Effect of dexmedetomidine combined with hypothermia on acute brain edema in mice with traumatic brain injury

Abstract

Objective To explore the effect of Dexmedetomidine (Dex) on acute brain edema in mice in condition with targeted temperature management (TTM) following traumatic brain injury (TBI). Methods A total of 180 male C57BL/6J mice were divided into control group, sham operation group, TBI group, TBI+ Dex group, TBI+ TTM group, and TBI+ Dex+ TTM group according to the random number table (n=30 per group). The sham operation group only opened the bone window but did not hit it, and the control group did not open the bone window. The TBI+ Dex, TBI+ TTM, and TBI+ Dex+ TTM groups were intraperitoneally injected with Dex (60 μg/kg once every 2 h for 3 times) and/or hypothermia after TBI. The brain tissue injury volume, EB extravasation and brain water content of each group were determined by toluidine blue, Evans blue staining and dry-wet weight method at 24 hours after injury. Real-time quantitative PCR and Western blot were used to detect the expression of Claudin-5 in the injured brain tissue. At 24, 48, and 72 hours after injury, the neurological deficiency degree was assessed using the modified neurological severity scores(mNSS). Results Compared with the sham operation group, TBI mice showed significant increase in brain tissue injury volume [(0.49±0.04)mm3vs. (11.57±1.01)mm3], blood-brain barrier permeability [(16.4±0.8)μg/g vs. (54.3±1.7)μg/g], brain tissue water content [(76.7±0.9)% vs. (83.1±0.8)%], and mNSS score [(1.6±0.7)points vs. (13.4±0.7)points] at 24 hour after TBI (all P<0.01). However, Dex or TTM treatment reduced brain tissue injury volume [(7.20±0.18)mm3 and (5.94±0.18)mm3], blood-brain barrier permeability [(32.7±1.2)μg/g and (27.6±1.0)μg/g], brain tissue water content [(78.5±0.4)% and (78.2±0.6)%], and neurological function [mNSS: (7.3±1.1)points and (5.8±1.3)points] (all P<0.01). Moreover, Dex+ TTM group showed better neuroprotection [reduced brain tissue injury volume: (3.92±0.05)mm3, reduced BBB permeability: (21.6±0.7)μg/g, reduced brain water content: (77.7±0.3)%, and reduced mNSS: (4.3±1.2)points] compared with Dex or TTM alone (all P<0.01). Additionally, the mRNA expression of Claudin-5 (0.23±0.01) decreased significantly at 24 hours after TBI compared with sham group (0.93±0.04, P<0.01), but Dex or TTM could increase the expression of Claudin-5 (0.47±0.01, and 0.54±0.09) compared with TBI group (P<0.01), especially that of TBI+ Dex+ TTM group (0.64±0.02, P<0.01). Furthermore, the protein expression of Claudin-5 was in accordance with the result of its mRNA expression. Conclusion Dex in condition with targeted temperature management can up-regulate Claudin-5 expression in early TBI, protect the integrity of blood-brain barrier, attenuate acute brain edema and neurological damage, and improve neurological function recovery. Key words: Dexmedetomidine; Brain injuries; Brain edema; Hypothermia; Claudin-5