The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Stefan Dhein - One of the best experts on this subject based on the ideXlab platform.
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Olesoxime Inhibits Cardioplegia-Induced Ischemia/Reperfusion Injury. A Study in Langendorff-Perfused Rabbit Hearts.
Frontiers in physiology, 2017Co-Authors: Aida Salameh, Maren Keller, Ingo Dähnert, Stefan DheinAbstract:Objective: During cardioplegia, which is often used in cardiac surgery, the heart is subjected to global ischemia/reperfusion injury, which can result in a post-operative impairment of cardiac function. Mitochondria permeability transition pores (MPTP) play a key role in cardiomyocyte survival after ischemia/reperfusion injury. It was shown in clinical settings that blockers of MPTP like cyclosporine might have a positive influence on cardiac function after cardioplegic arrest. Olesoxime, which is a new drug with MPTP blocking activity, has been introduced as a neuroprotective therapeutic agent. This drug has not been investigated on a possible positive effect in ischemia/reperfusion injury in hearts. Therefore, the aim of our study was to investigate possible effects of Olesoxime on cardiac recovery after cardioplegic arrest. Methods: We evaluated 14 mature Chinchilla bastard rabbits of 1500-2000g. Rabbit hearts were isolated and perfused with constant pressure according to Langendorff. After induction of cardioplegic arrest (30ml 4°C cold Custodiol cardioplegia without and with 5µmol/L Olesoxime, n=7 each) the hearts maintained arrested for 90-minutes. Thereafter, the hearts were re-perfused for 60 minutes. At the end of each experiment left ventricular samples were frozen in liquid nitrogen for ATP measurements. Furthermore, heart slices were embedded in paraffin for histological analysis. During the entire experiment hemodynamic and functional data such as left ventricular pressure (LVP), dp/dt(max) and (min), pressure rate product (PRP), coronary flow, pO2 and pCO2 were also assessed. Results: Histological analysis revealed that despite the same ischemic burden for both groups markers of nitrosative and oxidative stress were significantly lower in the Olesoxime group. Moreover, hearts of the Olesoxime-group showed a significantly faster and better hemodynamic recovery during reperfusion. In addition, tissue ATP-levels were significantly higher in the Olesoxime treated hearts. Conclusions: Olesoxime significantly protected the cardiac muscle from ischemia/reperfusion injury.
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Olesoxime inhibits cardioplegia induced ischemia reperfusion injury a study in langendorff perfused rabbit hearts
Frontiers in Physiology, 2017Co-Authors: Aida Salameh, Maren Keller, Ingo Dähnert, Stefan DheinAbstract:Objective: During cardioplegia, which is often used in cardiac surgery, the heart is subjected to global ischemia/reperfusion injury, which can result in a post-operative impairment of cardiac function. Mitochondria permeability transition pores (MPTP) play a key role in cardiomyocyte survival after ischemia/reperfusion injury. It was shown in clinical settings that blockers of MPTP like cyclosporine might have a positive influence on cardiac function after cardioplegic arrest. Olesoxime, which is a new drug with MPTP blocking activity, has been introduced as a neuroprotective therapeutic agent. This drug has not been investigated on a possible positive effect in ischemia/reperfusion injury in hearts. Therefore, the aim of our study was to investigate possible effects of Olesoxime on cardiac recovery after cardioplegic arrest. Methods: We evaluated 14 mature Chinchilla bastard rabbits of 1500-2000g. Rabbit hearts were isolated and perfused with constant pressure according to Langendorff. After induction of cardioplegic arrest (30ml 4°C cold Custodiol cardioplegia without and with 5µmol/L Olesoxime, n=7 each) the hearts maintained arrested for 90-minutes. Thereafter, the hearts were re-perfused for 60 minutes. At the end of each experiment left ventricular samples were frozen in liquid nitrogen for ATP measurements. Furthermore, heart slices were embedded in paraffin for histological analysis. During the entire experiment hemodynamic and functional data such as left ventricular pressure (LVP), dp/dt(max) and (min), pressure rate product (PRP), coronary flow, pO2 and pCO2 were also assessed. Results: Histological analysis revealed that despite the same ischemic burden for both groups markers of nitrosative and oxidative stress were significantly lower in the Olesoxime group. Moreover, hearts of the Olesoxime-group showed a significantly faster and better hemodynamic recovery during reperfusion. In addition, tissue ATP-levels were significantly higher in the Olesoxime treated hearts. Conclusions: Olesoxime significantly protected the cardiac muscle from ischemia/reperfusion injury.
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Olesoxime Inhibits Cardioplegia-Induced Ischemia/Reperfusion Injury. A Study in Langendorff-Perfused Rabbit Hearts
Frontiers Media S.A., 2017Co-Authors: Aida Salameh, Maren Keller, Ingo Dähnert, Stefan DheinAbstract:Objective: During cardioplegia, which is often used in cardiac surgery, the heart is subjected to global ischemia/reperfusion injury, which can result in a post-operative impairment of cardiac function. Mitochondria permeability transition pores (MPTP) play a key role in cardiomyocyte survival after ischemia/reperfusion injury. It was shown in clinical settings that blockers of MPTP like cyclosporine might have a positive influence on cardiac function after cardioplegic arrest. Olesoxime, which is a new drug with MPTP blocking activity, has been introduced as a neuroprotective therapeutic agent. This drug has not been investigated on a possible positive effect in ischemia/reperfusion injury in hearts. Therefore, the aim of our study was to investigate possible effects of Olesoxime on cardiac recovery after cardioplegic arrest.Methods: We evaluated 14 mature Chinchilla bastard rabbits of 1,500–2,000 g. Rabbit hearts were isolated and perfused with constant pressure according to Langendorff. After induction of cardioplegic arrest (30 ml 4°C cold Custodiol cardioplegia without and with 5 μmol/L Olesoxime, n = 7 each) the hearts maintained arrested for 90-min. Thereafter, the hearts were re-perfused for 60 min. At the end of each experiment left ventricular samples were frozen in liquid nitrogen for ATP measurements. Furthermore, heart slices were embedded in paraffin for histological analysis. During the entire experiment hemodynamic and functional data such as left ventricular pressure (LVP), dp/dt(max) and (min), pressure rate product (PRP), coronary flow, pO2, and pCO2 were also assessed.Results: Histological analysis revealed that despite the same ischemic burden for both groups markers of nitrosative and oxidative stress were significantly lower in the Olesoxime group. Moreover, hearts of the Olesoxime-group showed a significantly faster and better hemodynamic recovery during reperfusion. In addition, tissue ATP-levels were significantly higher in the Olesoxime treated hearts.Conclusions: Olesoxime significantly protected the cardiac muscle from ischemia/reperfusion injury
Muhammad K. Rafiq - One of the best experts on this subject based on the ideXlab platform.
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Prognostic factors for survival in patients with amyotrophic lateral sclerosis: analysis of a multi-centre clinical trial
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 2016Co-Authors: Emma Yates, Muhammad K. RafiqAbstract:Information regarding factors influencing prognosis and quality of life (QoL) in patients with amyotrophic lateral sclerosis (ALS) is useful for clinicians and also for patients and their carers. The aims of this study are to identify prognostic factors for survival in ALS and to determine the physical factors influencing QoL. This study is a retrospective analysis of a cohort of 512 patients who participated in a phase II/III clinical trial of Olesoxime. Cox multivariate regression analysis found older age, bulbar onset disease, low baseline forced vital capacity, low baseline manual muscle test (MMT) scores and a shorter diagnostic delay to be independently associated with poor survival outcome. Physical factors shown to have the strongest correlation with poor QoL were low weight and a reduced ability to climb stairs. Therapeutic interventions including gastrostomy and non-invasive ventilation had no positive impact on QoL in this cohort. The prognostic factors for survival identified here are consistent with other studies of ALS patients, with the additional identification of baseline MMT score as another predictor of prognosis. Furthermore, the correlation between both weight and poor lower limb function with QoL is novel and underlines the importance of careful nutritional management in this hypercatabolic condition.
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creatine kinase enzyme level correlates positively with serum creatinine and lean body mass and is a prognostic factor for survival in amyotrophic lateral sclerosis
European Journal of Neurology, 2016Co-Authors: Muhammad K. Rafiq, Mike Bradburn, Christopher J Mcdermott, Pamela J. ShawAbstract:Background and purpose Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition for which there is no single diagnostic test or biomarker. The level of the creatine kinase (CK) enzyme in serum may be mild to moderately elevated in some patients with ALS, the precise cause of which and its behaviour with disease progression is unknown. The aim of this study was to examine the usefulness of monitoring CK serially during the ALS disease trajectory and to determine whether CK levels mirror disease progression. Methods This was a prospective observational cohort study, using the clinical database of the Olesoxime (TRO19622) investigational medicinal product trial. Results The baseline CK was raised in 52% of the trial participants with the mean CK ± SD being 257 ± 239 U/l. The mean CK was significantly higher in male participants than in female participants (P < 0.001) and amongst participants with limb onset ALS compared to participants with bulbar onset ALS (P < 0.001). There was no significant difference in the CK levels between upper limb and lower limb onset disease (P = 0.746). The CK level co-related positively with serum creatinine and estimated lean body mass but there was no relationship between CK and muscle scores and limb function. A higher CKlog was associated with significantly better survival, even when adjusted for prognostic co-variants (P = 0.013). Conclusions The serum CK level seems to be an independent prognostic factor for survival in ALS. The cellular mechanism of CK enzyme suggests that it may be upregulated to provide energy in the face of metabolic stress in ALS.
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Prognostic Factors for Survival in Patients with Amyotrophic Lateral Sclerosis: Analysis of a Multi-Centre Clinical Trial (P1.139)
Neurology, 2016Co-Authors: Muhammad K. Rafiq, Emma YatesAbstract:Objectives: The study has the following objectives: 1) to determine the characteristics of ALS patients with better survival and 2) to determine which physical factors are associated with poor quality of life (QoL) and what impact supportive interventions have on QoL. Background: Information regarding factors influencing prognosis and QoL in patients with amyotrophic lateral sclerosis (ALS) are useful to clinicians and also for patients and their carers. Being aware of the specific clinical factors which significantly influence survival would help clinicians in scheduling appropriate interventions and also in terms of advising patients as to what to expect as their disease progresses. Methods: This study is a retrospective analysis of a cohort of 512 patients who participated in the phase II/III clinical trial of Olesoxime. Results: Cox multivariate regression analysis found older age, bulbar onset disease, low baseline forced vital capacity (FVC), low baseline manual muscle test (MMT) scores and a shorter diagnostic delay to be independently associated with poor survival outcome. Physical factors shown to have the strongest correlation with poor QoL were low weight and a reduced ability to climb stairs. Therapeutic interventions including gastrostomy and non-invasive ventilation (NIV) had no positive impact on QoL in this cohort. Conclusions: The prognostic factors for survival identified here are consistent with other studies of ALS patients, with the additional identification of baseline MMT score as another predictor of prognosis. Furthermore the correlation between both weight and poor lower limb function with QoL is novel and underlines the importance of careful nutritional management in this hypercatabolic condition. Disclosure: Dr. Rafiq has nothing to disclose. Dr. Yates has nothing to disclose.
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Effect of lipid profile on prognosis in the patients with amyotrophic lateral sclerosis: Insights from the Olesoxime clinical trial
Amyotrophic lateral sclerosis & frontotemporal degeneration, 2015Co-Authors: Muhammad K. Rafiq, Ellen Lee, Mike Bradburn, Christopher J Mcdermott, Pamela J. ShawAbstract:Patients with ALS may have insufficientenergy substrates, due to dysphagia and hypermetabolism, which adversely affects the prognosis. Hyperlipidaemia has been reported to be associated with ALS and to represent a significant prognostic factor for survival in ALS. The aim of this study was to examine the prevalence of dyslipidaemia among a cohort of patients with ALS and how the lipid profile of patients with ALS influenced the prognosis. This was a prospective observational cohort study comprising 512 ALS patients, recruited for the TRO19622 (Olesoxime) investigational medicinal product trial. Fasting serum concentrations of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured as part of routine monitoring in the trial. Seventy-three percent of the participants had hypercholesterolaemia (defined as total cholesterol ≥ 5.1 mmol/l) at the screening visit. The prevalence of hypercholesterolaemia decreased with time and was 64% at 18 months follow-up. On unadjusted analysis total cholesterol, LDL-C and LDL/HDL ratio had a statistically significant effect on survival (p = 0.015, 0.003 and 0.027, respectively). When adjusted for prognostic covariates, however, none of the lipid measures was found to have a statistically significant effect on survival. In conclusion, prognosis in ALS is not influenced by the lipid profile of patients.
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Elevated Creatine Kinase is Associated with a Better Prognosis in Patients with Amyotrophic Lateral Sclerosis (P6.099)
Neurology, 2015Co-Authors: Muhammad K. Rafiq, Ellen Lee, Christopher J Mcdermott, Pamela J. ShawAbstract:OBJECTIVE: To determine: 1. Whether amyotrophic lateral sclerosis (ALS) patients with raised creatine kinase (CK) differ from ALS patients with normal CK? 2. The implications of raised CK on disease outcome or prognosis? 3. Whether the magnitude of muscle enzyme release be used to predict the magnitude of muscle functional impairment? BACKGROUND: CK is commonly observed to be mild to moderately elevated in the patients with ALS. The precise cause of elevated CK in only a proportion of ALS cases and its behaviour with disease progression is unknown. DESIGN/METHODS: This is a prospective observational cohort study, using the clinical data base of Olesoxime (TRO19622) investigational medicinal product trial. RESULTS: Baseline CK was raised in 52[percnt] of the participants: mean CK 257 ± SD of 239 IU/L. Mean CK in male participants was significantly higher than in females (p
Rebecca Pruss - One of the best experts on this subject based on the ideXlab platform.
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Protective role of Olesoxime against wild-type α-synuclein-induced toxicity in human neuronally differentiated SHSY-5Y cells
British journal of pharmacology, 2014Co-Authors: C. Gouarné, Gwenaëlle Tardif, Thierry Bordet, J Tracz, M Giraudon Paoli, V Deluca, M Seimandi, M Xilouri, L Stefanis, Rebecca PrussAbstract:Background and Purpose Parkinson's disease (PD) is usually diagnosed clinically from classical motor symptoms, while definitive diagnosis is made postmortem, based on the presence of Lewy bodies and nigral neuron cell loss. α-Synuclein (ASYN), the main protein component of Lewy bodies, clearly plays a role in the neurodegeneration that characterizes PD. Additionally, mutation in the SNCA gene or copy number variations are associated with some forms of familial PD. Here, the objective of the study was to evaluate whether Olesoxime, a promising neuroprotective drug can prevent ASYN-mediated neurotoxicity. Experimental Approach We used here a novel, mechanistically approachable and attractive cellular model based on the inducible overexpression of human wild-type ASYN in neuronally differentiated human neuroblastoma (SHSY-5Y) cells. This model demonstrates gradual cellular degeneration, coinciding temporally with the appearance of soluble and membrane-bound ASYN oligomers and cell death combining both apoptotic and non-apoptotic pathways. Key Results Olesoxime fully protected differentiated SHSY-5Y cells from cell death, neurite retraction and cytoplasmic shrinkage induced by moderate ASYN overexpression. This protection was associated with a reduction in cytochrome c release from mitochondria and caspase-9 activation suggesting that Olesoxime prevented ASYN toxicity by preserving mitochondrial integrity and function. In addition, Olesoxime displayed neurotrophic effects on neuronally differentiated SHSY-5Y cells, independent of ASYN expression, by promoting their differentiation. Conclusions and Implications Because ASYN is a common underlying factor in many cases of PD, Olesoxime could be a promising therapy to slow neurodegeneration in PD.
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Olesoxime protects embryonic cortical neurons from camptothecin intoxication by a mechanism distinct from BDNF.
British journal of pharmacology, 2013Co-Authors: C. Gouarné, Gwenaëlle Tardif, Rebecca Pruss, Marc Giraudon-paoli, Mathieu Seimandi, Clotilde Biscarrat, Thierry BordetAbstract:Background and Purpose Olesoxime is a small cholesterol–oxime promoting rat embryonic motor neurons survival in the absence of trophic factors. Because Olesoxime can substitute for neurotrophic factors in many situations, and to gain further understanding of its mechanism of action, we wondered if it could prevent neuronal death induced by camptothecin (CPT) and compared its effects with those of brain-derived neurotrophic factor (BDNF). Experimental Approach E17 rat embryonic cortical neurons were treated with Olesoxime, BDNF or vehicle and intoxicated with CPT. Caspase-dependent and caspase-independent death pathways along with pro-survival pathways activation were explored. Key Results As previously reported for BDNF, Olesoxime dose-dependently delayed CPT-induced cell death. Both compounds acted downstream of p53 activation preventing cytochrome c release and caspases activation. When caspase activation was blocked, both Olesoxime and BDNF provided additional neuroprotective effect, potentially through the prevention of apoptosis-inducing factor release from mitochondria. While BDNF activates both the PI3K/Akt and the ERK pathway, Olesoxime induced only a late activation of the ERK pathways, which did not seem to play a major role in its neuroprotection against CPT. Rather, our results favour preserved mitochondrial membrane integrity by Olesoxime. Conclusions and Implications Albeit different, Olesoxime and BDNF mechanisms for neuroprotection converge to preserve mitochondrial function. These findings emphasize the importance of targeting the mitochondria in the process of neurodegeneration. Importantly Olesoxime, by mimicking neurotrophin pro-survival activities without impacting PI3K/Akt and ERK signalling, may have greater therapeutic potential in many diseases where neurotrophins were considered as a therapeutic solution.
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P06 Olesoxime improves specific features of the HD pathology
Journal of Neurology Neurosurgery & Psychiatry, 2012Co-Authors: Laura E. Clemens, M. Michaud, Rebecca Pruss, T. Bordet, Janett Eckmann, Schamim H. Eckert, Tt Wlodkowski, E Portal, Gunter P. EckertAbstract:Background Olesoxime, a cholesterol-oxime, is a neuroprotective compound initially developed for the treatment of ALS (Bordet et al 2007). It interacts with proteins on the outer membrane of mitochondria (OMM) and inhibits the opening of the mitochondrial permeability transition pore (mPTP). Furthermore, it was found to accelerate oligodendrocyte maturation, thereby enhancing myelination (Magalon et al 2012). Since both mitochondrial function and myelination are impaired in HD (Lin & Beal, 2006; Xiang et al 2010), we evaluated the effect of Olesoxime on the behavioural and neuropathological phenotype of the BACHD rat. Methods BACHD rats and their wild type littermates were fed ad libitum with either an Olesoxime-containing or a control diet beginning at 5 weeks of age (n=15/group). Behavioural observations were carried out during a 12 months study period and neuropathology and mitochondrial function were investigated subsequently (n=4–6/group). Results Olesoxime treatment improved the cognitive and psychiatric phenotype in BACHD rats, which might be associated with a reduced mhtt accumulation found in the prelimbic cortex that is involved in learning and emotionality. It further increased the width of axon bundles in the striatum, which was significantly decreased in BACHD rats compared to wild types, possibly due to an improved myelination. Olesoxime was further capable of restoring mitochondrial respiratory chain function, rescuing a deficit in the expression of OMM proteins and normalise mitochondrial membrane fluidity. Conclusions Olesoxime did not improve motor and metabolic function but it ameliorated the cognitive, psychiatric and mitochondrial pathology in the BACHD rat.
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Olesoxime accelerates myelination and promotes repair in models of demyelination
Annals of neurology, 2012Co-Authors: Karine Magalon, Celine Zimmer, Myriam Cayre, Joseph Khaldi, Clarisse Bourbon, Isabelle Robles, Gwenaëlle Tardif, Angèle Viola, Rebecca Pruss, Thierry BordetAbstract:Objective: Multiple sclerosis is a neurodegenerative disease characterized by episodes of immune attack of oligodendrocytes leading to demyelination and progressive functional deficit. One therapeutic strategy to address disease progression could consist in stimulating the spontaneous regenerative process observed in some patients. Myelin regeneration requires endogenous oligodendrocyte progenitor migration and activation of the myelination program at the lesion site. In this study, we have tested the ability of Olesoxime, a neuroprotective and neuroregenerative agent, to promote remyelination in the rodent central nervous system in vivo. Methods: The effect of Olesoxime on oligodendrocyte progenitor cell (OPC) differentiation and myelin synthesis was tested directly in organotypic slice cultures and OPC–neuron cocultures. Using naive animals and different mouse models of demyelination, we morphologically and functionally assessed the effect of the compound on myelination in vivo. Results: Olesoxime accelerated oligodendrocyte maturation and enhanced myelination in vitro and in vivo in naive animals during development and also in the adult brain without affecting oligodendrocyte survival or proliferation. In mouse models of demyelination and remyelination, Olesoxime favored the repair process, promoting myelin formation with consequent functional improvement. Interpretation: Our observations support the strategy of promoting oligodendrocyte maturation and myelin synthesis to enhance myelin repair and functional recovery. We also provide proof of concept that Olesoxime could be useful for the treatment of demyelinating diseases. ANN NEUROL 2012;71:213–226
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Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model.
Neuropharmacology, 2012Co-Authors: Claire Sunyach, Nathalie Bernard-marissal, Cédric Raoul, M. Michaud, T. Arnoux, Julianne Aebischer, V. Latyszenok, C. Gouarné, Rebecca Pruss, T. BordetAbstract:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. The pathology is mimicked to a striking degree in transgenic mice carrying familial ALS-linked SOD1 gene mutations. Olesoxime (TRO19622), a novel neuroprotective and reparative compound identified in a high-throughput screen based on motoneuron (MN) survival, delays disease onset and improves survival in mutant SOD1(G93A) mice, a model for ALS. The present study further analyses the cellular basis for the protection provided by Olesoxime at the neuromuscular junctions (NMJ) and the spinal cord. Studies were carried out at two disease stages, 60 days, presymptomatic and 104 days, symptomatic. Cohorts of wild type and SOD1(G93A) mice were randomized to receive Olesoxime-charged food pellets or normal diet from day 21 onward. Analysis showed that Olesoxime initially reduced denervation from 60 to 30% compared to SOD1(G93A) mice fed with control food pellets while at the symptomatic stage only a few NMJs were still preserved. Immunostaining of cryostat sections of the lumbar spinal cord with VAChT to visualize MNs, GFAP for astrocytes and Iba1 for microglial cells showed that Olesoxime strongly reduced astrogliosis and microglial activation and prevented MN loss. These studies suggest that Olesoxime exerts its protective effect on multiple cell types implicated in the disease process in SOD1(G93A) mice, slowing down muscle denervation, astrogliosis, microglial activation and MN death. A Phase 3 clinical study in ALS patients will determine whether Olesoxime could be beneficial for the treatment of ALS.
Jonasz J. Weber - One of the best experts on this subject based on the ideXlab platform.
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Olesoxime in neurodegenerative diseases: Scrutinising a promising drug candidate
Biochemical pharmacology, 2019Co-Authors: Jonasz J. Weber, Laura Emily Clemensson, Helgi B. Schiöth, Huu Phuc NguyenAbstract:Abstract Over the last years, the experimental compound Olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved Olesoxime’s neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to Olesoxime’s potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis. Although no significant benefits have been demonstrated in patients of amyotrophic lateral sclerosis, and only the first 12 months of a phase II/III clinical trial showed an improvement in motor symptoms of spinal muscular atrophy, this orphan drug may still offer undiscovered potential in the treatment of neurological diseases. In our earlier preclinical studies, we demonstrated that administration of Olesoxime in mouse and rat models of Huntington disease improved psychiatric and molecular phenotypes. Aside from stabilising mitochondrial function, the drug reduced the overactivation of calpains, a class of calcium-dependent proteases entangled in neurodegenerative conditions. This observation may be credited to Olesoxime’s action on calcium dyshomeostasis, a further hallmark in neurodegeneration, and linked to its targets TSPO and VDAC, two proteins of the outer mitochondrial membrane associated with mitochondrial calcium handling. Further research into the mode of action of Olesoxime under pathological conditions, including its effect on neuronal calcium homeostasis, may strengthen the untapped potential of Olesoxime or other similar compounds as a therapeutic for neurodegenerative diseases.
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L20 Olesoxime targets calpain overactivation in models of huntington’s disease
Journal of Neurology Neurosurgery & Psychiatry, 2016Co-Authors: Jonasz J. Weber, Laura E. Clemens, Midea Malena Ortiz-rios, Lukas Klumpp, Linda S. Kaltenbach, Stephan M. Huber, Olaf Riess, Huu P. NguyenAbstract:Background A long-term treatment study of BACHD rats with Olesoxime, a mitochondria-targeting drug, revealed beneficial effects on specific behavioural and neuropathological phenotypes. On the molecular level, Olesoxime suppressed the activation of calpains, calcium-dependent cysteine proteases which were associated with cleavage of mutant huntingtin, through a yet unknown mechanism. Aims As calcium dyshomeostasis represents a hallmark of affected neurons in Huntington’s disease and mitochondrial function is essential for the maintenance of calcium levels, Olesoxime might exert its calpain suppression by stabilising mitochondrial calcium buffering. By analysing Olesoxime’s effects on calpains and calcium homeostasis in further cell and animal models, we sought to elucidate its underlying molecular mode of action. Methods To reproduce the observations made in our BACHD rats, we treated a second animal model of Huntington’s disease, the HdhQ111 knock-in mouse, with Olesoxime. For a more precise investigation of Olesoxime’s molecular function, we utilised cell models and examined cell viability, calpain activation and calcium buffering capacity after drug treatment. Results We validated the decrease of calpain activation and huntingtin fragmentation by Olesoxime treatment in HdhQ111 knock-in mice. Furthermore, cell models showed beneficial effects of Olesoxime on cell viability and calcium buffering capacity. Conclusions Our improved understanding of Olesoxime’s mode of action can help us to optimise its application as a drug not only in Huntington’s disease but also in other disorders involving calpain overactivation.
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l20 Olesoxime targets calpain overactivation in models of huntington s disease
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Jonasz J. Weber, Laura E. Clemens, Lukas Klumpp, Linda S. Kaltenbach, Stephan M. Huber, Olaf Riess, Midea Malena Ortizrios, Huu P. NguyenAbstract:Background A long-term treatment study of BACHD rats with Olesoxime, a mitochondria-targeting drug, revealed beneficial effects on specific behavioural and neuropathological phenotypes. On the molecular level, Olesoxime suppressed the activation of calpains, calcium-dependent cysteine proteases which were associated with cleavage of mutant huntingtin, through a yet unknown mechanism. Aims As calcium dyshomeostasis represents a hallmark of affected neurons in Huntington’s disease and mitochondrial function is essential for the maintenance of calcium levels, Olesoxime might exert its calpain suppression by stabilising mitochondrial calcium buffering. By analysing Olesoxime’s effects on calpains and calcium homeostasis in further cell and animal models, we sought to elucidate its underlying molecular mode of action. Methods To reproduce the observations made in our BACHD rats, we treated a second animal model of Huntington’s disease, the HdhQ111 knock-in mouse, with Olesoxime. For a more precise investigation of Olesoxime’s molecular function, we utilised cell models and examined cell viability, calpain activation and calcium buffering capacity after drug treatment. Results We validated the decrease of calpain activation and huntingtin fragmentation by Olesoxime treatment in HdhQ111 knock-in mice. Furthermore, cell models showed beneficial effects of Olesoxime on cell viability and calcium buffering capacity. Conclusions Our improved understanding of Olesoxime’s mode of action can help us to optimise its application as a drug not only in Huntington’s disease but also in other disorders involving calpain overactivation.
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The calpain-suppressing effects of Olesoxime in Huntington's disease.
Rare diseases (Austin Tex.), 2016Co-Authors: Jonasz J. Weber, Laura E. Clemens, Olaf Riess, Midea M. Ortiz Rios, Huu P. NguyenAbstract:Olesoxime, a small molecule drug candidate, has recently attracted attention due to its significant beneficial effects in models of several neurodegenerative disorders including Huntington's disease. Olesoxime's neuroprotective effects have been assumed to be conveyed through a direct, positive influence on mitochondrial function. In a long-term treatment study in BACHD rats, the latest rat model of Huntington's disease, Olesoxime revealed a positive influence on mitochondrial function and improved specific behavioral and neuropathological phenotypes. Moreover, a novel target of the compound was discovered, as Olesoxime was found to suppress the activation of the calpain proteolytic system, a major contributor to the cleavage of the disease-causing mutant huntingtin protein into toxic fragments, and key player in degenerative processes in general. Results from a second model of Huntington's disease, the Hdh (Q111) knock-in mouse, confirm Olesoxime's calpain-suppressing effects and support the therapeutic value of Olesoxime for Huntington's disease and other disorders involving calpain overactivation.
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Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the bachd rat
Brain, 2015Co-Authors: Laura E. Clemens, Schamim H. Eckert, Jonasz J. Weber, Tanja T Wlodkowski, Libo Yutaeger, Magali Michaud, Carsten Calaminus, Janett Gaca, Andreas Weiss, Janine MaggAbstract:Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements. Here, we investigated the therapeutic potential of Olesoxime, a mitochondria-targeting, neuroprotective compound, in the BACHD rat model of Huntington's disease. BACHD rats were treated with Olesoxime via the food for 12 months. In vivo analysis covered motor impairments, cognitive deficits, mood disturbances and brain atrophy. Ex vivo analyses addressed Olesoxime's effect on mutant huntingtin aggregation and cleavage, as well as brain mitochondria function. Olesoxime improved cognitive and psychiatric phenotypes, and ameliorated cortical thinning in the BACHD rat. The treatment reduced cerebral mutant huntingtin aggregates and nuclear accumulation. Further analysis revealed a cortex-specific overactivation of calpain in untreated BACHD rats. Treated BACHD rats instead showed significantly reduced levels of mutant huntingtin fragments due to the suppression of calpain-mediated cleavage. In addition, Olesoxime reduced the amount of mutant huntingtin fragments associated with mitochondria, restored a respiration deficit, and enhanced the expression of fusion and outer-membrane transport proteins. In conclusion, we discovered the calpain proteolytic system, a key player in Huntington's disease and other neurodegenerative disorders, as a target of Olesoxime. Our findings suggest that Olesoxime exerts its beneficial effects by improving mitochondrial function, which results in reduced calpain activation. The observed alleviation of behavioural and neuropathological phenotypes encourages further investigations on the use of Olesoxime as a therapeutic for Huntington's disease.
Laura E. Clemens - One of the best experts on this subject based on the ideXlab platform.
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L20 Olesoxime targets calpain overactivation in models of huntington’s disease
Journal of Neurology Neurosurgery & Psychiatry, 2016Co-Authors: Jonasz J. Weber, Laura E. Clemens, Midea Malena Ortiz-rios, Lukas Klumpp, Linda S. Kaltenbach, Stephan M. Huber, Olaf Riess, Huu P. NguyenAbstract:Background A long-term treatment study of BACHD rats with Olesoxime, a mitochondria-targeting drug, revealed beneficial effects on specific behavioural and neuropathological phenotypes. On the molecular level, Olesoxime suppressed the activation of calpains, calcium-dependent cysteine proteases which were associated with cleavage of mutant huntingtin, through a yet unknown mechanism. Aims As calcium dyshomeostasis represents a hallmark of affected neurons in Huntington’s disease and mitochondrial function is essential for the maintenance of calcium levels, Olesoxime might exert its calpain suppression by stabilising mitochondrial calcium buffering. By analysing Olesoxime’s effects on calpains and calcium homeostasis in further cell and animal models, we sought to elucidate its underlying molecular mode of action. Methods To reproduce the observations made in our BACHD rats, we treated a second animal model of Huntington’s disease, the HdhQ111 knock-in mouse, with Olesoxime. For a more precise investigation of Olesoxime’s molecular function, we utilised cell models and examined cell viability, calpain activation and calcium buffering capacity after drug treatment. Results We validated the decrease of calpain activation and huntingtin fragmentation by Olesoxime treatment in HdhQ111 knock-in mice. Furthermore, cell models showed beneficial effects of Olesoxime on cell viability and calcium buffering capacity. Conclusions Our improved understanding of Olesoxime’s mode of action can help us to optimise its application as a drug not only in Huntington’s disease but also in other disorders involving calpain overactivation.
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l20 Olesoxime targets calpain overactivation in models of huntington s disease
Journal of Neurology Neurosurgery and Psychiatry, 2016Co-Authors: Jonasz J. Weber, Laura E. Clemens, Lukas Klumpp, Linda S. Kaltenbach, Stephan M. Huber, Olaf Riess, Midea Malena Ortizrios, Huu P. NguyenAbstract:Background A long-term treatment study of BACHD rats with Olesoxime, a mitochondria-targeting drug, revealed beneficial effects on specific behavioural and neuropathological phenotypes. On the molecular level, Olesoxime suppressed the activation of calpains, calcium-dependent cysteine proteases which were associated with cleavage of mutant huntingtin, through a yet unknown mechanism. Aims As calcium dyshomeostasis represents a hallmark of affected neurons in Huntington’s disease and mitochondrial function is essential for the maintenance of calcium levels, Olesoxime might exert its calpain suppression by stabilising mitochondrial calcium buffering. By analysing Olesoxime’s effects on calpains and calcium homeostasis in further cell and animal models, we sought to elucidate its underlying molecular mode of action. Methods To reproduce the observations made in our BACHD rats, we treated a second animal model of Huntington’s disease, the HdhQ111 knock-in mouse, with Olesoxime. For a more precise investigation of Olesoxime’s molecular function, we utilised cell models and examined cell viability, calpain activation and calcium buffering capacity after drug treatment. Results We validated the decrease of calpain activation and huntingtin fragmentation by Olesoxime treatment in HdhQ111 knock-in mice. Furthermore, cell models showed beneficial effects of Olesoxime on cell viability and calcium buffering capacity. Conclusions Our improved understanding of Olesoxime’s mode of action can help us to optimise its application as a drug not only in Huntington’s disease but also in other disorders involving calpain overactivation.
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The calpain-suppressing effects of Olesoxime in Huntington's disease.
Rare diseases (Austin Tex.), 2016Co-Authors: Jonasz J. Weber, Laura E. Clemens, Olaf Riess, Midea M. Ortiz Rios, Huu P. NguyenAbstract:Olesoxime, a small molecule drug candidate, has recently attracted attention due to its significant beneficial effects in models of several neurodegenerative disorders including Huntington's disease. Olesoxime's neuroprotective effects have been assumed to be conveyed through a direct, positive influence on mitochondrial function. In a long-term treatment study in BACHD rats, the latest rat model of Huntington's disease, Olesoxime revealed a positive influence on mitochondrial function and improved specific behavioral and neuropathological phenotypes. Moreover, a novel target of the compound was discovered, as Olesoxime was found to suppress the activation of the calpain proteolytic system, a major contributor to the cleavage of the disease-causing mutant huntingtin protein into toxic fragments, and key player in degenerative processes in general. Results from a second model of Huntington's disease, the Hdh (Q111) knock-in mouse, confirm Olesoxime's calpain-suppressing effects and support the therapeutic value of Olesoxime for Huntington's disease and other disorders involving calpain overactivation.
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Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the bachd rat
Brain, 2015Co-Authors: Laura E. Clemens, Schamim H. Eckert, Jonasz J. Weber, Tanja T Wlodkowski, Libo Yutaeger, Magali Michaud, Carsten Calaminus, Janett Gaca, Andreas Weiss, Janine MaggAbstract:Huntington's disease is a fatal human neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, which translates into a mutant huntingtin protein. A key event in the molecular pathogenesis of Huntington's disease is the proteolytic cleavage of mutant huntingtin, leading to the accumulation of toxic protein fragments. Mutant huntingtin cleavage has been linked to the overactivation of proteases due to mitochondrial dysfunction and calcium derangements. Here, we investigated the therapeutic potential of Olesoxime, a mitochondria-targeting, neuroprotective compound, in the BACHD rat model of Huntington's disease. BACHD rats were treated with Olesoxime via the food for 12 months. In vivo analysis covered motor impairments, cognitive deficits, mood disturbances and brain atrophy. Ex vivo analyses addressed Olesoxime's effect on mutant huntingtin aggregation and cleavage, as well as brain mitochondria function. Olesoxime improved cognitive and psychiatric phenotypes, and ameliorated cortical thinning in the BACHD rat. The treatment reduced cerebral mutant huntingtin aggregates and nuclear accumulation. Further analysis revealed a cortex-specific overactivation of calpain in untreated BACHD rats. Treated BACHD rats instead showed significantly reduced levels of mutant huntingtin fragments due to the suppression of calpain-mediated cleavage. In addition, Olesoxime reduced the amount of mutant huntingtin fragments associated with mitochondria, restored a respiration deficit, and enhanced the expression of fusion and outer-membrane transport proteins. In conclusion, we discovered the calpain proteolytic system, a key player in Huntington's disease and other neurodegenerative disorders, as a target of Olesoxime. Our findings suggest that Olesoxime exerts its beneficial effects by improving mitochondrial function, which results in reduced calpain activation. The observed alleviation of behavioural and neuropathological phenotypes encourages further investigations on the use of Olesoxime as a therapeutic for Huntington's disease.
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M06 Olesoxime Treatment Inhibits The Formation Of Mhtt Fragments Through Suppression Of Calpain Activity, And Leads To Behavioural And Neurological Improvements In The Bachd Rat
Journal of Neurology Neurosurgery & Psychiatry, 2014Co-Authors: Laura E. Clemens, M. Michaud, Schamim H. Eckert, Libo Yu-taeger, Jonasz J. Weber, Carsten Calaminus, Tt Wlodkowski, Jcd Magg, Nicolas Casadei, Janett EckmannAbstract:Background Proteolytic cleavage of the mutant huntingtin protein (mHtt) leads to toxic N-terminal mHtt fragments, which are known to disrupt mitochondrial function. Olesoxime, a small cholesterol-like molecule, targets mitochondria and has demonstrated therapeutic efficacy in a variety of disease models. Recent clinical investigations revealed exciting results in spinal muscular atrophy patients, where Olesoxime was found to be the first drug to efficiently block the progression of motor deficits in a clinical type II study. Furthermore, it was found to increase the survival of primary striatal neurons overexpressing mHtt, suggesting therapeutic potential also for HD. Aims To evaluate the therapeutic potential of Olesoxime in the BACHD rat model of HD. Methods Olesoxime was supplied to BACHD rats via drug-loaded food pellets from the age of 5 weeks on, and the rats’ behaviour was studied for 12 months. Brain atrophy was investigated with MRI at 13 months. Mitochondrial parameters, mHtt cleavage and aggregation were measured in brain lysates ex vivo . Results We found Olesoxime to specifically ameliorate psychiatric and cognitive disturbances of BACHD rats, to increase frontal cortex thickness and to improve mitochondrial function. Very interestingly, the beneficial effects seemed to be mediated by a downregulation of calpain activity, thereby drastically reducing the formation of mHtt fragments and aggregates, and increasing soluble mHtt levels. Conclusions Our study reveals new insights into Olesoxime’s mechanism of action and highlights Olesoxime as a novel tool for reducing toxic mHtt fragments.
