Mitochondrial uncouplers

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.
Post Reply
User avatar
Petr75
Family Elder
Posts: 955
Joined: Sat Oct 19, 2013 10:17 am
Location: Czech Republic

Mitochondrial uncouplers

Post by Petr75 » Thu Nov 14, 2019 9:34 am

2019 Dec
Department of Functional Anatomy and Neuroscience, Asahikawa Medical University, Asahikawa, Japan
Disease modifying mitochondrial uncouplers, MP101, and a slow release ProDrug, MP201, in models of Multiple Sclerosis.
https://www.ncbi.nlm.nih.gov/pubmed/31585135

Abstract
Mitochondrial dysfunction is thought to be involved in the pathogenesis of MS and here we tested if brain penetrant mitochondrial uncouplers, DNP (MP101) and a novel prodrug of DNP (MP201), have the pharmacology to suppress demyelination and axonal loss in two independent models of MS by modulating the entire organelle's physiology. First, the gold standard EAE mouse model for MS was evaluated by daily oral treatment Day 7-21 with either MP101 or MP201 post-immunization. Both MP101/MP201 significantly suppressed progression of paralysis with limited infiltration of inflammatory cells. Strikingly, although mitochondrial uncouplers do increase energy expenditure even at the low doses provided here, they paradoxically preserved body weight at all doses in comparison to wasting in advanced paralysis of the placebos. Second, the effects of the compounds on suppressing inflammation were also evaluated in the cuprizone model, independent of the immune system. MP101/MP201 had a striking effect preserving both myelination and protecting the axons, in comparison to the placebos where both were destroyed. Both MP101/MP201 induced a significant and sustained increase in neurotrophin, BDNF, in the spinal cords. Both MP101/MP201 suppressed the expression of inflammatory cytokines including IL-1β, TNF-α and iNOS. Results indicate that MP101/MP201 may be a "disease modifying" treatment for MS by specifically modulating mitochondrial physiology. This would be a completely novel treatment for MS, targeting the mitochondria directly using a unique platform, mitochondrial uncouplers, that initially act non-genomically based upon biophysics, but cascades into cellular remodeling, neuroprotection and pro-survival. Clinical Phase I testing of MP101 in Normal Healthy Volunteers (NHV) is currently underway allowing for the potential to subsequently evaluate translation in MS patients and other insidious diseases, at expected weight neutral doses.

User avatar
Petr75
Family Elder
Posts: 955
Joined: Sat Oct 19, 2013 10:17 am
Location: Czech Republic

Re: Mitochondrial uncouplers

Post by Petr75 » Thu Jan 30, 2020 3:44 am

2020 Jan 27
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford
Mitochondrial Dysfunction Mediated Through Dynamin-Related Protein 1 (Drp1) Propagates Impairment in Blood Brain Barrier in Septic Encephalopathy
https://pubmed.ncbi.nlm.nih.gov/3198704 ... halopathy/

Abstract

Background: Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target. Mitochondrial dysfunction is an important contributor of sepsis-induced multi-organ system failure. More recently, mitochondrial dysfunction in endothelial cells has been implicated in mediating BBB failure in stroke, multiple sclerosis and in other neuroinflammatory disorders. Here, we focused on Drp1-mediated mitochondrial dysfunction in endothelial cells as a potential target to prevent BBB failure in sepsis.
Methods: We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in a cell culture as well as in murine model of sepsis. BBB disruption was assessed by measuring levels of key tight-junction proteins. Brain cytokines levels, oxidative stress markers, and activity of mitochondrial complexes were measured using biochemical assays. Astrocyte and microglial activation were measured using immunoblotting and qPCR. Transwell cultures of brain microvascular endothelial cells co-cultured with astrocytes were used to assess the effect of LPS on expression of tight-junction proteins, mitochondrial function, and permeability to fluorescein isothiocyanate (FITC) dextran. Finally, primary neuronal cultures exposed to LPS were assessed for mitochondrial dysfunction.
Results: LPS induced a strong brain inflammatory response and oxidative stress in mice which was associated with increased Drp1 activation and mitochondrial localization. Particularly, Drp1-(Fission 1) Fis1-mediated oxidative stress also led to an increase in expression of vascular permeability regulators in the septic mice. Similarly, mitochondrial defects mediated via Drp1-Fis1 interaction in primary microvascular endothelial cells were associated with increased BBB permeability and loss of tight-junctions after acute LPS injury. P110, an inhibitor of Drp1-Fis1 interaction, abrogated these defects, thus indicating a critical role for this interaction in mediating sepsis-induced brain dysfunction. Finally, LPS mediated a direct toxic effect on primary cortical neurons, which was abolished by P110 treatment.
Conclusions: LPS-induced impairment of BBB appears to be dependent on Drp1-Fis1-mediated mitochondrial dysfunction. Inhibition of mitochondrial dysfunction with P110 may have potential therapeutic significance in septic encephalopathy.

User avatar
Petr75
Family Elder
Posts: 955
Joined: Sat Oct 19, 2013 10:17 am
Location: Czech Republic

Re: Mitochondrial uncouplers

Post by Petr75 » Wed Mar 11, 2020 8:55 am

2020 Feb 25
Research Laboratory, Ziv Medical Center, Zefat, Israel
Mitochondrial Activity Is Impaired in Lymphocytes of MS Patients in Correlation With Disease Severity
https://pubmed.ncbi.nlm.nih.gov/3214643 ... -severity/

Abstract

Background: Multiple sclerosis (MS) is a multifactorial disease of the central nervous system in young adults. Mitochondrial respiration provides fuel necessary for cellular function and is especially important in cells with large energy demand including neurons. Various studies suggest that the pathogenesis of MS may be associated with mitochondrial dysfunction.

Methods: We examined 145 volunteers including 62 MS patients and healthy controls. MS patients were divided into two groups according to their disease severity: those with mild disability (EDSS=0-3.0) and those with moderate-severe MS (EDSS=3.5-8). After signing an informed consent, blood was taken and was separated to platelets and lymphocytes. Mitochondria activity was monitored as mitochondrial transmembrane potential following staining with JC1 dye in platelets and lymphocytes utilizing flow cytometry.

Results: We examined mitochondria activity as JC1 values from all separated lymphocyte samples and found significantly higher levels of mitochondrial activity in lymphocytes separated from healthy controls vs. MS patients (mean of 87.9% vs. 75.6%, p = 0.001). Significant differences in mitochondrial activity were also found when comparing means of groups divided according to MS disease severity. Interestingly, there were no significant differences in mitochondrial activity between patients treated with diverse medications or untreated patients. Mitochondrial activity was also examined in platelets, but no significant differences were found between groups.

Conclusions: Results obtained here show that mitochondrial activity was significantly lower in MS patients in comparison to healthy controls. In addition, there was a significant difference in mitochondrial activity depending on MS degree of disability. These initial findings in a peripheral examination hold potential for new diagnostic biomarkers to be considered in the future.

User avatar
Petr75
Family Elder
Posts: 955
Joined: Sat Oct 19, 2013 10:17 am
Location: Czech Republic

Re: Mitochondrial uncouplers

Post by Petr75 » Sat Jul 11, 2020 9:48 pm

2020 Jun 22
Centre for Clinical Brain Sciences, University of Edinburgh, Chancellor's Building, Edinburgh, UK
Enhanced Axonal Response of Mitochondria to Demyelination Offers Neuroprotection: Implications for Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/32572598/

Abstract

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

Post Reply
  • Similar Topics
    Replies
    Views
    Last post

Return to “General Discussion”