title: Recombinant Slit2 Reduces Surgical Brain Injury Induced Blood Brain Barrier Disruption via Robo4 Dependent Rac1 Activation in a Rodent Model.
abstract: Brain tissue surrounding surgical resection site can be injured inadvertently due to procedures such as incision, retractor stretch, and electrocauterization when performing neurosurgical procedures, which is termed as surgical brain injury (SBI). Blood brain barrier (BBB) disruption due to SBI can exacerbate brain edema in the post-operative period. Previous studies showed that Slit2 exhibited vascular anti-permeability effects outside the brain. However, BBB protective effects of Slit2 following SBI has not been evaluated. The objective of this study was to evaluate whether recombinant Slit2 via its receptor roundabout4 (Robo4) and the adaptor protein, Paxillin were involved in reducing BBB permeability in SBI rat model. Our results showed that endogenous Slit2 increased in the surrounding peri-resection brain tissue post-SBI, Robo4 remained unchanged and Paxillin showed a decreasing trend. Recombinant Slit2 administered 1 h before injury increased BBB junction proteins, reduced BBB permeability, and decreased neurodeficits 24 h post-SBI. Furthermore, recombinant Slit2 administration increased Rac1 activity which was reversed by Robo4 and Paxillin siRNA. Our findings suggest that recombinant Slit2 reduced SBI-induced BBB permeability, possibly by stabilizing BBB tight junction via Robo4 mediated Rac1 activation. Slit2 may be beneficial for BBB protection during elective neurosurgeries.
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, 92354, USA.
authors.forename: Prativa
authors.initials: P
authors.lastname: Sherchan
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, 92354, USA.|Department of Anesthesiology, Loma Linda University, California, 92354, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, 92354, USA.
authors.forename: Onat
authors.initials: O
authors.lastname: Akyol
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, 92354, USA.
authors.forename: Cesar
authors.initials: C
authors.lastname: Reis
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, 92354, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, California, 92354, USA. johnzhang3910@yahoo.com.|Department of Anesthesiology, Loma Linda University, California, 92354, USA. johnzhang3910@yahoo.com.|Department of Neurosurgery, Loma Linda University, California, 92354, USA. johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007431:Intraoperative Complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D009928:Organ Specificity / Q000235:genetics; D051419:Paxillin / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D051419:Paxillin; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D020830:rac1 GTP-Binding Protein; D000098552:Slit Homolog 2 Protein; C578845:Robo4 protein, rat; D000097905:Roundabout Proteins