6-7-dihydroxyflavone and Depressive-Disorder

The search for new highly-effective, fast-acting antidepressant drugs is extremely relevant. Brain derived neurotrophic factor (BDNF) and signaling through its tropomyosin-related tyrosine kinase B (TrkB) receptor, represents one of the most promising therapeutic targets for treating depression. BDNF is a key regulator of neuroplasticity in the hippocampus and the prefrontal cortex, the dysfunction of which is considered to be the main pathophysiological hallmark of this disorder. BDNF itself has no favorable drug-like properties due to poor pharmacokinetics and possible adverse effects. The design of small, proteolytically stable BDNF mimetics might provide a useful approach for the development of therapeutic agents. Two small molecule BDNF mimetics with antidepressant-like activity have been reported, 7,8-dihydroxyflavone and the dimeric dipeptide mimetic of BDNF loop 4, GSB-106. The article reflects on the current literature on the role of BDNF as a promising therapeutic target in the treatment of depression and on the current advances in the development of small molecules on the base of this neurotrophin as potential antidepressants.

Topics: Antidepressive Agents; Brain-Derived Neurotrophic Factor; Depressive Disorder; Flavones; Hippocampus; Humans; Molecular Weight

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), signaling represent potential therapeutic targets for major depressive disorder. The purpose of this study is to examine whether TrkB ligands show antidepressant effects in an inflammation-induced model of depression.. In this study, we examined the effects of TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and TrkB antagonist ANA-12 on depression-like behavior and morphological changes in mice previously exposed to lipopolysaccharide (LPS). Protein levels of BDNF, phospho-TrkB (p-TrkB), and TrkB in the brain regions were also examined.. LPS caused a reduction of BDNF in the CA3 and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC), whereas LPS increased BDNF in the nucleus accumbens (NAc). Dexamethason suppression tests showed hyperactivity of the hypothalamic-pituitary-adrenal axis in LPS-treated mice. Intraperitoneal (i.p.) administration of 7,8-DHF showed antidepressant effects on LPS-induced depression-like behavior, and i.p. pretreatment with ANA-12 blocked its antidepressant effects. Surprisingly, ANA-12 alone showed antidepressant-like effects on LPS-induced depression-like behavior. Furthermore, bilateral infusion of ANA-12 into the NAc showed antidepressant effects. Moreover, LPS caused a reduction of spine density in the CA3, DG, and PFC, whereas LPS increased spine density in the NAc. Interestingly, 7,8-DHF significantly attenuated LPS-induced reduction of p-TrkB and spine densities in the CA3, DG, and PFC, whereas ANA-12 significantly attenuated LPS-induced increases of p-TrkB and spine density in the NAc.. The results suggest that LPS-induced inflammation may cause depression-like behavior by altering BDNF and spine density in the CA3, DG, PFC, and NAc, which may be involved in the antidepressant effects of 7,8-DHF and ANA-12, respectively.

Topics: Animals; Antidepressive Agents; Azepines; Benzamides; Brain-Derived Neurotrophic Factor; Dendritic Spines; Depressive Disorder; Disease Models, Animal; Flavones; Hippocampus; Lipopolysaccharides; Male; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Multiprotein Complexes; Nucleus Accumbens; Phosphorylation; Prefrontal Cortex; Receptor, trkB; TOR Serine-Threonine Kinases