Drugs

Other neuroprotective compounds. 

Statins protect from mitochondrial induced apoptosis

Regulation of central cholesterol homeostasis and neuropharmacology of statins.The use of statins for the prevention or treatment of different neurodegenerative diseases has generated considerable interest albeit with some controversy. Mechanisms of statin-induced neuroprotection are not well understood. Recently, we reported that simvastatin stimulated neuronal gene expression and protein levels of the major antiapoptotic protein Bcl-2 in vivo and in vitro. We have recently shown that simvastatin administration in vivo and in vitro up-regulates gene expression and protein levels of the major antiapoptotic protein Bcl-2 in mouse and guinea pig brain tissue and in mouse primary neurons and SH-SY5Y human neuroblastoma cells. Suppression of Bcl-2 protein levels markedly reduced the neuroprotective effects of simvastatin in SH-SY5Y cells and dissociated brain cells ex vivo. Effects were independent of cholesterol and other products of the 3-hydroxy-3-methylglutaryl-CoA reductase pathway. Recently, we reported novel findings showing that up-regulation of Bcl-2 by simvastatin involves ET-1 and the transcription factor NFATc3.

MVA groß

We currently investigate if this novel neuroprotective mechanism may provide benefit in stroke models.

Olesoxime for mitochondrial protection in neurodegeneration

TRO19622

The cholesterol-oxime Olesoxime, represents a novel mitochondrial pore modulator that was identified in the neuronal cell screening platform developed at Trophos Inc. Preclinical studies have demonstrated that this compound promote the function and survival of neurons and other cell types under disease relevant stress conditions (Bordet et al., JPET 322:709-720, 2007) through interactions with the mitochondrial permeability transition pore (mPTP). 

Olesoxieme has successfully completed phase I studies in healthy volunteers and phase Ib studies in ALS and SMA patients. These clinical trials demonstrated that the product is well tolerated, has an excellent safety profile and that once-a-day oral dosing achieves the predicted exposure level required for efficacy, based on preclinical models. 

Logo Mitotarget new

In the frame of the EU-funded research project MitoTarget we are currently characterize Olesoxime`s mitochondrial function in neurons to better understand how mitochondrial dysfunction, leading to oxidative stress and activation of cell death pathways, is implicated in various neurodegenerative diseases and aging. Using preclinical model systems, we and the other partners investigate the ability of this new cholesterol-oxime compound to correct mitochondrial dysfunction and promote neuron survival and axonal growth.

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© Prof. Dr. Gunter P. Eckert 2018