ABSTRACT
Clinical and experimental studies have shown that the sharp reduction of estrogen is one of the important reasons for the high incidence of Alzheimer's disease (AD) in elderly women, but there is currently no such drug for treatment of AD. Our group first designed and synthesized a novel compound R-9-(4fluorophenyl)-3-methyl-10,10,-Hydrogen-6-hydrogen-benzopyran named FMDB. In this study, our aim is to investigate the neuroprotective effects and mechanism of FMDB in APP/PS1 transgenic mice. 6 months old APP/PS1 transgenic mice were intragastrical administered with FMDB (1.25, 2.5 and 5 mg/kg) every other day for 8 weeks. LV-ERß-shRNA was injected bilaterally into the hippocampus of APP/PS1 mice to knockdown estrogen receptor ß (ERß). We found that FMDB ameliorated cognitive impairment in the Morris water maze and novel object recognition tests, increased hippocampal neurogenesis and prevented hippocampal apoptotic responses in APP/PS1 mice. Importantly, FMDB activated nuclear ERß mediated CBP/p300, CREB and brain-derived neurotrophic factor (BDNF) signaling, and membrane ERß mediated PI3K/Akt, CREB and BDNF signaling in the hippocampus. Our study demonstrated the contributions and mechanism of FMDB to cognition, neurogenesis and apoptosis in APP/PS1 mice. These lay the experimental foundation for the development of new anti-AD drugs.
Subject(s)
Alzheimer Disease , Neuroprotective Agents , Mice , Animals , Female , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Mice, Transgenic , Brain-Derived Neurotrophic Factor/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Phosphatidylinositol 3-Kinases , Estrogen Receptor beta , Cognition , Hippocampus/metabolism , Disease Models, Animal , Neurogenesis , Apoptosis , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Presenilin-1/geneticsABSTRACT
BACKGROUND: 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. METHODS: 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 (ERß)-ribonucleic acid interference (RNAi) was used to knockdown the ERß gene in SH-SY5Y cells. RESULTS: 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 ERß, and a high dose of Tozan (8 mg/kg) mediated CREB signaling by activating nuclear ERß in the hippocampus. Notably, Tozan did not have an anti-apoptosis and regeneration protective role in ERß gene knockdown cells. CONCLUSIONS: 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.
ABSTRACT
Estrogen receptors (ERs) are thought to be associated with the onset and progression of neurodegenerative injuries and diseases, but the relationship and mechanisms underlying between ERs and cognition in type 2 diabetes remain elusive. In the current study, we investigated the effects of ERα and ERß on the cognition, neurogenesis and apoptosis in high-fat diet and streptozocin-induced diabetic mice. We found that ERα and/or ERß activation using their agonists (0.5â¯mg/kg E2, PPT or DPN) ameliorate memory impairment in the Morris water maze and Y-maze tests, increase hippocampal neurogenesis and prevent hippocampal apoptotic responses. Importantly, treatment with the pharmacologic ERs agonists caused significant increases in the membrane ERα and ERß expression and subsequent PI3K/Akt, CREB and BDNF activation in the hippocampus of type 2 diabetes mellitus mice. Our data indicate that ERα and ERß are involved in the cognitive impairment in type 2 diabetes, and that activated ERs, such as application of ERs agonists, could be a novel and promising strategy for the treatment of diabetic cognitive impairment.
