Nakade Yukiomi, Yoneda Masashi, Nakamura Kimihide, Makino Isao, Terano Akira
Second Department of Medicine, Asahikawa Medical College, Asahikawa 078-8510, Japan.
Am J Physiol Regul Integr Comp Physiol. 2002 Jun;282(6):R1782-8. doi: 10.1152/ajpregu.00514.2001.
Central neuropeptides play important roles in many physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Central injection of corticotropin-releasing factor (CRF) aggravates carbon tetrachloride (CCl4)-induced acute liver injury through the sympathetic nervous pathway in rats. However, still nothing is known about a role of endogenous neuropeptides in the brain in hepatic pathophysiological regulations. Involvement of endogenous CRF in the brain in CCl4-induced acute liver injury was investigated by centrally injecting a CRF receptor antagonist in rats. Male fasted Wistar rats were injected with CRF receptor antagonist alpha-helical CRF-(9-41) (0.125-5 microg) intracisternally just before and 6 h after CCl4 (2 ml/kg) administration, and blood samples were obtained before and 24 h after CCl4 injection for measurement of hepatic enzymes. The liver sample was removed 24 h after CCl4 injection, and histological changes were examined. Intracisternal alpha-helical CRF-(9-41) dose dependently (0.25-2 microg) reduced the elevation of alanine aminotransferase and aspartate aminotransferase levels induced by CCl4. Intracisternal alpha-helical CRF-(9-41) reduced CCl4-induced liver histological changes, such as centrilobular necrosis. The effect of central CRF receptor antagonist on CCl4-induced liver injury was abolished by sympathectomy and 6-hydroxydopamine pretreatment but not by hepatic branch vagotomy or atropine pretreatment. These findings suggest the regulatory role of endogenous CRF in the brain in experimental liver injury in rats.
中枢神经肽在通过自主神经系统介导的许多生理和病理生理调节中发挥重要作用。就肝胆系统而言，几种神经肽在大脑中起作用以调节胆汁分泌、肝血流量和肝脏增殖。在大鼠中，中枢注射促肾上腺皮质激素释放因子（CRF）通过交感神经通路加重四氯化碳（CCl4）诱导的急性肝损伤。然而，关于内源性神经肽在大脑中对肝脏病理生理调节的作用仍一无所知。通过向大鼠脑室内注射CRF受体拮抗剂来研究内源性CRF在大脑中对CCl4诱导的急性肝损伤的影响。雄性禁食Wistar大鼠在给予CCl4（2 ml/kg）之前和之后6小时脑室内注射CRF受体拮抗剂α-螺旋CRF-（9-41）（0.125 - 5μg），在CCl4注射前和注射后24小时采集血样以测定肝酶。在CCl4注射后24小时取出肝脏样本，检查组织学变化。脑室内注射α-螺旋CRF-（9-41）剂量依赖性地（0.25 - 2μg）降低了CCl4诱导的丙氨酸转氨酶和天冬氨酸转氨酶水平的升高。脑室内注射α-螺旋CRF-（9-41）减轻了CCl4诱导的肝脏组织学变化，如小叶中心坏死。中枢CRF受体拮抗剂对CCl4诱导的肝损伤的作用通过交感神经切除术和6-羟基多巴胺预处理被消除，但肝支迷走神经切断术或阿托品预处理则不能消除。这些发现提示内源性CRF在大脑中对大鼠实验性肝损伤具有调节作用。
