sitagliptin-phosphate and Alzheimer-Disease

Sitagliptin is a member of a class of drugs that inhibit dipeptidyl peptidase (DPP-4). It increases the levels of the active form of incretins such as GLP-1 (glucagon-like peptide-1) or GIP (gastric inhibitory polypeptide) and by their means positively affects glucose metabolism. It is successfully applied in the treatment of diabetes mellitus type 2. The most recent scientific reports suggest beneficial effect of sitagliptin on diseases in which neuron damage occurs. Result of experimental studies may indicate a reducing influence of sitagliptin on inflammatory response within encephalon area. Sitagliptin decreased the levels of proinflammatory factors: TNF-

Topics: Alzheimer Disease; Animals; Blood Glucose; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hypoglycemic Agents; Incretins; Inflammation; Mice; Sitagliptin Phosphate

A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimer's disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the "Trojan Horse" effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; ATP Binding Cassette Transporter, Subfamily B; Cell Wall; Mice; Neuroinflammatory Diseases; Saccharomyces cerevisiae; Sitagliptin Phosphate

Sitagliptin is an anti-diabetic drug and its effects on Alzheimer's disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptin on the cognition in AD and its underlying molecular mechanism.. The APP/PS1 (a model of AD) mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. Then animals were subjected to behavioral experiment or sacrificed to histological staining and protein level analysis.. The MWM test showed that sitagliptin treatment significantly reduced the escape latency times in APP/PS1 mice in the learning phase (day 3-5) and elongated the time spent in the target quadrant in the probe test. Sitagliptin significantly reduced amyloid plaque deposition and elevated the spine density and the protein levels of synaptoneurosome GluA1- and GluA2-containing AMPA receptor (GluA1R and GluA2R) in the brain of the APP/PS1 mice. Sitagliptin treatment significantly up-regulated the brain BNDF protein and phosphorylation of tyrosine receptor kinase B (TrkB). Furthermore, exendin-(9-39) (a glucagon-like peptide-1 [GLP-1] receptor antagonist) and K252a (a Trk tyrosine kinase inhibitor) treatment significantly abolished the cognitive protective effect of sitagliptin in the MWM test.. Sitagliptin treatment effectively protected the cognition function of the AD mice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Brain-Derived Neurotrophic Factor; Cognition; Disease Models, Animal; Glucagon-Like Peptide 1; Mice; Receptors, AMPA; Sitagliptin Phosphate

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

The objective of this study was to evaluate the neuroprotective effect of sitagliptin (Sita), quercetin (QCR) and its combination in β-amyloid (Aβ) induced Alzheimer's disease (AD). Male Sprague-Dawley rats, weighing between 220 and 280 g were used for experiment. Rats were divided into 5 groups (n = 10) and the groups were as follows: (a) Sham control; (b) Aβ injected; (c) Aβ injected + Sita 100; (d) Aβ injected + QCR 100; and (e) Aβ injected + Sita 100 + QCR 100. Cognitive performance was observed by the Morris water maze (MWM), biochemical markers, for example, MDA, SOD, CAT, GSH, Aβ1-42 level, Nrf2/HO-1 expression and histopathological study of rat brain were estimated. Pretreatment with Sita, QCR and their combination showed a significant increase in escape latency in particular MWM cognitive model. Further co-administration of sita and QCR significantly reduced Aβ1-42 level when compared with individual treatment. Biochemical markers, for example, increased SOD, CAT and GSH, decreased MDA were seen, and histopathological studies revealed the reversal of neuronal damage in the treatment group. Additionally, Nrf2/HO-1 pathway in rat's brain was significantly increased by Sita, QCR and their combination. Pretreatment with QCR potentiates the action of Sita in Aβ induced AD in rats. The improved cognitive memory could be because of the synergistic effect of the drugs by decreasing Aβ1-42 level, antioxidant activity and increased expression of Nrf2/HO-1 in rat brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Catalase; Disease Models, Animal; Drug Therapy, Combination; Glutathione; Heme Oxygenase (Decyclizing); Male; Maze Learning; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidative Stress; Peptide Fragments; Quercetin; Rats, Sprague-Dawley; Signal Transduction; Sitagliptin Phosphate; Superoxide Dismutase

The present study aimed to evaluate effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4I), on cognitive functions in elderly diabetic patients with and without cognitive impairment.. 253 elderly patients with type 2DM, were enrolled in this prospective and observational study. After comprehensive geriatric assessment, the patients were divided into either sitagliptin or non-sitagliptin group.. A total of 205 patients who completed the study (52 with Alzheimer's Disease (AD)) were re-evaluated 6months later. Sixth-month evaluation revealed no difference between sitagliptin and non-sitagliptin groups in terms of weight, body mass index, and HbA1c (p>0.05). However, the number of patients that required reduced insulin dose was significantly higher in the sitagliptin group (p=0.01). Sitagliptin therapy was associated with an increase in the Mini-Mental State Examination (MMSE) scores (p=0.034); patients without AD receiving only sitagliptin or insulin showed higher MMSE scores as compared to the patients receiving metformin alone (p=0.024). Likewise, the change in MMSE scores in AD patients receiving sitagliptin was significant and indicated improvement as compared to the patients receiving metformin (p=0.047).. Besides its effects similar to those of insulin and metformin in glycemic control and in reducing need for insulin, 6-month sitagliptin therapy may also associated with improvement of cognitive function in elderly diabetic patients with and without AD. Further randomized controlled trials are needed to support these results.

Topics: Aged; Alzheimer Disease; Cognition; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Prospective Studies; Sitagliptin Phosphate

Increasing evidence supports an association between Alzheimer's disease (AD) and diabetes. In this context, anti-diabetic agents such as rosiglitazone and glucagon-like peptide (GLP)-1 have been reported to reduce pathologies associated with AD, including tau hyperphosphorylation, suggesting that such agents might be used to treat AD. One such anti-diabetic agent is sitagliptin, which acts through inhibition of dipeptidyl peptidase (DPP)-IV to increase GLP-1 levels. Given this action, sitagliptin would be predicted to reduce AD pathology. Accordingly, we investigated whether sitagliptin is effective in attenuating AD pathologies, focusing on tau phosphorylation in the OLETF type 2 diabetic rat model. Unexpectedly, we found that sitagliptin was not effective against pathological tau phosphorylation in the hippocampus of OLETF type 2 diabetes rats, and instead aggravated it. This paradoxically increased tau phosphorylation was attributed to activation of the tau kinase, GSK3β (glycogen synthase kinase 3β). Sitagliptin also increased ser-616 phosphorylation of the insulin receptor substrate (IRS)-1, suggesting increased insulin resistance in the brain. These phenomena were recapitulated in primary rat cortical neurons treated with sitagliptin, further confirming sitagliptin's effects on AD-related pathologies in neurons. These results highlight the need for caution in considering the use of sitagliptin in AD therapy.

Topics: Alzheimer Disease; Animals; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Hippocampus; Male; Neurons; Phosphorylation; Primary Cell Culture; Pyrazines; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Sitagliptin Phosphate; tau Proteins; Triazoles

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