Tert-butylhydroquinone protects PC12 cells against ferrous sulfate-induced oxidative and inflammatory injury via the Nrf2/ARE pathway

Wenzhe Xu, Feng Li, Zhenkuan Xu, Bin Sun, Jingwei Cao, Yuguang Liu, Chemico-Biological Interactions, Available online 2 June 2017, ISSN 0009-2797, doi:10.1016/j.cbi.2017.05.021

Increasing evidence had proved the critical role of iron in the pathogenesis of numerous neurodegenerative diseases because of its capacity to promote the formation of reactive oxygen species (ROS). Tert-butylhydroquinone (tBHQ) was a metabolite of butylated hydroxyanisole, a widely used food antioxidant. tBHQ could change the conformation of the Keap1-Nrf2 complex and helps Nrf2 escape from Keap1-mediated degradation, which can lead to Nrf2 stabilization. tBHQ has been proven to exert neuroprotective effects in different models of CNS injury and has been approved for human use

Free iron exhibits cytotoxicity because of its ability to promote the generation of reactive oxygen species (ROS), which could lead to lipid peroxidation, DNA strand breaks, degradation of biomolecules, and induce inflammatory response. Brain iron content tends to increase during healthy aging, while excessive iron deposits are found in neuritic plaques in brains with Alzheimer’s disease, substantia nigra in Parkinson’s disease, basal ganglia in Huntington’s disease and dorsal root ganglia in Friedreich’s ataxia (FRDA). This study proved the beneficial effects of tBHQ on the attenuation of iron-induced neurotoxicity, suggesting the therapeutic potential of tBHQ for neurodegenerative diseases.

Is Reata's Friedreich's Ataxia Study a Failure?

Rare Disease ReportData from a Phase 2 Friedreich’s ataxia (FA) study by Reata Pharmaceuticals is making its rounds on social media today. The data, according to Reata, is exceptional. However, according to many on Twitter, the trial is a failure.

In spite of what the critics think, the company and the advocacy group Friedreich’s Ataxia Research Alliance (FARA) are cautiously optimistic.

About: Rare Disease Report is a website and weekly e-newsletter that offers an independent voice for the Rare Disease Community. It strives to bring together medical, scientific, investment, regulatory, and advocate professionals interested in rare diseases and orphan drugs.


NOTE: This is a news published on the web, from a news source that is usually rigorous. I usually try to publish here all the scientific news around the FA, without censorship. This means that I do not always necessary should agree with the opinions.

Reata Pharmaceuticals, Inc. Announces Positive Data From Part One of Moxie Trial of Omaveloxolone for Friedreich’s Ataxia

IRVING, Texas, June 01, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced positive data from Part 1 of the Company’s Phase 2 trial (MOXIe) of omaveloxolone for the treatment of Friedreich’s ataxia (FA). The trial demonstrated that in FA patients, omaveloxolone induced Nrf2, which is suppressed in FA patients, and this was associated with improvements in mitochondrial and neurological function. Dose-dependent and time-dependent effects on the modified Friedreich’s Ataxia Rating Scale (mFARS) were observed at the pharmacodynamically active doses, and the maximum effect on mFARS was observed at the 160 mg dose level. The Company is planning to initiate Part 2 of MOXIe during the second half of 2017.

Friedreich’s ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency

Duncan E. Crombie, Claire L. Curl, Antonia JA Raaijmakers, Priyadharshini Sivakumaran, Tejal Kulkarni, Raymond CB Wong, Itsunari Minami, Marguerite V. Evans-Galea, Shiang Y. Lim, Lea Delbridge, Louise A. Corben, Mirella Dottori, Norio Nakatsuji, Ian A. Trounce, Alex W. Hewitt, Martin B. Delatycki, Martin F. Pera, Alice Pébay; Aging (Albany NY). 2017; 9:1440-1452. doi: 10.18632/aging.101247.

FRDA- cardiomyocytes display a significant increase in beat rate variability, demonstrating a potential for cardiac dysfunction, compared to the control cardiomyocytes. These data also suggest that impairment in Ca2+ handling is responsible for the observed electrophysiological phenotype. This was confirmed by assessing Ca2+ transients. In the FRDA-cardiomyocytes significantly lower diastolic and systolic Ca2+ levels and reduced transient amplitude signals were observed compared with control cardiomyocytes. Collectively, our data demonstrates a Ca2+ handling impairment in the FRDA cardiomyocytes.

Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders

Inder Singh, Vishnu Swarup, Sunil Shakya, Vinay Goyal, Mohammed Faruq, Achal Kumar Srivastava, Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders, Journal of the Neurological Sciences, Available online 22 May 2017, ISSN 0022-510X, doi:10.1016/j.jns.2017.05.042.

The nearly-accurate sizing of the normal and expanded allele was achieved in a shorter time (4–5 h), without DNA extraction and any risk of cross contamination, which suggests the BD-PCR to be a reliable, inexpensive, and rapid method to confirm TRDs. This technique can be introduced in routine diagnostic procedures of other tandem repeat disorders.

Developing gene and cell therapies for rare diseases: an opportunity for synergy between academia and industry

F Mavilio; Gene Therapy , (25 May 2017) doi:10.1038/gt.2017.36

For the last 20 years, academic research has been the major, and often only, driving force behind the spectacular development of gene transfer technology for the therapy of rare genetic diseases. Investors and industry became eventually interested in gene and cell therapy, due to the success of a series of pioneering clinical trials that proved efficacy and safety of last-generation technology, and to favorable orphan drug legislation in both Europe and the United States. Developing this forms of therapy is however complex and requires skills and knowledge not necessary available to the industry, which is better placed to develop processes and products and put them on the market. Cooperation between academia and industry is an opportunity to de-risk innovative approaches and ensure a faster and more economical development of therapies for diseases with high unmet medical needs and low-profit expectations.

Blood–brain barrier peptide shuttles

Macarena Sánchez-Navarro, Ernest Giralt, Meritxell Teixidó, Current Opinion in Chemical Biology, Volume 38, June 2017, Pages 134-140, ISSN 1367-5931, doi:10.1016/j.cbpa.2017.04.019.

Brain delivery is hampered by the presence of the blood–brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics.

Peptides shuttles present several advantages over the brain delivery system alternatives. For instance, peptides are amenable for chemical synthesis, and present low toxicity. Some of the challenges of its application are already being solved. The recent development of new and more efficient BBB-shuttles will lead to more pre- clinical studies, and hopefully, to clinical evaluations in the following years.

Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study

Harding, I. H., Corben, L. A., Delatycki, M. B., Stagnitti, M. R., Storey, E., Egan, G. F. and Georgiou-Karistianis, N. (2017), Mov. Disord.. doi: 10.1002/mds.27023

Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia.

Contemporary theories, models, and evidence of neural compensation and neural reserve firmly support the notion that neurofunctional changes underlying degenerative diseases are not only detrimental but also may be compensatory. This idea has driven a groundswell of research into novel therapeutic approaches designed to stimulate or maintain these compensatory cerebral processes through, for example, noninvasive brain stimulation, or cognitive therapies. Given the evidence that cerebral compensation may also operate in FRDA, these novel means of intervention represent exciting pathways for future research.

The present study motivates a reconceptualization of cerebral contributions to FRDA. In particular, cerebral alterations are likely not just secondary repercussions of cerebellar and spinal insults. Rather, cerebral changes may represent capacity limited compensatory processes operating at the network level of brain function, which serve to mitigate the behavioral impacts of progressive pathology. Critically, these novel findings inform development of new avenues of clinical intervention for FRDA.

In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles

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.

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).