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  • In the preclinical evaluation of CRF receptor antagonists ef

    2020-11-19

    In the preclinical evaluation of CRF1 receptor antagonists, effects were mainly focused on the regulation of hyperactivated HPA axis and the modulation of anxiety or depressive-like behaviors in CRF challenge [16], [17], [18] or stress models [16], [19], [20]. However, it remains to be concluded whether the antagonism of CRF1 receptor in the peripheral, central, or both systems, is required to exert anxiolytic or antidepressive efficacy. Recently, multiple reports have indicated that central, especially limbic, CRF1 receptors modulate anxiety-related behavior independent of endocrinological HPA regulation. Conditional knockout mice of limbic CRF1 receptors reduced the anxiety behavior, but not the stress-induced increase of ACTH secretion [13]. Transient over-expression of CRF in the forebrain induced neuroendocrinological and behavioral changes [21]; however, the overexpression of CRF only in the pituitary did not induce anxiety behavior [22]. The CRF1 receptor antagonist SSR125543 attenuated long-term cognitive deficit induced by acute inescapable stress independent of the regulation of the HPA axis [23]. In this study, to investigate the roles of peripheral or central CRF signaling in endocrinological and behavioral changes, we measured the activity of HPA axis as plasma ACTH concentration, locomotion, and anxiety behavior after peripheral or central CRF challenges. Moreover, two CRF1 receptor antagonists, Compound A and Compound B, were identified from our drug discovery research. They were found to have different binding profiles for central CRF1 receptors indicated in the ex vivo binding assay with rat cortex homogenate, and were used to study the in vivo effects of antagonism of peripheral and central CRF1 receptors.
    Materials and methods
    Results
    Discussion Mood disorders such as depression and anxiety are medicated by selective serotonin reuptake inhibitors (SSRI) and benzodiazepine anxiolytics in the current clinical situation [28]. SSRIs enhance monoamine neurotransmission by inhibiting its reuptake. Benzodiazepine works by activating GABAA receptors. Various SSRIs and Benzodiazepines have been launched so far; however, there are still high unmet needs in the early onset of efficacy and safety. CRF1 receptor antagonists have been expected to be one candidate of the new drug for mood disorders with new mechanism of action, however, clinical trials conducted so far have not succeeded in showing the expected efficacy [29]. Nevertheless, as stress is related to mood disorders [30], CRF1 receptor antagonists may still have opportunities to provide efficacy on stress-related mental diseases, such as anxiety and post-traumatic stress disorder. This study confirmed that the central CRF challenge, but not peripheral challenge, induced behavioral changes in locomotion and anxious behavior, whereas endocrinological response in the HPA axis can be activated by both central and peripheral CRF challenges. These results are in agreement with the reported findings in rats [31] and indicate that the regulation of CRF signaling related to locomotion and anxiety in the hiv integrase may be independent from HPA axis regulation. The other was that a CRF1 receptor antagonist, Compound A, which inhibits binding of [125I]-CRF in the frontal cortex and the pituitary, decreased behavioral changes induced by central CRF challenge, whereas Compound B, another CRF1 receptor antagonist which inhibits binding of [125I]-CRF only at the pituitary located outside the BBB, did not. These results indicate that the central CRF1 receptor antagonism would be involved in anxiolytic and other behavioral effects. Although the relationship between central and peripheral regulation of CRF signaling is yet to be elucidated, an accumulation of findings indicates independent regulation between central and peripheral CRF signaling. For example, i.c.v. administration of CRF to hypophysectomized rats induced locomotor activation [32] and anxiety behavior [33], but not HPA axis activation. Pryce et al. also compared central and peripheral responses of CRF in endocrinological and behavioral changes. In this report, i.c.v. CRF induced the activation of HPA axis and locomotor inactivity in mice, and the hyper-HPA axis was blocked only by i.p.-injected astressin, and not by i.c.v.-injected astressin, although locomotion was blocked only by i.c.v.-injected astressin [34]. This indicates that the HPA axis may be regulated by CRF at the pituitary level. Results from conditional knockout mice of Crhr1 only in the anterior forebrain using calcium/calmodulin-dependent kinase II╬▒ promoter suggest that the mice showed reduced anxiety with the normal system of HPA axis, although the feedback process of the HPA axis would be impaired by causing the absence of cortical CRF1 receptor [13]. In our experiment, peripheral or central challenges of CRF were conducted to understand endocrinological and behavioral changes induced by CRF. Although HPA activation was induced by both peripheral and central CRF challenges (Fig. 1), increase in locomotion (Fig. 2) and anxiety behavior (Fig. 3) were induced only by central CRF challenge, which are consistent with the earlier reported results. Preclinical effects of CRF1 receptor antagonists have been reported in behavioral assays with exogenously administered CRF [16], [35]. Central challenges of CRF have been known to induce direct peripheral effects on stimulation of the pituitary corticotropic cell, located outside the BBB [36], [37]. Therefore the central administration of CRF activates HPA axis via direct activation of CRF1 receptors in the anterior pituitary, which is outside the BBB [38]. In contrast, most reported studies do not show evidence of direct central effects after peripheral CRF challenge [39]. A report by Kastin et al. regarding blood-to-brain entry of [125I]-CRH indicates that the influx of CRF into the brain was low and there would be a saturable efflux system out of the brain [40], which indicates that the activation of HPA axis after i.v. administration of CRF can be induced only by CRF receptor activation in the anterior pituitary. In this aspect, evaluating CRF1 receptor antagonists on behavioral or neurochemical changes by central CRF challenges may provide key information for identifying potential drug candidates as novel anxiolytics or antidepressants. Further hiv integrase research, especially regarding the regulation of CRF signaling under these physiological conditions, may be important because it is reported that permeability of the BBB may be changed by peripheral CRF activation under acute stress [41] or according to developmental stages [42].