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    • Somatostatin analogs also bind to somatostatin receptors It

    2022-11-17

    Somatostatin analogs also bind to somatostatin receptors. It has been reported that octreotide has a high affinity for hSSTR2, moderate affinity for hSSTR3 and hSSTR5, and does not bind to hSSTR1 or hSSTR4 (Ben-Shlomo and Melmed 2008). Compared to octreotide, pasireotide displays 40-, 30-, and 5-fold higher binding affinities for hSSTR5, hSSTR1, and hSSTR3, respectively, and a 2.5 fold lower binding affinity for hSSTR2 (Bruns et al. 2002). Pasireotide and octoretide were both shown to reduce basal ACTH release and CRH-induced ACTH release in an in vitro study using canine ACTH adenomas (de Bruin et al. 2008). In Europe and the United States, the use of pasireotide has recently been approved for the treatment of adult patients with Cushing's disease for whom pituitary surgery is not a therapeutic option or has not been curative (Cuevas-Ramos and Fleseriu 2014). In human patients with Cushing's disease treated by pasireotide, it was found that urinary-free SR 59230A hydrochloride levels decreased by approximately 50%, and clinical symptoms diminished (Colao et al. 2012). In canine ACTH-secreting pituitary adenoma cells, SSTR2, DA2R and SSTR5 mRNA expression has been shown to be high, moderate, and low, respectively (de Bruin et al. 2008). It has also been reported in veterinary medical science that pasireotide decreased ACTH level, urinary cortisol/creatinine ratio, and pituitary tumor size, and also improved the clinical signs of Cushing's disease dogs (Castillo et al. 2011). Dopamine is produced in the arcuate nucleus of the hypothalamus and in the periventricular dopaminergic neurons; subsequently, it is released into the hypothalamic-hypophysial portal vein and regulates pituitary hormone secretions via the dopamine D2 receptor (DA2R) in the anterior lobe. In particular, dopamine strongly inhibits prolactin secretion. In contrast, the pars intermedia, which is relatively avascular, is controlled by neural regulation. The secretion of ACTH from the pars intermedia is under tonic negative regulation by dopamine secreted from the hypothalamic arcuate nucleus (Feldman et al., 2015) Cabergoline and bromocriptine, dopamine agonists that bind to DA2R, are first-choice treatments for human prolactin-secreting pituitary adenoma because of their high efficacy. DA2R has been found to be expressed in approximately 80% of human ACTH-secreting pituitary adenomas (Pivonello et al. 2004). There are some reports of the effectiveness of cabergoline and bromocriptine for human Cushing's disease. It was shown that bromocriptine inhibited ACTH secretion in half of patients with Cushing's disease during the early treatment period; whereas, effectiveness was limited with long-term use (de Bruin et al. 2009). Cabergoline has a higher affinity for DA2R and a longer duration of activity compared to bromocriptine. It has been described that the urinary free cortisol levels were reduced in 60% of patients with Cushing's disease who were treated with cabergoline, and levels were normalized in 40% (Pivonello et al. 2004). In another study, 20% of patients with Cushing's disease who were treated with cabergoline for 24 months showed tumor shrinkage (Pivonello et al. 2009). In an in vitro study using canine ACTH-secreting pituitary adenomas, CRH-induced ACTH secretion was reduced by cabergoline (de Bruin et al. 2008). Somatostatin analogs and dopamine agonists are known to be effective for the treatment of Cushing's disease in humans. It is important to know the expression of those target receptors. In veterinary medical science, the mRNA expression of SSTR2, SSTR5 and DA2R in ACTH-secreting pituitary adenomas and the histologic protein expression of SSTR2 in normal canine pituitary glands and ACTH-secreting pituitary adenomas have been reported (de Bruin et al. 2008). However, the histologic protein expression of SSTR5 and DA2R in normal canine pituitary glands and ACTH-secreting pituitary adenomas are unknown. In this study, we immunohistologically evaluated SSTR2, SSTR5, and DA2R in ACTH-positive cells of healthy dogs and dogs with Cushing's disease.