Peripherally administered cisplatin activates a parvocellular neuronal subtype expressing arginine vasopressin and enhanced green fluorescent protein in the paraventricular nucleus of a transgenic rat

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.

Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

“…Both agents resulted in a marked increase in both GDF15 and corticosterone. Cisplatin has previously been reported to activate the HPA axis in rats and dogs (9,10). There is one report in humans (48), which describes the opposite effect but blood sampling in this study was limited to the first 6 h after drug administration and to a small number of patients.…”

“…Earlier literature contains several reports of increases in circulating glucocorticoid levels in rodents occurring in response to a range of toxins, including honey bee and snake venom (6,7), cyanide (8), and purified diphtheria toxin (8). More recently, genotoxins such as cisplatin have been shown to activate the HPA axis in dogs and rats (9,10).…”

The Testicular Protection Effect of Thiamine Pyrophosphate Against Cisplatin-treated Male Rats

“…Anterior pituitary gland secret LH in response to GnRH which in turn stimulates Leydig cells to produce testosterone. Therefore, the expected low level of testosterone may be due to the direct chemical influence of cisplatin on Leydig cells and the effect of epithelial layers of germ cells on LH-Leydig cell-axis, or indirectly by downregulating the sensitivity hypothalamic-pituitary axis to the negative feedback mechanism, i.e., cisplatin stimulate inhibitory neuron circuit that controls feedback mechanism, including arginine vasopressin (AVP) in the CNS [27] . This, in turn, stimulates Corticotrophin-Releasing Hormone (CRH) and ACTH from the medullary region of the adrenal gland in the PKC-dependent pathway [28] .…”