Neuroprotective effects of novel compound Tozan on cognition, neurogenesis and apoptosis in diabetes

Cognitive impairment is a serious complication of diabetes that manifests as an impairment of spatial memory and learning ability. Its pathogenesis is unclear, and effective therapeutic drugs are very limited. Our group designed and synthesized a novel compound named 3-p-tolyl-9H-xanthen-9-one (Tozan). In this study, we sought to investigate the effects and mechanism of Tozan on diabetic cognitive impairment.

Methylglyoxal (MG)-induced SH-SY5Y cells and streptozotocin (STZ)-induced type 1 diabetic mice were treated with Tozan. Methyl thiazolul tetrazolium (MTT) and lactate dehydrogenase (LDH) were used to test cytotoxicity. Morris water maze (MWM) and Y-maze tests were used to evaluate cognitive function. Immunofluorescence and western blot analyses were used to evaluate neurogenesis, apoptosis, and signal transduction pathway-related proteins. In addition, Lentivirus (LV)-estrogen receptor beta (ERβ)-ribonucleic acid interference (RNAi) was used to knockdown the ERβ gene in SH-SY5Y cells.

We found that Tozan ameliorated MG-induced cytotoxicity in SH-SY5Y cells, improved cognitive dysfunction in STZ-induced type 1 diabetic mice, increased neurogenesis, and prevented apoptotic responses in vitro and in vivo. Importantly, Tozan (2, 4, and 8 mg/kg) mediated phosphatidylinositol-3-kinase and protein kinase B cAMP-response element binding protein (PI3K/Akt-CREB) signaling by activating membrane ERβ, and a high dose of Tozan (8 mg/kg) mediated CREB signaling by activating nuclear ERβ in the hippocampus. Notably, Tozan did not have an anti-apoptosis and regeneration protective role in ERβ gene knockdown cells.

Our study demonstrates Tozan's contributions to and role in cognition, neurogenesis, and apoptosis in diabetes, and lays an experimental foundation for the development of new anti-diabetic cognitive impairment drugs.