Antidepressant effect of PT-31, an α2-adrenoceptor agonist, on lipopolysaccharide-induced depressive-like behavior in mice.

Increasing evidence indicates that neuroinflammation, oxidative stress, and neurotrophic factors play a key role in the pathophysiology of major depressive disorder (MDD). In addition, the attenuation of inflammatory response has been considered a putative mechanism for MDD treatment. PT-31 is an imidazolidine derivative and a putative α2-adrenoceptor agonist that has previously demonstrated antinociceptive activity. The present study aimed to investigate the effect of PT-31 on depressive-like behavior and lipopolysaccharide-induced neurochemical changes. To this end, mice received intraperitoneally saline or lipopolysaccharide (600 µg/kg), and 5 h postinjection animals were orally treated with saline, PT-31 (3, 10, and 30 mg/kg), or fluoxetine (30 mg/kg). Mice were subjected to the open field test (OFT) 6 and 24 h after lipopolysaccharide administration and to the tail suspension test (TST) 24 h postlipopolysaccharide. Subsequently, animals were euthanized, and brains were dissected for neurochemical analyses. The administration of lipopolysaccharide-induced sickness- and depressive-like behaviors, besides promoting an increase in myeloperoxidase activity and a reduction in brain-derived neurotrophic factor (BDNF) levels. Noteworthy, PT-31 3 mg/kg attenuated lipopolysaccharide-induced decreased locomotor activity 6 h after lipopolysaccharide in the OFT. All tested doses of PT-31 significantly reduced the immobility time of animals in the TST and attenuated lipopolysaccharide-induced increased myeloperoxidase activity in the cortex of mice. Our results demonstrate that PT-31 ameliorates behavioral changes promoted by lipopolysaccharide in OFT and TST, which is possibly mediated by attenuation of the inflammatory response.

Evaluation of the action of LPSF/GQ-16 on cytokines and PPAR-γ gene expression after in vitro irradiation of peripheral blood mononuclear cells.

PURPOSE: Patients submitted to radiotherapy (RT) may present in their healthy tissues surrounding the treated tumor, some typical acute inflammatory reactions induced by ionizing radiation (IR). The manifestation of inflammatory processes is a result of exacerbation of the immune system, as a response to radiation exposure, and this can be a limiting factor for RT protocols. To counteract this, some thiazolidinediones, such as LPSF/GQ-16, may be useful for modulating the patient's radioinduced inflammatory response in normal tissues. In this context, the present work aims to evaluate the activity of LPSF/GQ-16 on the levels of cytokines and the expression of the gene PPARγ in mononuclear cells irradiated in vitro, to analyze the immunomodulatory activity of the molecule and its action on radiomitigation. MATERIALS AND METHODS: For this, blood samples from eight donors were collected and irradiated with 2 Gy, then the PBMC (peripheral blood mononuclear cells) were cultured and treated with LPSF/GQ-16. The levels of cytokines TNF-α, IFN-γ, IL-2 and IL-4 were quantified by CBA, while the genes of TNF-α, IFN-γ and PPARγ were analyzed by RT-PCR. RESULTS: LPSF/GQ-16 significantly reduced the expression of proinflammatory cytokines (IFN-γ and TNF-α) in irradiated and nonirradiated groups. There was no significant reduction of anti-inflammatory cytokines (IL-2 and IL-4) by LPSF/GQ-16. The mRNA expression of PPAR-γ, IFN-γ and TNF-α in the presence of LPSF/GQ-16 was higher in the nonirradiated sample. CONCLUSION: LPSF/GQ-16 showed effective activity after irradiation, with an important immunomodulatory activity in irradiated PBMCs.