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Antidepressant effect of PT-31, an α₂-adrenoceptor agonist, on lipopolysaccharide-induced depressive-like behavior in
Juliana Machado Kayser1, Fernanda Petry2,3, Maryelen Alijar Souza3
1Postgraduate Program in Toxicology and Analytical Toxicology, Health Sciences Institute, Feevale University, Novo Hamburgo.
Abstract:
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.
Insights
PT-31, a potential antidepressant, reduced depressive-like behaviors and neuroinflammation in mice. This imidazolidine derivative may offer a novel therapeutic approach for major depressive disorder (MDD) by targeting inflammatory pathways.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Major depressive disorder (MDD) pathophysiology involves neuroinflammation, oxidative stress, and altered neurotrophic factors.
- Attenuating inflammatory responses is a potential therapeutic strategy for MDD.
- PT-31, an imidazolidine derivative and α₂-adrenoceptor agonist, exhibits antinociceptive properties.
Purpose of the Study:
- To investigate the effects of PT-31 on depressive-like behaviors.
- To examine PT-31's impact on lipopolysaccharide (LPS)-induced neurochemical changes.
- To explore PT-31 as a potential treatment for MDD.
Main Methods:
- Mice were administered LPS to induce sickness and depressive-like behaviors.
- Animals were treated with saline, PT-31 (3, 10, 30 mg/kg), or fluoxetine (30 mg/kg).
- Behavioral tests (OFT, TST) and neurochemical analyses (myeloperoxidase activity, BDNF levels) were performed.
Main Results:
- LPS administration induced depressive-like behaviors, increased myeloperoxidase activity, and reduced BDNF levels.
- PT-31 (3 mg/kg) attenuated LPS-induced decreases in locomotor activity in the OFT.
- All PT-31 doses reduced immobility in the TST and attenuated LPS-induced increases in myeloperoxidase activity.
Conclusions:
- PT-31 ameliorates LPS-induced behavioral changes in mice.
- The antidepressant-like effects of PT-31 may be mediated by the attenuation of neuroinflammation.
- PT-31 shows promise as a novel therapeutic agent for MDD.
