sitagliptin-phosphate and Memory-Disorders

Glucagon-like peptide-1 (GLP-1) signaling in the brain plays an important role in the regulation of glucose metabolism, which is impaired in Alzheimer's disease (AD). Here, we detected the GLP-1 and GLP-1 receptor (GLP-1R) in AD human brain and APP/PS1/Tau transgenic (3xTg) mice brain, finding that they were both decreased in AD human and mice brain. Enhanced GLP-1 exerts its protective effects on AD, however, this is rapidly degraded into inactivated metabolites by dipeptidyl peptidase-4 (DPP-4), resulting in its extremely short half-time. DPP-4 inhibitors, thus, was applied to improve the level of GLP-1 and GLP-1R expression in the hippocampus and cortex of AD mice brains. It is also protected learning and memory and synaptic proteins, increased the O-Glycosylation and decreased abnormal phosphorylation of tau and neurofilaments (NFs), degraded intercellular β-amyloid (Aβ) accumulation and alleviated neurodegeneration related to GLP-1 signaling pathway.

Topics: Adamantane; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cerebral Cortex; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycosylation; Hippocampus; Humans; Intermediate Filaments; Learning; Memory Disorders; Mice; Mice, Transgenic; Nerve Degeneration; Phosphorylation; Signal Transduction; Sitagliptin Phosphate; tau Proteins

Parkinson's disease (PD) is a neurodegenerative disease with high morbidity among adults worldwide that causes tremendous trouble to people's lives. The purpose of this study was to investigate the impact of sitagliptin on PD and its potential mechanism.. First, the memory of rats in each group was evaluated with the Morris water maze (MWM) test and the passive avoidance test. Then, both brain-derived neurotrophic factor (BDNF) protein and mRNA levels were detected by ELISA and qPCR assays, respectively. Then, rapid Golgi impregnation was used to observe the density of dendritic spines in the hippocampal CA1 area. Finally, k252a, an antagonist of Trk receptors, was used to block the binding of BDNF with its receptors, and the effects of sitagliptin on PD improvement were detected.. Our study showed that sitagliptin improved memory deficits in PD rats. Meanwhile, the expression level of BDNF and tyrosine hydroxylase (TH) was upregulated, and the density of dendritic spine was increased by sitagliptin administration. Moreover, K252a administration blocked the positive effects of sitagliptin on memory in PD rats.. Sitagliptin rescued the memory deficits, which was achieved by upregulating BDNF to prevent neuronal death and dendritic spine loss. Our findings indicate that sitagliptin might be a promising potential drug for PD treatment in the future.

Topics: Animals; Antiparkinson Agents; Avoidance Learning; Brain-Derived Neurotrophic Factor; Carbazoles; Enzyme Inhibitors; Indole Alkaloids; Male; Maze Learning; Memory Disorders; Neurons; Neuroprotective Agents; Nootropic Agents; Parkinsonian Disorders; Random Allocation; Rats, Wistar; Sitagliptin Phosphate; Tyrosine 3-Monooxygenase; Up-Regulation

Recent evidence has demonstrated that insulin resistance is related to the development of type 2 diabetes mellitus. Our previous study found that high-fat diet (HFD) consumption caused not only peripheral and brain insulin resistance but also brain mitochondrial dysfunction and cognitive impairment. Vildagliptin and sitagliptin, dipeptidyl-peptidase-4 inhibitors, are recently developed anti-diabetic drugs. However, the effects of both drugs on cognitive behaviors and brain mitochondrial function in HFD-induced insulin-resistant rats have not yet been investigated. Sixty male Wistar rats were divided into two groups to receive either normal diet or HFD for 12 weeks. Rats in each group were then further divided into three treatment groups to receive either vehicle, vildagliptin (3 mg/kg per day), or sitagliptin (30 mg/kg per day) for 21 days. The cognitive behaviors of the rats were tested using the Morris Water Maze test. Blood samples were collected to determine metabolic parameters and plasma oxidative stress levels. Upon completion of the study, the animals were killed and the brains were removed to investigate brain and hippocampal mitochondrial function as well as to determine oxidative stress levels. We demonstrated that both drugs significantly improved the metabolic parameters and decreased circulating and brain oxidative stress levels in HFD-induced insulin-resistant rats. In addition, both drugs completely prevented brain and hippocampal mitochondrial dysfunction and equally improved the learning behaviors impaired by the HFD. Our findings suggest that the inhibition of dipeptidyl-peptidase-4 enzymes with vildagliptin or sitagliptin in insulin-resistant rats not only increases peripheral insulin sensitivity but also decreases brain dysfunction.

Topics: Adamantane; Animals; Behavior, Animal; Brain; Cognition Disorders; Diabetes Mellitus, Type 2; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Hippocampus; Insulin Resistance; Male; Maze Learning; Memory; Memory Disorders; Mitochondria; Nitriles; Obesity; Oxidative Stress; Pyrazines; Pyrrolidines; Rats; Rats, Wistar; Sitagliptin Phosphate; Triazoles; Vildagliptin

We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age. Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage. The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits. All these effects much more evident for the dose of 20 mg/kg sitagliptin. The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Memory Disorders; Mice; Mice, Transgenic; Motor Activity; Pyrazines; Sitagliptin Phosphate; Triazoles