TrkB Receptor Agonist 7, 8 Dihydroxyflavone Triggers Profound Gender- Dependent Neuroprotection in Mice After Perinatal Hypoxia and Ischemia

Abstract

In this study, we investigated the effects of a bioactive high-affinity TrkB receptor agonist 7,8-dihydroxyflavone (7,8 DHF) on neonatal brain injury in female and male mice after hypoxia ischemia (HI). HI was induced by exposure of postnatal day 9 (P9) mice to 10% O2 for 50 minutes at 37°C after unilateral ligation of the left common carotid artery. Animals were randomly assigned to HI-vehicle control group [phosphate buffered saline (PBS), intraperitoneally (i.p.)] or HI + 7,8 DHF-treated groups (5 mg/kg in PBS, i.p at 10 min, 24 h, or with subsequent daily injections up to 7 days after HI). The HI-vehicle control mice exhibited neuronal degeneration in the ipsilateral hippocampus and cortex with increased Fluoro-Jade C positive staining and loss of microtubule associated protein 2 expression. In contrast, the 7,8 DHF-treated mice showed less hippocampal neurodegeneration and astrogliosis, with more profound effects in female than in male mice. Moreover, 7,8 DHF-treated mice improved motor learning and spatial learning at P30-60 compared to the HI-vehicle control mice. Diffusion tensor imaging of ex-vivo brain tissues at P90 after HI revealed less reduction of fractional anisotropy values in the ipsilateral corpus callosum of 7,8 DHF-treated brains, which was accompanied with better preserved myelin basic protein expression and CA1 hippocampal structure. Taken together, these findings strongly suggest that TrkB agonist 7,8 DHF is protective against HI-mediated hippocampal neuronal death, white matter injury, and improves neurological function, with a more profound response in female than in male mice.

Polygalasaponin XXXII, a triterpenoid saponin from Polygalae Radix, attenuates scopolamine-induced cognitive impairments in mice

“…Activation of TrkB by BDNF results in the phosphorylation of several tyrosine residues and subsequently the stimulation of intracellular signal transduction pathways, such as the MAPK, PI3K and phospholipase C-γ pathways [32] . Phosphorylation of TrkB is associated with the recruitment of pro-survival signaling pathways that lead to long-term neuroprotection and improved cognition [33] . We have demonstrated previously that PGS32 can activate ERK and CREB and further increase the expression of BDNF [34] .…”

7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

“…Previous researches mainly focused on its protective effects on nervous system [25–27]. 7,8-DHF has been demonstrated to protect neurons from ischemic stroke, which may be at least attributable to its antiapoptotic, antioxidative, and anti-inflammatory actions [27–29]. Since hypoxia is the leading cause of AKI, which involves apoptosis, oxidative stress, and inflammation, we thought that 7,8-DHF may have evident effects on AKI.…”

Suppression of microglia activation after hypoxia–ischemia results in age-dependent improvements in neurologic injury

“…Spatial learning was assessed by the MWM test at P60 (51 days post-HI) on HI-vehicle control and minocycline-treated mice as described previously (Uluc et al, 2013). Mice were trained to locate a hidden escape platform in a circular pool full of opaque water by use of visual cues.…”