Weidenfeld J, Corcos A P, Wohlman A, Feldman S
Department of Neurology, Hadassah University Hospital, Jerusalem, Israel.
Endocrinology. 1994 Apr;134(4):1924-31. doi: 10.1210/endo.134.4.8137760.
In the present study we examined the mechanisms involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis after administration of the glucose analog 2-deoxyglucose (2-DG), which inhibits intracellular glucose use. Adult male rats were injected with either 2-DG (400 mg/kg body wt ip) or vehicle and were killed 60 min later. 2-DG increased serum ACTH and corticosterone (CS) by 3- and 7-fold, respectively, as compared to vehicle-treated rats. Bilateral lesions of the lateral hypothalamic area completely inhibited the 2-DG-induced HPA axis activation. Administration of 2-DG caused a significant depletion in the CRF-41 content of the median eminence (ME). Pretreatment with dexamethasone (80 micrograms/kg body wt ip) inhibited the 2-DG-induced depletion of ME CRF-41 and the increase in serum ACTH and CS. To investigate the role of type I and type II corticosteroid receptors in mediating the feedback effect of endogenous glucocorticoids on the responses to 2-DG, specific type I (RU-28318) or type II (RU-38486) receptor antagonists were injected intracerebroventricularly (icv) (1 microgram/kg body wt). In rats pretreated with these antagonists, the recovery of serum ACTH and CS to basal levels after 2-DG was markedly inhibited. Injection of the serotonin (5-HT) neurotoxin, 5,7-dihydroxy-tryptamine, either into the raphe nuclei or icv, which caused a 50 and 70% depletion of the hypothalamic 5-HT content, respectively, did not affect the HPA axis responses to 2-DG. In contrast, icv injection of ketanserin, a 5-HT2 receptor antagonist, completely inhibited the 2-DG-induced activation of the HPA axis. The results suggest that: 1) the lateral hypothalamic area is involved in the mediation of the HPA axis responses to 2-DG; 2) CRF-41 released from the ME plays a dynamic role in mediating the 2-DG-induced adrenocortical response; 3) the effect of 2-DG is sensitive to inhibition by dexamethasone, and the feedback effect exerted by endogenous glucocorticoids is mediated by both type I and type II corticosteroid receptors; and 4) 5-HT is involved in the activation of the HPA axis after 2-DG via its interactions with 5-HT2 receptors.
在本研究中，我们检测了给予葡萄糖类似物2-脱氧葡萄糖（2-DG）后下丘脑-垂体-肾上腺（HPA）轴激活所涉及的机制，2-DG可抑制细胞内葡萄糖利用。成年雄性大鼠腹腔注射2-DG（400mg/kg体重）或溶剂，60分钟后处死。与溶剂处理的大鼠相比，2-DG使血清促肾上腺皮质激素（ACTH）和皮质酮（CS）分别增加了3倍和7倍。下丘脑外侧区双侧损伤完全抑制了2-DG诱导的HPA轴激活。给予2-DG导致正中隆起（ME）中促肾上腺皮质激素释放因子（CRF-41）含量显著减少。地塞米松（80μg/kg体重腹腔注射）预处理可抑制2-DG诱导的ME中CRF-41减少以及血清ACTH和CS增加。为研究I型和II型糖皮质激素受体在介导内源性糖皮质激素对2-DG反应的反馈作用中的作用，将特异性I型（RU-28318）或II型（RU-38486）受体拮抗剂脑室内注射（icv）（1μg/kg体重）。在用这些拮抗剂预处理的大鼠中，2-DG后血清ACTH和CS恢复至基础水平受到明显抑制。将5-羟色胺（5-HT）神经毒素5,7-二羟基色胺注射到中缝核或脑室内，分别导致下丘脑5-HT含量减少50%和70%，但不影响HPA轴对2-DG的反应。相反，脑室内注射5-HT2受体拮抗剂酮色林完全抑制了2-DG诱导的HPA轴激活。结果表明：1）下丘脑外侧区参与介导HPA轴对2-DG的反应；2）从ME释放的CRF-41在介导2-DG诱导的肾上腺皮质反应中起重要作用；3）2-DG的作用对地塞米松抑制敏感，内源性糖皮质激素发挥的反馈作用由I型和II型糖皮质激素受体介导；4）5-HT通过与5-HT2受体相互作用参与2-DG后HPA轴的激活。
