Nerves, brain cells and spinal cord
A drug that can encourage nerves in the spinal cord to grow and repair injuries has been developed by US scientists.
The study on rats, published in the journal Nature, showed some degree of movement and bladder control could be restored.
The drug works by disrupting the "sticky glue" that prevents nerve cells from growing during an injury.
Further tests still need to take place, but the charity Spinal Research said "real progress" was being made.
Damage to the spinal cord interrupts the constant stream of electrical signals from the brain to the body.
It can lead to paralysis below an injury.
The team at Case Western Reserve University School of Medicine, in Ohio, said scar tissue that formed after an injury prevented spinal cord repair.
Sugary proteins are released by the scar tissue which act like glue.
The long spindly part of the nerve - the axon - gets trapped in the glue if it tries to cross the site of the injury.
The research team injected a chemical under the skin which crossed into the spinal cord and disrupted the activity of the glue.
"It was amazing - the axons kept growing and growing," said lead researcher Prof Jerry Silver.
In the tests, 21 out of 26 rats showed some degree of recovery either in their ability to move or in bladder function.
Prof Silver told the BBC: "What we could see was really remarkable. Some recovered to a fantastic extent and so well you could hardly tell there was an injury."
He says further testing in larger animals is needed before human trials can take place.
But he sees any future therapy resulting from the research as working in conjunction with other treatments being pioneered such as nerve transplants and electrical stimulation.
Dr Mark Bacon, from the charity Spinal Research, said: "I like Prof Silver's work.
"We believe plasticity - the reorganisation and rerouting of signal pathways - is the major mechanism responsible for the spontaneous recovery we see in patients with spinal cord injury, but is very limited.
"Enhancing plasticity is therefore a major goal for the field.
"Preliminary data here suggests that real progress is being made towards this."
Dr Lyn Jakeman, from the US National Institute of Neurological Disorders and Stroke, said: "There are currently no drug therapies available that improve the very limited natural recovery from spinal cord injuries that patients experience.
"This is a great step towards identifying a novel agent for helping people recover."
Source: BBC News © British Broadcasting Corporation 2014 (04/12/14)
A study published in the October, 2014 issue of Nature Medicine points to a new target for the treatment of multiple sclerosis (M.S.). Inhibiting this target, in a mouse model of the disease, was shown to inhibit the disease in its most advanced stages.
The landmark paper, “B4GALT6 regulates astrocyte activation during CNS inflammation,” was authored by Lior Mayo, Francisco J. Quinta et al. at Harvard Medical School. Abdolmohamad Rostami, M.D. Ph.D., professor and chair of the department of neurology at Thomas Jefferson University, together with Assistant Professor of Neurology Bogoljub Ciric, Ph.D., authored a commentary article, “Astrocyte-derived lactosylceramide implicated in multiple sclerosis,” about the research for Nature Medicine.
“These findings provide a basis for targeting astrocytes, in particular LacCer signaling, as an alternative to most existing M.S. therapies, which modulate the immune system,” said Dr. Rostami. Patients and researchers have been frustrated by the limited effectiveness of available therapies for M.S., especially for “progressive” M.S., a devastating form of the disease that continues to progress with no interruption.
As Rostami and Ciric write in their commentary, the researchers started by investigating a puzzle in M.S. biology. M.S. is thought of as a disease in which the immune cells attack the neuron’s “insulating” tissue, myelin, which helps speed the signals passing from one cell to the next. A type of brain cell, called an astrocyte, appears to play two roles in the disease – protecting and re-myleninating cells early on, and then later, it appears to participate in the inflammatory reaction that fuels the disease.
Exploring this question, the researchers found that the gene B4GALT6 encodes an enzyme that makes LaCer (latosylceramide) — a lipid-signaling molecule. Increasing LaCer production worsens the disease, while inhibiting LaCer halts progression in a mouse model of late-stage disease, suggesting that this enzyme could be a potent target for developing a novel class of therapies against M.S.
Rostami and Ciric write that LaCer appears to contribute to disease progression by activating astrocytes, which in turn activate inflammatory signals that damage nerve cells; it also contributes to the repression of genes associated with remyelinization.
Drs. Rostami and Ciric were particularly impressed with the studies that bridged the finding to human disease. The Harvard team also showed that in samples taken from humans with M.S., B4GALT6 expression levels were increased, as were markers of astrocyte activation, suggesting that a similar pathway may be at play in humans.
Source: Thomas Jefferson University Copyright © 2014 Thomas Jefferson University (15/10/14)
A spice commonly found in curries may boost the brain's ability to heal itself, according to a report in the journal Stem Cell Research and Therapy.
The German study suggests a compound found in turmeric could encourage the growth of nerve cells thought to be part of the brain's repair kit.
Scientists say this work, based in rats, may pave the way for future drugs for strokes and Alzheimer's disease.
But they say more trials are needed to see whether this applies to humans.
Researchers from the Institute of Neuroscience and Medicine in Julich, Germany, studied the effects of aromatic-turmerone - a compound found naturally in turmeric.
Rats were injected with the compound and their brains were then scanned.
Particular parts of the brain, known to be involved in nerve cell growth, were seen to be more active after the aromatic-turmerone infusion.
Scientists say the compound may encourage a proliferation of brain cells.
In a separate part of the trial, researchers bathed rodent neural stem cells (NSCs) in different concentrations of aromatic-tumerone extract.
NSCs have the ability to transform into any type of brain cell and scientists suggest they could have a role in repair after damage or disease.
Dr Maria Adele Rueger, who was part of the research team, said: "In humans and higher developed animals their abilities do not seem to be sufficient to repair the brain but in fish and smaller animals they seem to work well."
The research found the higher the concentration of aromatic-turmerone, the greater the growth of the NSCs.
And the cells bathed in the turmeric compound seemed to specialise into certain types of brain cells more rapidly too.
Dr Rueger added: "It is interesting that it might be possible to boost the effectiveness of the stem cells with aromatic-turmerone.
"And it is possible this in turn can help boost repair in the brain."
She is now considering whether human trials may be feasible.
Dr Laura Phipps at the charity, Alzheimer's Research UK, said: "It is not clear whether the results of this research would translate to people, or whether the ability to generate new brain cells in this way would benefit people with Alzheimer's disease.
"We'd need to see further studies to fully understand this compound's effects in the context of a complex disease like Alzheimer's, and until then people shouldn't take this as a sign to stock up on supplies of turmeric for the spice rack."
Aromatic-turmerone is the lesser-studied of two major compounds in turmeric that may have an effect on the human body.
Previous studies suggest the other compound, curcumin, could reduce inflammation in the body and have anti-cancer benefits.
Source: BBC News © British Broadcasting Corporation 2014 (26/09/14)
Dock3 protects myelin in the cuprizone model for demyelination.
Namekata K, Kimura A, Harada C, Yoshida H, Matsumoto Y, Harada T.
Dedicator of cytokinesis 3 (Dock3) belongs to an atypical family of the guanine nucleotide exchange factors. It is predominantly expressed in the neural tissues and causes cellular morphological changes by activating the small GTPase Rac1.
We previously reported that Dock3 overexpression protects retinal ganglion cells from excitotoxic cell death. Oligodendrocytes are the myelinating cells of axons in the central nervous system and these cells are damaged in demyelinating disorders including multiple sclerosis (MS) and optic neuritis.
In this study, we examined if Dock3 is expressed in oligodendrocytes and if increasing Dock3 signals can suppress demyelination in a cuprizone-induced demyelination model, an animal model of MS.
We demonstrate that Dock3 is expressed in oligodendrocytes and Dock3 overexpression protects myelin in the corpus callosum following cuprizone treatment. Furthermore, we show that cuprizone demyelinates optic nerves and the extent of demyelination is ameliorated in mice overexpressing Dock3.
Cuprizone treatment impairs visual function, which was demonstrated by multifocal electroretinograms, an established non-invasive method, and Dock3 overexpression prevented this effect.
In mice overexpressing Dock3, Erk activation is increased, suggesting this may at least partly explain the observed protective effects.
Our findings suggest that Dock3 may be a therapeutic target for demyelinating disorders including optic neuritis.
Source: Cell Death and Disease (2014) 5, e1395; doi:10.1038/cddis.2014.357 & Pubmed PMID: 25165881 (09/09/14)
Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?
Lee J, Taghian K, Petratos S.
Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages.
While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS.
Specialised imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS).
A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies.
The clinical translation of a combined Na+ and Ca2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS.
In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.
Source: Acta Neuropathol Commun. 2014 Aug 27;2(1):97. [Epub ahead of print] & Pubmed PMID: 25159125 (02/09/14)
Atrophy and structural variability of the upper cervical cord in early multiple sclerosis.
Biberacher V, Boucard CC, Schmidt P, Engl C, Buck D, Berthele A, Hoshi MM, Zimmer C, Hemmer B, Mühlau M.
BACKGROUND: Despite agreement about spinal cord atrophy in progressive forms of multiple sclerosis (MS), data on clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) are conflicting.
OBJECTIVE: To determine the onset of spinal cord atrophy in the disease course of MS.
METHODS: Structural brain magnetic resonance imaging (MRI) was acquired from 267 patients with CIS (85) or RRMS (182) and 64 healthy controls (HCs). The upper cervical cord cross-sectional area (UCCA) was determined at the level of C2/C3 by a segmentation tool and adjusted for focal MS lesions. The coefficient of variation (CV) was calculated from all measurements between C2/C3 and 13 mm above as a measure of structural variability.
RESULTS: Compared to HCs (76.1±6.9 mm2), UCCA was significantly reduced in CIS patients (73.5±5.8 mm2, p=0.018) and RRMS patients (72.4±7.0 mm2, p<0.001). Structural variability was higher in patients than in HCs, particularly but not exclusively in case of focal lesions (mean CV HCs/patients without/with lesions: 2.13%/2.55%/3.32%, all p-values<0.007). UCCA and CV correlated with Expanded Disability Status Scale (EDSS) scores (r =-0.131/0.192, p=0.044/<0.001) and disease duration (r=-0.134/0.300, p=0.039/< 0.001). CV additionally correlated with hand and arm function (r=0.180, p=0.014).
CONCLUSION: In MS, cervical cord atrophy already occurs in CIS. In early stages, structural variability may be a more meaningful marker of spinal cord pathology than atrophy.
Source: Mult Scler. 2014 Aug 19. pii: 1352458514546514 & Pubmed PMID: 25139943 (27/08/14)
Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis.
Lukas C, Knol DL, Sombekke MH, Bellenberg B, Hahn HK, Popescu V, Weier K, Radue EW, Gass A, Kappos L, Naegelin Y, Uitdehaag BM, Geurts JJ, Barkhof F, Vrenken H.
OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort.
METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24?months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24?months.
RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24?months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24?months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression.
CONCLUSIONS: SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.
Source : J Neurol Neurosurg Psychiatry. 2014 Jun 27. pii: jnnp-2014-308021. doi: 10.1136/jnnp-2014-308021. [Epub ahead of print] & Pubmed PMID: 24973341 (30/06/14)
Researchers at VIB and Ghent University have unraveled the mechanism of necroptosis. This is a type of cell death that plays a crucial role in numerous diseases, from viral infections and loss of auditory nerve cells to multiple sclerosis, acute heart failure and organ transplantation. Having detailed knowledge of the cell death process enables a targeted search for new drugs.
Peter Vandenabeele (VIB/UGent): "The molecular mechanism of necroptosis was a complete mystery for a long time. Cells explode. But exactly how they do this was unclear. Now we have found that cells activate pore-forming molecules that make holes in the membrane. This basic research provides entirely new perspectives for the treatment of numerous chronic and acute inflammatory and degenerative diseases where necroptosis needs to be blocked. But it can also be useful to stimulate necroptosis in a controlled way, for example to circumvent the resistance of cancer cells to chemotherapy or to resensitize cancer cells to cell death."
Inflammatory reactions due to cell death
Many diseases are associated with dying cells. That is why understanding the cell death process is essential for the search for new medications. Peter Vandenabeele has many years of expertise in researching cell death, including with 'necroptosis'. In this type of cell death the cell explodes, as it were, and the cell content is released. This causes inflammatory reactions in the surrounding tissue.
Prior research shows that necroptosis occurs with a number of diseases, including viral infections, septic shock, detached retina, loss of auditory nerve cells, multiple sclerosis, acute heart failure, stroke, kidney failure and organ transplant complications. It also occurs in the presence of bad blood circulation and oxygen deficiency in the extremities or organs such as with atherosclerosis or type II diabetes.
A new therapeutic strategy: counteracting pore formation
Yves Dondelinger and Peter Vandenabeele discovered that the cellular explosion during necroptosis is paired with the formation of pores consisting of MLKL proteins. These MLKL pores are formed on the cell surface and cause the cells to absorb too much water. Because of this the cells ultimately explode. Detailed knowledge about how MLKL proteins create pores offers possibilities for developing medications for combatting or tolerating cell death by preventing or temporarily blocking this process.
Source: Medical Xpress © Medical Xpress 2011-2014 (05/06/14)
A $500,000 drug development grant from the National Multiple Sclerosis Society (NMSS) was awarded to a partnership between a multiple sclerosis research team at the Icahn School of Medicine at Mount Sinai and Karyopharm Therapeutics Inc., a clinical stage pharmaceutical company. Dr. Patrizia Casaccia, MD, PhD, Professor in the Departments of Neuroscience and Genetics and Genomics, at Icahn School of Medicine at Mount Sinai, will be the academic lead. She will test the effectiveness of a novel Karyopharm compound that can be orally administered and aimed at stopping the progressive phase of the disease. With the 14-month grant, Dr. Casaccia also hopes to gather information that will help design future clinical trials for MS treatments.
Karyopharm specializes in the synthesis of Selective Inhibitors of Nuclear Export, also known as SINE compounds. These compounds are thought to prevent the cause of irreversible damage to neurons, by blocking the early stages of neurodegeneration. Dr. Casaccia's laboratory first identified nuclear export as an important mechanism related to the initial events occurring in neurons and eventually leading to neurodegeneration. As inhibitors, these novel compounds target the nucleus in neurons, and block the accumulation of toxic substances in the axons. Axons are coated with myelin, and they can be damaged because myelin is destroyed or because they can be directly attacked by toxic factors that accumulate during the MS disease process. Neurodegenerative symptoms result from loss of myelin. Electrical signals are transmitted from the cell body of the neuron down an axon to other nerve cells, muscles, and other cells. Signal transmission slows down and progressive disability results from damage to the axons and loss of neurons, due to neurodegeneration.
Dr. Casaccia underscored the new strategy in MS drug development. "What's unique about this work is that SINE compounds target and prevent nuclear export, which is critically important for the neurodegenerative phase of the disease," she said. Preliminary experiments in Dr. Casaccia's laboratory have been encouraging. In mouse models, oral administration of the new compound to mice with paralysis of the tail and hindlimb, allowed them to walk again.
"The idea of rebuilding the nervous system and protecting it from ongoing MS damage was just a dream a few years ago," said Timothy Coetzee, Chief Advocacy, Services and Research Officer at the National MS Society. "Now, because of efforts by the research community as well as focused investments by the Society, we can see a future where people with MS will have treatments that could restore what's been lost."
In partnering with Karyopharm Therapeutics Inc., Dr. Casaccia will test these oral compounds in preclinical models and unravel their mechanism of action. The work would not be possible if the National MS Society did not invest $500,000 with Karyopharm through Fast Forward, as part of a comprehensive approach to MS research and treatment focusing on accelerating commercial development of promising research discoveries.
"We look forward to collaborating with Dr. Casaccia, who has dedicated herself to advancing research in multiple sclerosis and other important diseases," said Karyopharm Founder, Chief Scientific Officer, and President of Research and Development, Sharon Shacham, PhD, MBA.
Fred Lublin, MD, Saunders Family Professor of Neurology and the Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center also applauded this research. "Developing novel approaches to treating the neurodegenerative component of MS is critically important for our efforts at halting this disease and then reversing the damage. Existing medications for MS only aim to reduce the number of relapses. They are not restorative to the nervous system."
Source: The Mount Sinai Hospital (22/11/13)