The Nociceptin/Orphanin FQ peptide receptor antagonist, SB-612111, improves cerebral blood flow in a rat model of traumatic brain injury.
The Nociceptin/Orphanin FQ peptide receptor antagonist, SB-612111, improves cerebral blood flow in a rat model of traumatic brain injury.
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DOI：
10.3389/fphar.2023.1272969
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发表时间：
2023
影响因子：
5.6
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中科院分区：
文献类型：
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创伤性脑损伤（TBI）每年影响美国超过250万人，是1至44岁儿童和成人死亡和残疾的主要原因。大约90%的TBI病例被归类为轻度，但仍可能导致急性有害影响，如脑血流量（CBF）受损，导致高达15%的患者的脑功能和生活质量受到长期影响。我们以前报道过，孤啡肽/N/OFQ肽（NOP）受体拮抗剂逆转轻度冲击波TBI诱导的前庭功能障碍，并防止缺氧。为了探索NOP受体-N/OFQ途径调节缺氧和其他TBI后遗症的机制，在本研究中测试了NOP拮抗剂SB-612111（SB）逆转TBI诱导的CBF和相关损伤标志物变化的能力。雄性Wistar大鼠随机接受假开颅术或开颅术+ TBI通过控制皮质撞击。1小时后评估损伤严重程度（改良神经系统严重程度评分（mNSS））。在损伤后2小时，使用激光散斑对比成像评估暴露皮质上方的CBF变化，以响应向脑表面直接应用浓度递增的溶剂或SB（1、10和100 µM）。与基线相比，TBI增加了mNSS评分，并证实了轻度TBI（mTBI）的严重程度。与对侧和假手术大鼠相比，mTBI后同侧脑CBF显著受损。SB剂量依赖性地改善CBF的同侧mTBI后SB的影响，对各自的同侧的假手术大鼠，但对对侧CBF或未受伤的大鼠没有影响。mTBI后脑脊液（CSF）中N/OFQ水平升高，这与同侧CBF的百分比降低相关。TBI后3小时内还激活ERK和cofilin; ERK激活与CSF N/OFQ增加相关。总之，这项研究揭示了一个显着的贡献N/OFQ-NOP受体系统TBI诱导的脑血管失调，并建议NOP受体应被视为一个潜在的治疗靶点TBI。
Traumatic brain injury (TBI) affects more than 2.5 million people in the U.S. each year and is the leading cause of death and disability in children and adults ages 1 to 44. Approximately 90% of TBI cases are classified as mild but may still lead to acute detrimental effects such as impaired cerebral blood flow (CBF) that result in prolonged impacts on brain function and quality of life in up to 15% of patients. We previously reported that nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonism reversed mild blast TBI-induced vestibulomotor deficits and prevented hypoxia. To explore mechanisms by which the NOP receptor-N/OFQ pathway modulates hypoxia and other TBI sequelae, the ability of the NOP antagonist, SB-612111 (SB), to reverse TBI-induced CBF and associated injury marker changes were tested in this study. Male Wistar rats randomly received sham craniotomy or craniotomy + TBI via controlled cortical impact. Injury severity was assessed after 1 h (modified neurological severity score (mNSS). Changes in CBF were assessed 2 h post-injury above the exposed cortex using laser speckle contrast imaging in response to the direct application of increasing concentrations of vehicle or SB (1, 10, and 100 µM) to the brain surface. TBI increased mNSS scores compared to baseline and confirmed mild TBI (mTBI) severity. CBF was significantly impaired on the ipsilateral side of the brain following mTBI, compared to contralateral side and to sham rats. SB dose-dependently improved CBF on the ipsilateral side after mTBI compared to SB effects on the respective ipsilateral side of sham rats but had no effect on contralateral CBF or in uninjured rats. N/OFQ levels increased in the cerebral spinal fluid (CSF) following mTBI, which correlated with the percent decrease in ipsilateral CBF. TBI also activated ERK and cofilin within 3 h post-TBI; ERK activation correlated with increased CSF N/OFQ. In conclusion, this study reveals a significant contribution of the N/OFQ-NOP receptor system to TBI-induced dysregulation of cerebral vasculature and suggests that the NOP receptor should be considered as a potential therapeutic target for TBI.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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作者：
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作者：
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DOI：
10.1046/j.1440-1681.2002.03634.x
发表时间：
2002-03-01
影响因子：
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通讯作者：
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