作者: Eckert, Gunter P ; Eckert, Schamim H ; Joppe, Aljoscha ; Pohland, Maximilian ; Reutzel, Martina ; Berressem, Dirk ; Pellowska, Maren ; Schubert-Zsilavecz, Manfred ; Hagl, Stephanie ; Wurglics, Mario ; Asseburg, Heike

BACKGROUNDCurrent approved drugs for Alzheimer's disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPP_SL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD.METHODSThree-month-old Thy-1 AβPP_SL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ_1-40 and Aβ_1-42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively.RESULTSMH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence.CONCLUSIONSMH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.

2016-02-01·Neurochemical Research3区 · 医学

MH84: A Novel γ-Secretase Modulator/PPARγ Agonist—Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer’s Disease

3区 · 医学

Article

作者: Pellowska, Maren ; Pohland, Maximilian ; Eckert, Gunter P ; Schubert-Zsilavecz, Manfred ; Hagl, Stephanie ; Wurglics, Mario

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 (Aβ1-42) and mitochondrial dysfunction. MH84 is a derivate of pirinixic acid belonging to a novel class of γ-secretase modulators, which combines γ-secretase modulation with activation of peroxisome proliferator-activator receptor gamma (PPARγ). The mitochondria modifying Dimebon, the γ-secretase blocker DAPT, and the PPARγ agonist pioglitazone were used as controls. MH84 protects against nitrosative stress, increased mitochondrial respiration, citrate synthase (CS) activity and protein levels of PGC1α indicating enhanced mitochondrial content at nano-molar concentrations. Concurrently, MH84 decreased protein levels of APP, Aβ1-42, and C-terminal fragments at micro-molar concentrations. Both Dimebon and DAPT reduced cellular Aβ1-42 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.

2015-01-01·Journal of Pharmaceutical and Biomedical Analysis3区 · 医学

Pharmacokinetic properties of MH84, a γ-secretase modulator with PPARγ agonistic activity

3区 · 医学

Article

作者: Eckert, G P ; Wurglics, M ; Klein, J ; Stein, C ; Pellowska, M ; Pohland, M ; Schubert-Zsilavecz, M ; Merk, D

Alzheimer's disease (AD) is the most common cause of dementia. Since no causative treatment is available, new therapeutic options are utmost needed. Several pirinixic acid derivatives, including MH84 (2-((4,6-bis(4-(trifluoromethyl)phenethoxy)pyrimidin-2-yl)thio)hexanoic acid), have shown promising in vitro results as γ-secretase modulators as well as PPARγ activators as potential pharmacological compounds against AD. Using a newly developed and validated sensitive LC-MS (APCI-qTOF mass analyzer) method, the pharmacokinetic and long-term accumulating properties as well as the blood-brain-barrier permeability of MH84 were evaluated in a preclinical animal study. MH84 was administered to mice by oral gavage with a dose of 12 mg/kg. Nine time points from 0.5 to 48 h with 6 animals per point were investigated. Additionally 6 animals were fed daily, for 21 days with an identical dose to determine possible long-term accumulation in plasma and brain tissue. The sample preparation was performed by a liquid-liquid extraction on Extrelut(®) columns whereas the LC separation was operated on a MulthoHigh 100 RP 18-5 μ column (125 × 4 mm) using an isocratic mobile phase of formic acid (0.1% (v/v))-methanol mixture (11:89 (v/v)) at a flow rate of 1 ml/min. The validation confirmed the new LC-MS method to be precise, accurate and reliable. After oral application, Cmax and Tmax of unmetabolized MH84 was determined to be 10.90 μg/ml and 3h in plasma. In brain tissue a constant level of 300 to maximum 320.64 ng/g was found after 1.5-6h. Daily gavage for 21 days did not lead to a long-term drug accumulation in the brain. The efficacy of the obtained MH84 levels needs to be investigated in further preclinical pharmacodynamic animal studies.

100 项与 MH-84 (Alzheimer's disease) 相关的药物交易

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