Investigation of the Pharmacokinetic Properties and Theoretical Chemical Activities of 7,8-Dihydroxyflavone and 4'-Dimethylamino-7,8-Dihydroxyflavone

Abstract

Flavonoids naturally exist in plants as secondary metabolites. In this study, the aim is to determine and compare the theoretical and in vivo chemical activities of 7,8-dihydroxyflavone (7,8-DHF) and 4'dimethylamino-7,8-dihydroxyflavone (4’-DMA-7,8-DHF), tyrosine receptor kinase B (TrkB) receptor agonist flavonoid molecules with reported potent neuroprotective effects. BDNF has been thought to be a potent therapeutic agent against neurological disorders via its receptor TrkB. However, BDNF has poor pharmacokinetic properties and cannot cross the blood-brain barrier. It has been demonstrated that 7,8-DHF and 4''-DMA-7,8-DHF can bind and activate TrkB receptors and pass the blood-brain barrier. It has been thought that 4''-DMA-7,8-DHF may be more potent than 7,8-DHF due to strong TrkB activity and supporting neurogenesis at lower concentrations. However, there is no detailed study on this yet. method was used for the theoretical chemical analysis. For the in vivo studies, 6-month-old Wistar rats were used in two groups (n=8). 7,8-DHF and 4’-DMA-7,8-DHF (5 mg/kg) were administered intraperitoneally (ip) to each group. Then, plasma samples were collected by carotid catheterization, and brain samples by the microdialysis technique were collected simultaneously for 12 h from awake rats. The level of 7,8-DHF and 4’-DMA-7,8-DHF in blood and brain samples were analyzed and their pharmacokinetics were determined. Flavonoids naturally exist in plants as seconder metabolites. In this study, the aim is to determine and compare the theoretical and in vivo chemical activities of 7,8-DHF and 4’-DMA-7,8-DHF, tyrosine receptor kinase B (TrkB) receptor agonist flavonoid molecules with reported potent neuroprotective effects. Theoretical calculations show that 7,8-DHF is slightly more stable than 4’-DMA-7,8-DHF. The in vivo pharmacokinetic results show that the maximum concentration of 7,8-DHF was about 48 ng/mL, whereas it was only 8 ng/mL for 4’-DMA-7,8-DHF. Our results suggest that the 4'-DMA-7,8-DHF is more unstable and is more prone to binding to TrkB than 7,8-DHF. On the other hand, the in vivo pharmacokinetic results show that 7,8-DHF is more stable than 4’-DMA-7,8-DHF when it is applied systemically at therapeutic concentrations. Theoretical calculations show that 7,8-DHF is slightly more stable than 4’-DMA-7,8-DHF. The in vivo pharmacokinetic results show that the maximum concentration of 7,8-DHF was about 48 ng/mL, whereas it was only 8 ng/mL for 4’-DMA-7,8-DHF. 7.8-DHF seems more suitable for pharmacological applications.