Onat Akyol1, Prativa Sherchan1, Gokce Yilmaz1, Cesar Reis1, Wingi Man Ho1, Yuechun Wang1, Lei Huang2, Ihsan Solaroglu3, John H Zhang4. 1. Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA. 2. Department of Neurosurgery, Loma Linda University, CA 92354, USA. 3. Koç University, School of Medicine, Department of Neurosurgery, Rumelifeneri Yolu, 34450 Sarıyer, Istanbul, Turkey. 4. Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA; Department of Neurosurgery, Loma Linda University, CA 92354, USA; Department of Anesthesiology, Loma Linda University, CA 92354, USA. Electronic address: johnzhang3910@yahoo.com.
Abstract
BACKGROUND: Surgical brain injury (SBI) which occurs due to the inadvertent injury inflicted to surrounding brain tissue during neurosurgical procedures can potentiate blood brain barrier (BBB) permeability, brain edema and neurological deficits. This study investigated the role of neurotrophin 3 (NT-3) and tropomyosin related kinase receptor C (TrkC) against brain edema and neurological deficits in a rat SBI model. METHODS: SBI was induced in male Sprague Dawley rats by partial right frontal lobe resection. Temporal expression of endogenous NT-3 and TrkC was evaluated at 6, 12, 24 and 72 h after SBI. SBI rats received recombinant NT-3 which was directly applied to the brain surgical injury site using gelfoam. Brain edema and neurological function was evaluated at 24 and 72 h after SBI. Small interfering RNA (siRNA) for TrkC and Rap1 was administered via intracerebroventricular injection 24 h before SBI. BBB permeability assay and western blot was performed at 24 h after SBI. RESULTS: Endogenous NT-3 was decreased and TrkC expression increased after SBI. Topical administration of recombinant NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. Recombinant NT-3 administration increased the expression of phosphorylated Rap1 and Erk5. The protective effect of NT-3 was reversed with TrkC siRNA but not Rap1 siRNA. CONCLUSIONS: Topical application of NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. The protective effect of NT-3 was possibly mediated via TrkC dependent activation of Erk5.
BACKGROUND: Surgical brain injury (SBI) which occurs due to the inadvertent injury inflicted to surrounding brain tissue during neurosurgical procedures can potentiate blood brain barrier (BBB) permeability, brain edema and neurological deficits. This study investigated the role of neurotrophin 3 (NT-3) and tropomyosin related kinase receptor C (TrkC) against brain edema and neurological deficits in a rat SBI model. METHODS: SBI was induced in male Sprague Dawley rats by partial right frontal lobe resection. Temporal expression of endogenous NT-3 and TrkC was evaluated at 6, 12, 24 and 72 h after SBI. SBI rats received recombinant NT-3 which was directly applied to the brain surgical injury site using gelfoam. Brain edema and neurological function was evaluated at 24 and 72 h after SBI. Small interfering RNA (siRNA) for TrkC and Rap1 was administered via intracerebroventricular injection 24 h before SBI. BBB permeability assay and western blot was performed at 24 h after SBI. RESULTS: Endogenous NT-3 was decreased and TrkC expression increased after SBI. Topical administration of recombinant NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. Recombinant NT-3 administration increased the expression of phosphorylated Rap1 and Erk5. The protective effect of NT-3 was reversed with TrkC siRNA but not Rap1 siRNA. CONCLUSIONS: Topical application of NT-3 reduced brain edema, BBB permeability and improved neurological function after SBI. The protective effect of NT-3 was possibly mediated via TrkC dependent activation of Erk5.
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