Lucia Montenegro, Maria N. Modica, Loredana Salerno, Anna Maria Panico, Lucia Crascì, Giovanni Puglisi and Giuseppe Romeo; Molecules 2017, 22(6), 887; doi:10.3390/molecules22060887
Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters’ water solubility while increasing and prolonging their antioxidant activity.
In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy.
Sunday, May 28, 2017
Saturday, May 27, 2017
Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI
Thiago Junqueira R. Rezende, Alberto Rolim M. Martinez, Ingrid Faber, Karen Girotto, José Luiz Pedroso, Orlando G. Barsottini, Iscia Lopes-Cendes, Fernando Cendes, Andreia V. Faria and Marcondes C. França; Hum Brain Mapp. 2017 May 23. doi: 10.1002/hbm.23655. [Epub ahead of print]
The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.
Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P < 0.001).
The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.
Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P < 0.001).
Friday, May 26, 2017
Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich’s ataxia cardiomyopathy
Stram AR, Wagner GR, Fogler BD, Pride PM, Hirschey MD, Payne RM (2017). PLoS ONE 12(5): e0178354. doi:10.1371/journal.pone.0178354
Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function.
These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.
Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function.
These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.
Wednesday, May 24, 2017
Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015
GBD 2015 Healthcare Access and Quality Collaborators (Ryan M Barber, Nancy Fullman, Reed J D Sorensen, Thomas Bollyky, Martin McKee, Ellen Nolte, Amanuel Alemu Abajobir, Kalkidan Hassen Abate, Cristiana Abbafati, Kaja M Abbas et al); The Lancet, Volume null, Issue null, DOI:10.1016/S0140-6736(17)30818-8
Funding: Bill & Melinda Gates Foundation.
Unfortunately those affected by a rare disease need a good response from the health system throughout all life, perhaps more than those who are affected by common diseases. Although it is a paper about public health in general it could give us an idea about what we can expect from our national health systems in 195 different countries.
National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.
Funding: Bill & Melinda Gates Foundation.
Unfortunately those affected by a rare disease need a good response from the health system throughout all life, perhaps more than those who are affected by common diseases. Although it is a paper about public health in general it could give us an idea about what we can expect from our national health systems in 195 different countries.
National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.
Tuesday, May 23, 2017
Regulators of frataxin PATENT WO 2017037567 A1
Pfizer Inc., 9 Mar 2017. This invention relates to a method of treating a condition or a disease associated with decreased levels or activity of frataxin, including Friedreich's ataxia, comprising administering to a subject in needthereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof. Related methods, pharmaceutical uses and pharmaceutical compositions are disclosed herein.
Related press releases:
Recent Publication and Patent Application Referencing Apabetalone Support its Continued Development and Success,
CALGARY, May 23, 2017 /CNW/ - Resverlogix Corp. ("Resverlogix" or the "Company") (TSX: RVX) today highlighted two additional works involving its lead drug, apabetalone, one recently published by third party academics and one in the form of a patent application by Pfizer Inc. (Pfizer).
Findings on Frataxin Expression and Friedreich's Ataxia:
Recently, Pfizer applied for a patent titled: "Regulators of Frataxin" (WO 2017/037567 A1), their invention relates to the expression of frataxin by utilizing BET-bromodomain inhibitors. The purpose of the invention is for the potential treatment of a rare disease called Friedreich' ataxia (FA). RVX-208 (apabetalone) was listed as a potentially effective agent against this disease which is present in about 1 in 50,000 people. The ataxia of Friedreich's ataxia occurs from the degeneration of nerve tissue in the spinal cord. Symptoms usually begin between 5 to 15 years of age, leading to wheelchair requirements and can eventually lead to early death often related to cardiovascular disease.
Related press releases:
Recent Publication and Patent Application Referencing Apabetalone Support its Continued Development and Success,
CALGARY, May 23, 2017 /CNW/ - Resverlogix Corp. ("Resverlogix" or the "Company") (TSX: RVX) today highlighted two additional works involving its lead drug, apabetalone, one recently published by third party academics and one in the form of a patent application by Pfizer Inc. (Pfizer).
Findings on Frataxin Expression and Friedreich's Ataxia:
Recently, Pfizer applied for a patent titled: "Regulators of Frataxin" (WO 2017/037567 A1), their invention relates to the expression of frataxin by utilizing BET-bromodomain inhibitors. The purpose of the invention is for the potential treatment of a rare disease called Friedreich' ataxia (FA). RVX-208 (apabetalone) was listed as a potentially effective agent against this disease which is present in about 1 in 50,000 people. The ataxia of Friedreich's ataxia occurs from the degeneration of nerve tissue in the spinal cord. Symptoms usually begin between 5 to 15 years of age, leading to wheelchair requirements and can eventually lead to early death often related to cardiovascular disease.
Saturday, May 20, 2017
Nrf2, cellular redox regulation, and neurologic implications
Eduardo E. Benarroch, MD; Neurology May 16, 2017, 88:20 1942-1950; published ahead of print April 19, 2017, 1526-632X
Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently. Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia. Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection. This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.
Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently. Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia. Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection. This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.
Friday, May 19, 2017
Mitochondria-Derived Damage-Associated Molecular Patterns in Neurodegeneration
Wilkins HM, Weidling IW, Ji Y and Swerdlow RH (2017). Front. Immunol. 8:508. doi: 10.3389/fimmu.2017.00508
Friedreich’s ataxia is caused by autosomal recessive inheritance of a mutant Frataxin gene. The product of the Frataxin gene is responsible for iron homeostasis within mitochondria, and loss of this gene in Schwann cells leads to reduced mitochondrial respiration, inflammation, increased mitochondrial iron concentrations, and cell death. COX2 expression is elevated in both animal models and Friedreich’s ataxia patient lymphocytes, an indicator of increased inflammation.
Friedreich’s ataxia is caused by autosomal recessive inheritance of a mutant Frataxin gene. The product of the Frataxin gene is responsible for iron homeostasis within mitochondria, and loss of this gene in Schwann cells leads to reduced mitochondrial respiration, inflammation, increased mitochondrial iron concentrations, and cell death. COX2 expression is elevated in both animal models and Friedreich’s ataxia patient lymphocytes, an indicator of increased inflammation.
Thursday, May 18, 2017
Nonpublication of Trial Results for New Neurological Drugs: A Systematic Review
Hakala, A. K., Fergusson, D. and Kimmelman, J., Ann Neurol.. Accepted Author Manuscript. doi:10.1002/ana.24952
Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively. Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials.
Result data were not publicly available in any form for 10% (16/163) and 46% (94/203) of trials of licensed and stalled drugs, respectively. Results of trials for stalled drugs are heavily underreported. This deprives research and care communities of evidence about pathophysiology, drug class effects, and the value of surrogate endpoints in trials.
Wednesday, May 17, 2017
Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron–Sulfur Cluster Biosynthesis
Cai K, Tonelli M, Frederick RO, Markley JL. Biochemistry. 2017;56(3):487-499. doi:10.1021/acs.biochem.6b00447.
Monday, May 15, 2017
Physical Therapy for Cerebellar Ataxia
Akiyoshi Matsugi (2017). Physical Therapy for Cerebellar Ataxia, Neurological Physical Therapy, Prof. Toshiaki Suzuki (Ed.), InTech, ISBN 978-953-51-3114-4, Print ISBN 978-953-51-3113-7, Published: May 10, 2017 under CC BY 3.0 license.
Intensive physical therapy more than 1 hour per day for at least 4 weeks, focused on balance, gait, and strength training in hospital and home for patients with degenerative cerebellar ataxia can improve ataxia, gait ability, and activity of daily living. Furthermore, the weighting on the torso, using treadmill, noninvasive brain stimulation over the cerebellum for neuromodulation to facilitate motor learning, and neurophysiological assessment have a potential to improve the effect of physical therapy on cerebellar ataxia. Previous findings indicated that physical therapy is time restricted; therefore, its long-term effect and the effect of new optional neurophysiological methods should be studied.
Intensive physical therapy more than 1 hour per day for at least 4 weeks, focused on balance, gait, and strength training in hospital and home for patients with degenerative cerebellar ataxia can improve ataxia, gait ability, and activity of daily living. Furthermore, the weighting on the torso, using treadmill, noninvasive brain stimulation over the cerebellum for neuromodulation to facilitate motor learning, and neurophysiological assessment have a potential to improve the effect of physical therapy on cerebellar ataxia. Previous findings indicated that physical therapy is time restricted; therefore, its long-term effect and the effect of new optional neurophysiological methods should be studied.
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