Spexin-Based Galanin Receptor Type 2 Agonist for Comorbid Mood Disorders and Abnormal Body Weight

Abstract

Despite the established comorbidity between mood disorders and abnormal eating behaviors, the underlying molecular mechanism and therapeutics remain to be resolved. Here, we show that a spexin-based galanin receptor type 2 agonist (SG2A) simultaneously normalized mood behaviors and body weight in corticosterone pellet-implanted (CORTI) mice, which are underweight and exhibit signs of anhedonia, increased anxiety, and depression. Administration of SG2A into the lateral ventricle produced antidepressive and anxiolytic effects in CORTI mice. Additionally, SG2A led to a recovery of body weight in CORTI mice while it induced significant weight loss in normal mice. In Pavlovian fear-conditioned mice, SG2A decreased contextual and auditory fear memory consolidation but accelerated the extinction of acquired fear memory without altering innate fear and recognition memory. The main action sites of SG2A in the brain may include serotonergic neurons in the dorsal raphe nucleus for mood control, and proopiomelanocortin/corticotropin-releasing hormone neurons in the hypothalamus for appetite and body weight control. Furthermore, intranasal administration of SG2A exerted the same anxiolytic and antidepressant-like effects and decreased food intake and body weight in a dose-dependent manner. Altogether, these results indicate that SG2A holds promise as a clinical treatment for patients with comorbid mood disorders and abnormal appetite/body weight.

Evolution of Structural and Functional Diversity of Spexin in Mammalian and Non-mammalian Vertebrate Species

“…Schematic drawing of the representative localization of SPX1, GALR2a/2b, and GARL3 in the sagittal sections of the brain of various vertebrate species. SPX1 has only localized in rodent (2, 25, 26), goldfish (7), and zebrafish (27, 28). GALR2a/2b was not localized in goldfish.…”

“…Cortex of adrenal gland in the adult rats (29) and Type I glomic cells within the carotid body of both rat and human (30) are also positive for SPX. Intriguingly, SPX signals was detected in the medial habenula and suprachiasmatic nucleus of the hypothalamus in mice (26).…”

“…Furthermore, intranasal application of this agonist produced the same effect as i.c.v. administration, increasing the therapeutic application of this agonist (26).…”

Exploring the molecular structures that confer ligand selectivity for galanin type II and III receptors

“…Like SPX, SG2A interacts with GALR2 to induce G q -coupled stimulatory signaling with little internalization of the receptor, but it lacks activity toward GALR3 [15]. Treatment of cortisolinduced depression-like mice with SG2A led to a decrease in anxiety and depressive behaviors, likely via the activation of serotonergic neurons located in the dorsal raphe nucleus [27]. That result is in good agreement with previous reports of GALR2-mediated anxiolytic and antidepressant effects [28,29], suggesting that SG2A and SPX activate GALR2 similarly under pathophysiological conditions.…”

The unique expression profile of FAM19A1 in the mouse brain and its association with hyperactivity, long-term memory and fear acquisition

“…Before commencing the behavioral tests, all male mice (8-12 weeks old) were handled for 5 min daily for 3 days to habituate them to the hands of the test instructor. See the Supplementary Information for details on the elevated plus maze (EPM) test, open field test (OFT), tail suspension test (TST), Y-maze, novel object recognition (NOR) test, Pavlovian fear conditioning and unconditioned innate fear response, which were performed as previously described 64 .…”