Pinar Eser Ocak1, Umut Ocak2, Prativa Sherchan3, Marcin Gamdzyk3, Jiping Tang3, John H Zhang4. 1. Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Neurosurgery, Uludag University School of Medicine, Bursa 16120, Turkey. 2. Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Emergency Medicine, Bursa Yuksek Ihtisas Training and Research Hospital, University of Health Sciences, Bursa 16310, Turkey; Department of Emergency Medicine, Bursa City Hospital, Bursa 16110, Turkey. 3. Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. 4. Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Neurology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Department of Neurosurgery, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. Electronic address: johnzhang3910@yahoo.com.
Abstract
INTRODUCTION: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. MATERIALS AND METHODS: Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. RESULTS: Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. CONCLUSIONS: Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.
INTRODUCTION: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. MATERIALS AND METHODS:Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. RESULTS:Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2aattenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. CONCLUSIONS:Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.
Authors: Umut Ocak; Pinar Eser Ocak; Lei Huang; Weilin Xu; Yuchun Zuo; Peng Li; Marcin Gamdzyk; Gang Zuo; Jun Mo; Guangyu Zhang; John H Zhang Journal: J Neuroinflammation Date: 2020-05-04 Impact factor: 8.322