Moxonidine

Huntington's disease (HD)-associated depression is a prevalent psychiatric symptom affecting between one-third and over two-thirds of patients, significantly impacting their quality of life. Agmatine, a biogenic amine produced by the decarboxylation of L-arginine, has recently garnered attention for its antidepressant-like effects by modulating imidazoline receptors in neurodegenerative and mood disorders. This study aimed to investigate the effect of agmatine in attenuating depression-like behavior through its interaction with imidazoline receptors in a 3-Nitropropionic acid (3-NP) rat model of HD. 3-NP is a selective mitochondrial toxin known to induce bilateral striatal lesions by inhibiting succinate dehydrogenase enzyme, thereby contributing to psychiatric symptoms observed in HD. Rats received 3-NP (10 mg/kg, i.p.) on days 1, 3, 5, 7, and 9, followed by agmatine treatment on days 18-20. Systemic administration of 3-NP produced significant depressive-like behaviors, neurochemical imbalance, and neuroinflammation. However, treatment with imidazoline I1/I2 receptor agonist agmatine (10-20 mg/kg; i.p.), imidazoline I1 receptor agonist moxonidine (0.25 mg/kg; i.p.), and imidazoline I2 receptor agonist 2-(2-Benzofuranyl)-2-imidazoline hydrochloride (3 mg/kg; i.p.) with agmatine (5 mg/kg, i.p.) resulted in marked improvement in behavioral abnormalities exhibited by reduced immobility time in forced swim test, normalization of GABA/glutamate levels, decreased proinflammatory cytokines, and restored BDNF expression. Conversely, anti-depressant effects of agmatine were blocked by I1 receptor antagonist efaroxan (1 mg/kg; i.p.) and I2 receptor antagonist idazoxan (1 mg/kg; i.p.), signifying the involvement of imidazoline receptors in the beneficial effects of agmatine. In conclusion, these findings highlight the therapeutic potential of agmatine in mitigating psychiatric complications associated with HD through receptor-mediated mechanisms.

Previous studies have confirmed that microinjection of agmatine into the preoptic area (POA) induces hyperthermia in male rats, yet its receptor mechanism is known little. In the present study, using agonists and antagonists for imidazoline receptors (IRs) and α2-adrenoceptors (α2-ARs), to which agmatine binds with high affinity, we explored the roles of IRs and α2-ARs in hyperthermia induced by intra-POA agmatine in male rats. We found that intra-POA administration of the I1R agonist moxonidine elevated the core temperature and physical activity in conscious rats, enhanced brown adipose tissue (BAT) thermogenesis and shivering in anesthetized rats, and depressed the warm-sensitive neurons (WSNs) in POA slices in vitro, which aligned with previously demonstrated agmatine effects. Meanwhile, the selective I1R antagonist AGN192403 attenuated these effects. Moreover, fluorescence immunohistochemical analysis of Nischarin (a natural functional I1R) indicated that I1Rs were distributed in the POA. However, neither agonists nor antagonists for I2R or α2-ARs mimicked or attenuated the effects of intra-POA agmatine. In conclusion, we demonstrated that it is I1R rather than I2R or α2-ARs that mediates intra-POA agmatine-induced hyperthermia by elevating physical activity, BAT thermogenesis and shivering, likely through depression of POA WSNs. These results indicate an important role of the preoptic agmatine-I1R system in the thermoregulation.