL-16, Cd70, Mif, and Faslg) but potentiated four anti-inflammatory and/or neuroregenerative genes (Bmp6, IL-10, IL-22, and IL-6). Prior depletion of cerebral HSP70 with gene silence significantly reversed the beneficial effects of EP in reducing neurological injuries and altered gene profiles after a TBI. A positive Pearson correlation exists between IL-6 and HSP70 in the peripheral blood or in the cerebral levels. In addition, gene silence of cerebral HSP70 significantly reduced the overexpression of NF-κB, IL-6, and synapsin I in the ipsilateral brain regions after an EP in rats.ConclusionsTBI causes neurological deficits associated with stimulating several pro-inflammatory gene profiles but inhibiting several anti-inflammatory gene profiles of cytokines and chemokines. Exercise protects against neurological injuries via stimulating an anti-inflammatory HSP70/NF-κB/IL-6/synapsin I axis in the injured brains.

Dataset Information

Inhibition of Epac2 Attenuates Neural Cell Apoptosis and Improves Neurological Deficits in a Rat Model of Traumatic Brain Injury.

Publications

Inhibition of Epac2 Attenuates Neural Cell Apoptosis and Improves Neurological Deficits in a Rat Model of Traumatic Brain Injury.

Similar Datasets

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