Difference between revisions of "Pohland 2016 Neurochem Res"
(Created page with "{{Publication |title=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel Ī³-secretase modulator/PPARĪ³ agonist-improves mitochondrial...") Ā |
|||
| Line 1: | Line 1: | ||
{{Publication | {{Publication | ||
|title=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel Ī³-secretase modulator/PPARĪ³ agonist-improves mitochondrial dysfunction in a cellular model of Alzheimer's disease. Neurochem Res 41:231-42. Ā | |title=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel Ī³-secretase modulator/PPARĪ³ agonist-improves mitochondrial dysfunction in a cellular model of Alzheimer's disease. Neurochem Res 41:231-42. | ||
|info=[https://www.ncbi.nlm.nih.gov/pubmed/26721513 PMID: 26721513] | |info=[https://www.ncbi.nlm.nih.gov/pubmed/26721513 PMID: 26721513] | ||
|authors=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP | |authors=Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP | ||
|year=2016 | |year=2016 | ||
|journal=Neurochem Res | |journal=Neurochem Res | ||
|abstract=Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293<sub>APPwt</sub> model of AD, characterized by elevated beta amyloid protein levels (AĪ²1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of Ī³-secretase modulators, which combines Ī³-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARĪ³). The mitochondria modifying Dimebon, the Ī³-secretase blocker DAPT, and the PPARĪ³ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1Ī± indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, AĪ²1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular AĪ²1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action. Ā | |abstract=Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293<sub>APPwt</sub> model of AD, characterized by elevated beta amyloid protein levels (AĪ²1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of Ī³-secretase modulators, which combines Ī³-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARĪ³). The mitochondria modifying Dimebon, the Ī³-secretase blocker DAPT, and the PPARĪ³ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1Ī± indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, AĪ²1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular AĪ²1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action. | ||
|keywords=Alzheimerās disease, Drug candidate, Mitochondrial dysfunction, Multifunctional agents, PGC1Ī±, PPARĪ³-agonists, Ī³-Secretase modulators | |keywords=Alzheimerās disease, Drug candidate, Mitochondrial dysfunction, Multifunctional agents, PGC1Ī±, PPARĪ³-agonists, Ī³-Secretase modulators, HEK 293 cells | ||
|mipnetlab=DE Giessen Eckert GP, DE Frankfurt Eckert GP | |mipnetlab=DE Giessen Eckert GP, DE Frankfurt Eckert GP | ||
}} | }} | ||
| Line 18: | Line 18: | ||
|pathways=N, S, CIV, NS, ROX | |pathways=N, S, CIV, NS, ROX | ||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional= | |additional=2016-11, | ||
}} | }} | ||
Revision as of 11:42, 9 November 2017
| Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) MH84: a novel Ī³-secretase modulator/PPARĪ³ agonist-improves mitochondrial dysfunction in a cellular model of Alzheimer's disease. Neurochem Res 41:231-42. |
Pohland M, Hagl S, Pellowska M, Wurglics M, Schubert-Zsilavecz M, Eckert GP (2016) Neurochem Res
Abstract: Developing new therapeutic strategies for Alzheimer's disease (AD) is a current challenge. Approved drugs merely act symptomatically and delay the progression of the disease for a relatively short period of time. Here, we investigated the effectiveness of MH84 in a cellular HEK293APPwt model of AD, characterized by elevated beta amyloid protein levels (AĪ²1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of Ī³-secretase modulators, which combines Ī³-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARĪ³). The mitochondria modifying Dimebon, the Ī³-secretase blocker DAPT, and the PPARĪ³ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1Ī± indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, AĪ²1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular AĪ²1-42 levels. Dimebon improved mitochondrial functions and DAPT decreased mitochondrial membrane potential. Pioglitazone had no effects on APP processing and mitochondrial function. Our data emphasizes MH84 as possible novel therapeutic agent with mitochondria-based mode of action. ā¢ Keywords: Alzheimerās disease, Drug candidate, Mitochondrial dysfunction, Multifunctional agents, PGC1Ī±, PPARĪ³-agonists, Ī³-Secretase modulators, HEK 293 cells
ā¢ O2k-Network Lab: DE Giessen Eckert GP, DE Frankfurt Eckert GP
Labels: MiParea: Respiration, Pharmacology;toxicology
Pathology: Alzheimer's
Organism: Human Tissue;cell: Kidney, HEK Preparation: Permeabilized cells
Coupling state: LEAK, OXPHOS, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property.
Pathway: N, S, CIV, NS, ROX
HRR: Oxygraph-2k
2016-11
