15 research outputs found
Neuronal cell-based high-throughput screen for enhancers of mitochondrial function reveals luteolin as a modulator of mitochondria-endoplasmic reticulum coupling
Background: Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases.
Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this study, we have
set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential.
Results: Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and
identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose
response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in
neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not
affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that
luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased
mitochondrial calcium (Ca2+) and Ca2+-dependent pyruvate dehydrogenase activity. This signaling pathway likely
contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly,
we observed that increased mitochondrial functions were dependent on the activity of ER Ca2+-releasing channels
inositol 1,4,5-trisphosphate receptors (IP3Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin
treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans
expressing an expanded polyglutamine tract of the huntingtin protein.
Conclusion: We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we
describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with
potential therapeutic validity for treatment of a variety of human diseases
Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and results in severe neurodegeneration and progressive cognitive decline. Neurotrophins are growth factors involved in the development and survival of neurons, but also in underlying mechanisms for memory formation such as hippocampal long-term potentiation. Our aim was to identify small molecules with stimulatory effects on the signaling of two neurotrophins, the nerve growth factor (NGF) and the brain derived neurotrophic factor (BDNF). To identify molecules that could potentiate neurotrophin signaling, 25,000 molecules were screened, which led to the identification of the triazinetrione derivatives ACD855 (Ponazuril) and later on ACD856, as positive allosteric modulators of tropomyosin related kinase (Trk) receptors. ACD855 or ACD856 potentiated the cellular signaling of the neurotrophin receptors with EC50 values of 1.9 and 3.2 or 0.38 and 0.30 µM, respectively, for TrkA or TrkB. ACD855 increased acetylcholine levels in the hippocampus by 40% and facilitated long term potentiation in rat brain slices. The compounds acted as cognitive enhancers in a TrkB-dependent manner in several different behavioral models. Finally, the age-induced cognitive dysfunction in 18-month-old mice could be restored to the same level as found in 2-month-old mice after a single treatment of ACD856. We have identified a novel mechanism to modulate the activity of the Trk-receptors. The identification of the positive allosteric modulators of the Trk-receptors might have implications for the treatment of Alzheimer’s diseases and other diseases characterized by cognitive impairment
Creation of Novel Cores for β‑Secretase (BACE-1) Inhibitors: A Multiparameter Lead Generation Strategy
In order to find optimal core structures
as starting points for
lead optimization, a multiparameter lead generation workflow was designed
with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer’s
disease. De novo design of core fragments was connected with three
predictive in silico models addressing target affinity, permeability,
and hERG activity, in order to guide synthesis. Taking advantage of
an additive SAR, the prioritized cores were decorated with a few,
well-characterized substituents from known BACE-1 inhibitors in order
to allow for core-to-core comparisons. Prediction methods and analyses
of how physicochemical properties of the core structures correlate
to in vitro data are described. The syntheses and in vitro data of
the test compounds are reported in a separate paper by Ginman et al.
[<i>J. Med. Chem.</i> <b>2013</b>, <i>56</i>, 4181–4205]. The affinity predictions are described in detail
by Roos et al. [<i>J. Chem. Inf.</i> <b>2014</b>,
DOI: 10.1021/ci400374z]