Peptide LCGA-17 Attenuates Behavioral and Neurochemical Deficits in Rodent Models of PTSD and Depression

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 15; no. 4; p. 462
• Main Authors: Malyshev, Anton V, Sukhanova, Iuliia A, Ushakova, Valeria M, Zorkina, Yana A, Abramova, Olga V, Morozova, Anna Y, Zubkov, Eugene A, Mitkin, Nikita A, Pavshintsev, Vsevolod V, Doronin, Igor I, Gedzun, Vasilina R, Babkin, Gennady A, Sanchez, Sergio A, Baker, Miah D, Haile, Colin N
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.04.2022; MDPI
• Subjects: Animals; Antidepressants; Anxiety; Behavior; biogenic amines; chronic stress; Drug dosages; Drug therapy; Mental depression; novel treatment; peptide drug; Peptides; Physiology; Post traumatic stress disorder; Serotonin; Social research; Sucrose; Urine; biogenic amines; peptide drug; chronic stress; novel treatment
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph15040462

We have previously described the LCGA-17 peptide as a novel anxiolytic and antidepressant candidate that acts through the α2δ VGCC (voltage-gated calcium channel) subunit with putative synergism with GABA-A receptors. The current study tested the potential efficacy of acute and chronic intranasal (i.n.) LCGA-17 (0.05 mg/kg and 0.5 mg/kg) in rats on predator odor-induced conditioned place aversion (POCPA), a model of post-traumatic stress disorder (PTSD), and chronic unpredictable stress (CUS) that produce a range of behavioral and physiological changes that parallel symptoms of depression in humans. CUS and LCGA-17 treatment effects were tested in the sucrose preference (SPT) social interaction (SI), female urine sniffing (FUST), novelty-suppressed feeding (NSFT), and forced swim (FST) tests. Analysis of the catecholamines content in brain structures after CUS was carried out using HPLC. The efficacy of i.n. LCGA-17 was also assessed using the Elevated plus-maze (EPM) and FST. Acute LCGA-17 administration showed anxiolytic and antidepressant effects in EPM and FST, similar to diazepam and ketamine, respectively. In the POCPA study, LCGA-17 significantly reduced place aversion, with efficacy greater than doxazosin. After CUS, chronic LCGA-17 administration reversed stress-induced alterations in numerous behavioral tests (SI, FUST, SPT, and FST), producing significant anxiolytic and antidepressant effects. Finally, LCGA-17 restored the norepinephrine levels in the hippocampus following stress. Together, these results support the further development of the LCGA-17 peptide as a rapid-acting anxiolytic and antidepressant.