RESUMEN
An antidiabetic agent sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin has been revealed to bind to catalytic anionic site of acetylcholinesterase (AChE), which is considered to be associated with the cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of the present study was thus to probe the effect of ertugliflozin on AD. Intracerebroventricular injection of streptozotocin (STZ/i.c.v) (3 mg/kg) was done bilaterally in male Wistar rats at 7-8 weeks of age. Two treatment doses (5 mg/kg and 10 mg/kg) of ertugliflozin were given intragastrically to STZ/i.c.v-induced rats for 20 days daily for behavioral assessment. Biochemical estimations of cholinergic activity, neuronal apoptosis, mitochondrial function and synaptic plasticity were performed. Behavioral results with ertugliflozin treatment revealed attenuation of cognitive deficit. Ertugliflozin also inhibited hippocampal AChE activity, downregulated pro-apoptotic marker expression, as well as mitigated mitochondrial dysfunction and synaptic damage in STZ/i.c.v rats. Importantly, we found that the hyperphosphorylation of tau in the hippocampus of STZ/i.c.v rats was decreased after oral administration of ertugliflozin, which was accompanied by decreased Phospho.IRS-1Ser307/Total.IRS-1 ratio and increased Phospho.AktSer473/Total.Akt and Phospho.GSK3ßSer9/Total.GSK3ß ratios. Our results indicated that treatment with ertugliflozin reversed AD pathology, which may be associated with inhibition of insulin signaling disruption-induced tau hyperphosphorylation.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Simportadores , Ratas , Masculino , Animales , Enfermedad de Alzheimer/metabolismo , Insulina/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas tau/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Acetilcolinesterasa/metabolismo , Ratas Wistar , Encéfalo/metabolismo , Estreptozocina , Glucosa/metabolismo , Simportadores/metabolismo , Simportadores/farmacología , Simportadores/uso terapéutico , Sodio , Modelos Animales de EnfermedadRESUMEN
Diabetic peripheral neuropathy is a common and serious complication of diabetes. Bone morphogenetic protein 5 (BMP5) is a multifunctional protein involved in the nervous system. Nevertheless, its effect on diabetic peripheral neuropathy remained uncharacterized. In this study, diabetic neuropathy in mice was induced by a single dose of 150 mg/kg streptozotocin (STZ) via intraperitoneal injection. Lentivirus expressing BMP5 (LV-BMP5) administration improved pain sensitivity, nerve conduction velocities and morphological alterations of the sciatic nerve of diabetic mice. Elevated BMP5 by LV-BMP5 suppressed cell apoptosis in the sciatic nerve, as evidenced by declined TUNEL-positive cells and down-regulated cleaved caspase-3 and cleaved caspase-9 levels. BMP5 enhanced mitochondrial membrane potential and ATP level. BMP5 also increased the phosphorylation of Smad1/5/9. Besides, the role of BMP5 in high glucose (HG)-stimulated Schwann cells was determined. Results of in vitro studies were in line with the in vivo findings. These experimental data seem to imply that BMP5 prevents the development of diabetic neuropathy via the maintenance of Smad1/5/9-mediated mitochondrial function.
Asunto(s)
Diabetes Mellitus Experimental , Neuropatías Diabéticas , Animales , Ratones , Apoptosis , Proteína Morfogenética Ósea 5/metabolismo , Proteína Morfogenética Ósea 5/farmacología , Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/complicaciones , Mitocondrias/metabolismo , Células de Schwann/metabolismo , Nervio Ciático/metabolismoRESUMEN
OBJECTIVE: To investigate the effect of ß-sheet breaker peptide H102 on APP associated secretase in the hippocampus brain regions of APP/PS1 double transgenic mice(AD mice). METHODS: Thirty 6-month-old APP/PS1 double transgenic mice were randomly divided into AD group and H102 group, a group of C57BL/6J mice with the same age, number and background was set as controls(n=15). H102 (5.8 mg/kg) 5 µl was infused by intranasal administration to mice in H102 treatment group, and equal volume of blank solution of H102 was given to mice in control group and AD group. The ability of spatial reference memory was tested by Morris water maze after 30 days of treatment. And then immunohistochemistry tests and Western blot were used to detect the content of α-secretase (ADAM10, ADAM17), ß-secretase (BACE1), γ-secretase (PS1, APH1a, PEN2) in the hippocampus brain regions. RESULTS: Compared with the control group, the expression of BACE1, PS1, PEN-2 and APH1-a protein in the hippocampus of AD group were significantly increased, ADAM10, ADAM17 protein expression were significantly reduced (P<0.05); Compared with the model group, H102 could significantly improve the spatial learning and memory ability of AD mice, significantly decreased the expression of BACE1, PS1, PEN-2 and APH1-a protein in the hippocampus, significantly increased the expression of ADAM10 and ADAM17 protein(P<0.05). CONCLUSIONS: ß sheet peptides blocked H102 can reduce the formation of Aß in the hippocampus brain area, improve the activity of α-secretase in the hippocampus brain region, decrease the activity of ß-and γ-secretase, improve the learning and memory ability of AD mice.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Hipocampo/enzimología , Memoria/efectos de los fármacos , Aprendizaje Espacial/efectos de los fármacos , Proteína ADAM10/metabolismo , Proteína ADAM17/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Modelos Animales de Enfermedad , Endopeptidasas/metabolismo , Hipocampo/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/metabolismo , Conformación Proteica en Lámina betaRESUMEN
OBJECTIVE: To investigate the effects of ß-sheet breaker peptide H102 on NF-κB signal pathway in brain of APP/PS1 double transgenic mice. METHODS: Thirty 8-week-old APP/PS1 double transgenic mice were randomly divided into model group and treatment group. A group of C57BL/6J mice with the same age and background were served as controls (n=15). H102 5 µl(5.8 mg/kg) was infused by intranasal administration to mice in H102 treatment group, and equal volume of blank solution of H102 (chitosan, BSA) was given to mice in control group and model group. After 16 weeks, the ability of spatial reference memory was tested by Morris Water Maze. Then immunohistochemistry tests and Western blot technique were used to detect the content of amyloid beta peptide 1-42(Aß1-42), nuclear factor-kappa B (NF-κB), inhibitor of NF-κB (IκB), IκB kinase (IKK), the corresponding phosphorylated proteins (p-NF-κBãp-IκBãp-IKK), inducible nitric oxide synthase (iNOS) and cleaved Caspase 3 proteins in mice brain. RESULTS: â The ability of learning and memory was significantly lowered in model group than that in control group. And the ability of learning and memory was significantly improved in treatment group than that in model group (P<0.05). â¡The contents of Aß1-42, p-IKK, p-NF-κB, p-IκB, intranuclear NF-κB,iNOS and cleaved Caspase 3 in mouse brain were significantly increased in model group than those of control group, and these protein expressions were significantly lowered in treatment group than those in model group (P<0.05). CONCLUSIONS: H102 can inhibit NF-κB signal pathway in brain of APP/PS1 double transgenic mice, reduce the levels of inflammation and apoptosis in nerve cells, and improve the ability of learning and memory in transgenic AD mice.
Asunto(s)
Encéfalo/efectos de los fármacos , FN-kappa B/metabolismo , Péptidos/farmacología , Transducción de Señal/efectos de los fármacos , Enfermedad de Alzheimer , Animales , Caspasa 3/metabolismo , Aprendizaje , Memoria , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
OBJECTIVE: To investigate the effects ofß-sheet breaker peptide H102 on expression of synaptic plasticity associated proteins and learning and memory functions in double transgenic Alzheimer's disease(AD) mice,and to discuss its mechanisms. METHODS: Thirty APP-swe/PS1dE9 double transgenic male mice of 8 weeks were randomly divided into model group and H102 treatment group (15 mice per group). In addition,a group of C57BL/6J mice with the same age and background was set as normal. H102 (5.8 mg/kg) 5 µl was infused by in-tranasal administration to mice in H102 treatment group,and equal volume of blank solution of H102 (chitosan,BSA) was given to mice in con-trol group and model group. The ability of spatial reference memory was tested by Morris Water Maze after 16 weeks treatment,then immunohis-tochemistry tests and Western blot technique were used to detect the content ofß-amyloid peptide(Aß1-42) protein and phospho protein kinase C αãß2ãγ(p-PKCα, p-PKCß2, p-PKCγ), phospho-N-methyl-D-aspartate receptor1(p-NMDAR1), phospho-Calcium/Calmodulin dependent pro-tein kinaseâ ¡α(p-CaMKâ ¡α) and phospho-cAMP response element binding protein(p-CREB) of synaptic plasticity associated proteins in mice brain. RESULTS: The ability of learning and memory was significantly improved in H102 treatment group than that in model group by the test of Morris Water Maze. The contents of Aß1-42 proteins and p-PKCα, p-PKCß2, p-PKCγ, p-NMDAR1, p-CaMKâ ¡αand p-CREB of synaptic plas-ticity associated proteins in mice brain were improved significantly in H102 treatment group than those in model group by the test of immunohis-tochemistry tests and Western blot technique. CONCLUSIONS: ß-sheet breaker peptide H102 can significantly improve synaptic plasticity and the ability of learning and memory in double transgenic AD mice.
Asunto(s)
Péptidos beta-Amiloides/análisis , Aprendizaje por Laberinto , Plasticidad Neuronal , Fragmentos de Péptidos/análisis , Péptidos/química , Conformación Proteica en Lámina beta , Enfermedad de Alzheimer , Animales , Encéfalo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
ß-amyloid hypothesis is the predominant hypothesis in the study of pathogenesis of Alzheimer's disease. This hypothesis claims that aggregation and neurotoxic effects of amyloid ß (Aß) is the common pathway in a variety of etiological factors for Alzheimer's disease. Aß peptide derives from amyloid precursor protein (APP). ß-sheet breaker peptides can directly prevent and reverse protein misfolding and aggregation in conformational disorders. Based on the stereochemical structure of Aß1-42 and aggregation character, we had designed a series of ß-sheet breaker peptides in our previous work and screened out a 10-residue peptide ß-sheet breaker peptide, H102. We evaluated the effects of H102 on expression of P-tau, several associated proteins, inflammatory factors and apoptosis factors, and examined the cognitive ability of APP transgenic mice by behavioral test. This study aims to validate the ß-amyloid hypothesis and provide an experimental evidence for the feasibility of H102 treatment for Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Modelos Biológicos , Péptidos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/genética , Animales , Humanos , Ratones , Ratones Transgénicos , Péptidos/química , Péptidos/genética , Estructura Secundaria de ProteínaRESUMEN
OBJECTIVE: To study the effect of combining the injection of beta-sheet breaker H102 with human umbilical cord mesenchymal stem cell (hUCMSC) on APP transgenic mice behavior, P-tau, apoptosis and the expression of relevant enzymes in the brain. METHODS: APP transgenic mice were randomly divided into model group, hUCMSC group, H102 group, H102 with hUCMSC group and a group of C57BL/6J mice with the same age and background was set as normal. After two weeks and four weeks, the ability of spatial reference memory was tested by Morris Water Maze. After four weeks, immunohistochemical stain and Western blot were done to detect the content of Bad, Bax, Bcl-2, Bcl-xl, P-tau, GSK-3beta, PP-2A and PP-1 in mice brain. RESULTS: The ability of memory of hUCMSC in 2 weeks group was slightly improved than that in the model group. hUCMSC in four weeks group, H102 group and H102 with hUCMSC group significantly improved the ability of and memory, and reduced the phosphorylation of tau and brain cell's apoptosis of the Alzheimer disease (AD) mice. CONCLUSION: Beta-sheet breaker H102 together with transplanting hUCMSC is an effective therapeutic strategy for AD.