Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema.
Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema.
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选择性 V1a 受体拮抗剂 SR49059 调节 AQP4 表达可减少创伤引起的脑水肿。
DOI：
10.1007/978-3-211-85578-2_83
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Marmarou,Anthony
中科院分区：
文献类型：
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作者：
Taya,Keisuke;Gulsen,Salih;Okuno,Kenji;Prieto,Ruth;Marmarou,ChristinaR;Marmarou,Anthony
背景目前，对于创伤性脑水肿和随后的颅内压升高，还没有可用的药物治疗方法。有证据表明，水通道蛋白-4(Aqua-porin-4，AQP4)在脑水肿的发病机制中起重要作用。此前，我们已报道SR49059可减轻继发性脑缺血引起的脑水肿。因此，我们研究了选择性V1a受体拮抗剂SR49059是否通过调节AQP4的表达来减轻皮质挫伤(CCI)后的脑水肿。方法32只成年雄性SD大鼠采用侧方挫伤(6.0m/s，3 mm深度)造成创伤性脑损伤(TBI)。动物随机分为赋形剂组(n=16)和SR49059治疗组(n=16)和给药组(960μL/小时静脉注射)。受伤后立即服用，超过5小时。采用湿/干法测定脑组织含水量，免疫印迹法检测AQP4蛋白表达，以AQP4/亲环素A密度比值表示。结果损伤侧右前(RA)和右后(RP)段AQP4表达水平和水含量均高于健侧(包括左前(LA)和右前(RA)段)。SR药物治疗组动物挫伤区水通道蛋白4平均表达水平(RA：1.313±0.172，RP：1.308±0.175)明显低于赋形剂治疗组(RA：2.181±0.232，RP：2.303±0.370，p=0.001，p=0.003)。SR治疗组损伤侧大脑半球水含量(78.89±0.14)较对照组(80.38±0.38)显著降低(P<0.01)。结论SR49059能显著降低创伤后挫伤侧大脑半球AQP4表达的上调。此外，随着AQP4的抑制，脑组织含水量也显著降低。这些数据进一步支持了血管加压素(AVP)和V1a受体可以通过调节AQP4的表达来控制星形胶质细胞质膜的水通量。综合来看，这些结果证实了我们实验室的观点，即AQP4可以被有效的药理学调节。
BackgroundCurrently, there are no pharmacological treatments available for traumatically induced brain edema and the subsequent rise of ICP. Evidence indicates that Aqua-porin-4 (AQP4) plays a significant role in the pathophys-iology of brain edema. Previously we have reported that SR49059 reduced brain edema secondary to ischemia. We, therefore, examined whether the selective V1a receptor antagonist, SR49059, reduces brain edema by modulating AQP4 expression following cortical contusion injury (CCI).MethodsTraumatic brain injury (TBI) was produced in thirty-two adult male Sprague-Dawley rats by lateral CCI (6.0 m/sec, 3 mm depth). Animals were randomly assigned to vehicle (n=16) or SR49059 treatment (n=16) groups and administered drug (960 μl/hr i.v.) immediately after injury over a 5 hr period. Animals were sacrificed for assessment of brain water content by Wet/Dry method and AQP4 protein expression by immunoblotting expressed as the ratio of AQP4 and Cyclophilin-A densitometries.FindingsElevated AQP4 expression levels and water content were observed on the right injured side in both the right anterior (RA) and right posterior (RP) section compared to the left non-injured side inclusive of the left anterior (LA) and right anterior (RA) sections. The average AQP4 expression levels in contused areas for animals receiving SR drug treatment (RA: 1.313±0.172, RP: 1.308± 0.175) were significantly decreased from vehicle-treated animals (RA: 2.181±0.232, RP: 2.303±0.370, p=0.001, p= 0.003). Water content levels on SR treatment (78.89±0.14) was also significantly decreased from vehicle levels (80.38± 0.38, p<0.01) in the traumatized hemisphere.ConclusionsSR49059 significantly reduced trauma-induced AQP4 up-regulation in the contused hemisphere. Moreover, brain water content was also significantly reduced paralleling the AQP4 suppression. These data provide further support that vasopressin (AVP) and V1a receptors can control water flux through astrocytic plasma membranes by regulating AQP4 expression. Taken in concert, these results affirm our laboratories contention that AQP4 can be effectively modulated pharmacologically.