Abstract
Cisplatin is one of the most potent anti-cancer drugs, though several side effects can induce stress responses such as activation of the hypothalamic–pituitary adrenal (HPA) axis. Arginine vasopressin (AVP) and corticotrophin-releasing hormone (CRH) expressed in the parvocellular division of the paraventricular nucleus (pPVN) play an important role in the stress-induced activation of the HPA axis. We aimed to evaluate whether intraperitoneal (i.p.) administration of cisplatin could activate parvocellular neurons in the pPVN, using a transgenic rat model that expresses the fusion gene of AVP and enhanced green fluorescent protein (eGFP). Along with the induction of FosB, a marker of neuronal activation, i.p. administration of cisplatin significantly increased eGFP fluorescent intensities in the pPVN. In situ hybridization histochemistry revealed that AVP-eGFP and CRH mRNAs in the pPVN were increased significantly in cisplatin-treated rats. These results suggest that cisplatin administration increases neuronal activation and upregulates AVP and CRH expression in the pPVN.
Highlights
Recent advances in anti-cancer drug therapy have improved patients’ survival rates; various side effects such as fatigue, nausea, and vomiting occur frequently during chemotherapy
We focused on arginine vasopressin (AVP) in the hypothalamus, which is known to be secreted under chronic stressful condition [4] and related to anorexia [5]
Quantification of enhanced green fluorescent protein (eGFP) intensity in the parvocellular division of the paraventricular nucleus (pPVN) after i.p. administration of cisplatin The representative images captured on a fluorescent microscopic show marked increases in eGFP fluorescence in the pPVN 12 h after i.p. administration of cisplatin compared with pre-injected baseline (0 h) (Fig. 1Ae)
Summary
Recent advances in anti-cancer drug therapy have improved patients’ survival rates; various side effects such as fatigue, nausea, and vomiting occur frequently during chemotherapy. We focused on characterizing the effects of intraperitoneal (i.p.) administration of cisplatin on AVP synthesis in the pPVN, using a transgenic rat model that expressed the fusion gene of the AVP and the enhanced green fluorescent proteins (eGFP) [9]. This AVP-eGFP transgenic rat is a useful animal model to evaluate the hypothalamic synthesis of AVP; increased AVP expression in reflected by changes in eGFP fluorescent intensity under various stressful conditions [10,11,12,13]. A past study showed that eGFP fluorescent intensity in the pPVN was increased dramatically after bilateral adrenalectomy (ADX) and this upregulation could be reversed by dexamethasone administration in AVP-eGFP transgenic rats [11]
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