Arnaud Chevalier, Mohammad Parvez Alam, Omar M. Khdour, Margaret Schmierer, Pablo M. Arce, Cameron D. Cripe, Sidney M. Hecht,Bioorganic & Medicinal Chemistry, Available online 23 August 2016, ISSN 0968-0896, doi:10.1016/j.bmc.2016.08.039.
The compounds were evaluated for their ability to suppress ROS and lipid peroxidation, and for their effects on mitochondrial membrane potential, and their ability to protect cultured FRDA lymphocytes from oxidative stress induced by glutathione depletion. The compounds were also evaluated for their ability to increase ATP levels in FRDA lymphocytes.
Tuesday, August 30, 2016
Monday, August 29, 2016
Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia
Marissa Z. McMackin, Chelsea K. Henderson, Gino A. Cortopassi, Behavioural Brain Research SreeTestContent1 SreeTestContent1, Available online 26 August 2016, ISSN 0166-4328, doi:/10.1016/j.bbr.2016.08.053.
The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA.
The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA.
Sunday, August 28, 2016
Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery
Benjamí Oller-Salvia, Macarena Sánchez-Navarro, Ernest Giralt and Meritxell Teixidó, (Review Article) Chem. Soc. Rev., 2016, 45, 4690-4707 DOI: 10.1039/C6CS00076B
Open Access Article
Although the BBB remains a formidable obstacle, since the Trojan horse concept was coined in the 1980s, the field of drug delivery to the brain has made remarkable progress. In the last few years, a plethora of new BBB shuttle peptides have emerged and hold great promise to overcome the limitations of the first generation of shuttles dominated by large proteins. Peptides are more affordable, easier to characterize and to link to nanocarriers or proteins. Moreover, they have lower immunogenicity and often have a reduced effect on the activity of the cargo than their larger counterparts. Furthermore, many peptide shuttles do not compete with endogenous substrates in contrast to endogenous proteins, nor stay bound to the receptor unlike some antibodies. BBB shuttle peptides have so far provided promising results in terms of brain delivery in preclinical settings. In addition, a relevant increase in the therapeutic effect has been proven in a wide variety of animal disease models, with a focus on brain tumours but also including neurodegenerative and lysosomal diseases as well as epilepsy among others.
Despite the considerable achievements described, new shuttles with higher transport capacity and selectivity are required. Approaches like phage display and natural sources of peptides that reach the CNS offer an excellent opportunity to explore the multitude of poorly characterized or still unknown routes into the brain. These strategies should be complemented with additional efforts in the characterization of the transport mechanisms and in global proteomic approaches to identify new receptors. Also, further comparative studies between shuttles and a more accurate quantification of the free drug in the brain parenchyma would enable a more efficient identification and optimization of BBB shuttles. The next generation of BBB shuttle peptides should aim for an enhanced metabolic stability, a higher transendothelial transport and an improved selectivity for the brain – even for particular regions of this organ – possibly through yet uncharacterized transctytotic pathways.
Acknowledgements: IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We appreciate financial support from MINECO-FEDER (Bio2013-40716-R and CTQ2013-49462-EXP), MINECO (PCIN-2015-051 Cure2DIPG), RecerCaixa-2014-Gate2Brain, Generalitat de Catalunya (XRB and 2014-SGR-521), FARA and GENEFA. B.O.-S. and M.S.-N. are grateful for “La Caixa”/IRB Barcelona and Juan de la Cierva fellowships, respectively.
Open Access Article
Although the BBB remains a formidable obstacle, since the Trojan horse concept was coined in the 1980s, the field of drug delivery to the brain has made remarkable progress. In the last few years, a plethora of new BBB shuttle peptides have emerged and hold great promise to overcome the limitations of the first generation of shuttles dominated by large proteins. Peptides are more affordable, easier to characterize and to link to nanocarriers or proteins. Moreover, they have lower immunogenicity and often have a reduced effect on the activity of the cargo than their larger counterparts. Furthermore, many peptide shuttles do not compete with endogenous substrates in contrast to endogenous proteins, nor stay bound to the receptor unlike some antibodies. BBB shuttle peptides have so far provided promising results in terms of brain delivery in preclinical settings. In addition, a relevant increase in the therapeutic effect has been proven in a wide variety of animal disease models, with a focus on brain tumours but also including neurodegenerative and lysosomal diseases as well as epilepsy among others.
Despite the considerable achievements described, new shuttles with higher transport capacity and selectivity are required. Approaches like phage display and natural sources of peptides that reach the CNS offer an excellent opportunity to explore the multitude of poorly characterized or still unknown routes into the brain. These strategies should be complemented with additional efforts in the characterization of the transport mechanisms and in global proteomic approaches to identify new receptors. Also, further comparative studies between shuttles and a more accurate quantification of the free drug in the brain parenchyma would enable a more efficient identification and optimization of BBB shuttles. The next generation of BBB shuttle peptides should aim for an enhanced metabolic stability, a higher transendothelial transport and an improved selectivity for the brain – even for particular regions of this organ – possibly through yet uncharacterized transctytotic pathways.
Acknowledgements: IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We appreciate financial support from MINECO-FEDER (Bio2013-40716-R and CTQ2013-49462-EXP), MINECO (PCIN-2015-051 Cure2DIPG), RecerCaixa-2014-Gate2Brain, Generalitat de Catalunya (XRB and 2014-SGR-521), FARA and GENEFA. B.O.-S. and M.S.-N. are grateful for “La Caixa”/IRB Barcelona and Juan de la Cierva fellowships, respectively.
CONTINUUM: Lifelong Learning in Neurology
Ashizawa, Tetsuo MD, FAAN; Xia, Guangbin MD, PhD; August 2016 - Volume 22 - Issue 4, Movement Disorders - p 1208–1226 doi: 10.1212/CON.0000000000000362
Purpose of Review: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia.
Purpose of Review: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia.
Wednesday, August 24, 2016
Movement disorders in mitochondrial diseases
Tranchant, Anheim. Rev Neurol (Paris). 2016 Jul 28. pii: S0035-3787(16)30025-X. doi: 10.1016/j.neurol.2016.07.003.
Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns–Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function.
Mitochondrial diseases (MIDs) are a large group of heterogeneous disorders due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes, the latter encoding proteins involved in mitochondrial function. A multisystem clinical picture that involves several organs, including both the peripheral and central nervous systems, is a common presentation of MID. Movement disorders, even isolated ones, are not rare. Cerebellar ataxia is common in myoclonic epilepsy with ragged red fibers (MERFF) due to mutations in the mitochondrial transfer RNA (tRNA) lysine gene, in Kearns–Sayre syndrome due to mtDNA deletions, in sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO) due to nuclear POLG1 gene mutations, and also in ARCA2, Friedreich's ataxia, SPG7, SCA28 and autosomal-recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) due to mutations in nuclear genes involved in mitochondrial morphology or function.
Tuesday, August 23, 2016
Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes
Nishaki Mehta, Paul Chacko, James Jin, Tam Tran, Thomas W. Prior, Xin He, Gunjan Agarwal, and Subha V. Raman (2016). Texas Heart Institute Journal: August 2016, Vol. 43, No. 4, pp. 305-310.
doi:10.14503/THIJ-14-4198
We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.
doi:10.14503/THIJ-14-4198
We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.
Monday, August 22, 2016
Tech giants moving into health may widen inequalities and harm research, unless people can access and share their data, warn John T. Wilbanks and Eric J. Topol.
John T. Wilbanks & Eric J. Topol, Nature 535, 345–348 (21 July 2016) doi:10.1038/535345a
Nature-Comment OPEN
Citizens worldwide have too long a history of being passive players in health care — blindly following instructions from providers. And studies that have tracked reactions to revelations about global surveillance programmes suggest that most people are resigned to the idea that ownership and control of personal information is incompatible with the Internet age.
Yet just as social networking has rocketed around the world in a decade, a worldwide knowledge resource could soon be used to identify the best course of treatment for an individual on the basis of the experiences of millions. This resource will never be built unless each of us takes responsibility for our own health and disease, and for the information that we can generate about ourselves. When it comes to control over our own data, health data must be where we draw the line.
Nature-Comment OPEN
Citizens worldwide have too long a history of being passive players in health care — blindly following instructions from providers. And studies that have tracked reactions to revelations about global surveillance programmes suggest that most people are resigned to the idea that ownership and control of personal information is incompatible with the Internet age.
Yet just as social networking has rocketed around the world in a decade, a worldwide knowledge resource could soon be used to identify the best course of treatment for an individual on the basis of the experiences of millions. This resource will never be built unless each of us takes responsibility for our own health and disease, and for the information that we can generate about ourselves. When it comes to control over our own data, health data must be where we draw the line.
Drug screening: Drug repositioning needs a rethink
Xianting Ding, Nature 535, 355 (21 July 2016) doi:10.1038/535355d Published online 20 July 2016
Repurposing drugs to treat illnesses for which they were not originally intended can be faster and cheaper than developing new ones. Disease is often an integration of multiple pathologies, so these are potentially treatable with different drug combinations that act in synergy.
For commercial reasons, pharmaceutical firms tend to dismiss reposition testing of drugs that are off patent. I therefore suggest that governments step in to fund the repurposing of established drugs to broaden the search.
Repurposing drugs to treat illnesses for which they were not originally intended can be faster and cheaper than developing new ones. Disease is often an integration of multiple pathologies, so these are potentially treatable with different drug combinations that act in synergy.
For commercial reasons, pharmaceutical firms tend to dismiss reposition testing of drugs that are off patent. I therefore suggest that governments step in to fund the repurposing of established drugs to broaden the search.
Sunday, August 21, 2016
Cerebral and cerebellar grey matter atrophy in Friedreich ataxia: the IMAGE-FRDA study.
Selvadurai LP , Harding IH , Corben LA , Stagnitti MR , Storey E , Egan GF , Delatycki MB , Georgiou-Karistianis N
J Neurol [2016] doi:10.1007/s00415-016-8252-7
This study supports a disease model involving neural aberrations within the cerebral and cerebellar cortices, beyond those traditionally associated with this disorder.
J Neurol [2016] doi:10.1007/s00415-016-8252-7
This study supports a disease model involving neural aberrations within the cerebral and cerebellar cortices, beyond those traditionally associated with this disorder.
Saturday, August 20, 2016
Increased Frataxin Levels Protect Retinal Ganglion Cells After Acute Ischemia/Reperfusion in the Mouse Retina In Vivo
Rowena Schultz; Otto W. Witte; Christian Schmeer; Investigative Ophthalmology & Visual Science August 2016, Vol.57, 4115-4124. doi:10.1167/iovs.16-19260
OPEEN ACCES This work is licensed under a Creative Commons
OPEEN ACCES This work is licensed under a Creative Commons
Subscribe to:
Posts (Atom)
