Wednesday, 19 September 2012

Research: Modelling MS for repair and protection for MS

Ravikumar et al. An Organotypic Spinal Cord Slice Culture Model to Quantify Neurodegeneration. J Neurosci Methods. 2012 pii: S0165-0270(12)00375-5. doi: 10.1016/j.jneumeth.2012.09.004.

Activated microglia cells have been implicated in the neurodegenerative process of Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis; however, the precise roles of microglia in disease progression are unclear. Despite these diseases having been described for more than a century, current FDA approved therapeutics are symptomatic in nature with little evidence to supporting a neuroprotective effect. Furthermore, identifying novel therapeutics remains challenging due to undetermined aetiology, a variable disease course, and the paucity of validated targets. 

Here, we describe the use of a novel ex vivo spinal cord culture system that offers the ability to screen potential neuroprotective agents, while maintaining the complexity of the in vivo environment. To this end, we treated spinal cord slice cultures with lipopolysaccharide and quantified neuron viability in culture using measurements of axon length and FluoroJadeC intensity. To simulate a microglia-mediated response to cellular debris, antigens, or implanted materials/devices, we supplemented the culture media with increasing densities of microspheres, facilitating microglia-mediated phagocytosis of the particles, which demonstrated a direct correlation between the phagocytic activities of microglia and neuronal health. To validate our model's capacity to accurately depict neuroprotection, cultures were treated with resveratrol, which demonstrated enhanced neuronal health. Our results successfully demonstrate the use of this model to reproducibly quantify the extent of neurodegeneration through the measurement of axon length and FluoroJadeC intensity, and we suggest this model will allow for accurate, high-throughput screening, which could result in expedited success in translational efficacy of therapeutic agents to clinical trials.

                         Fluorojade C in neurons (green blobs)

The question is how do we speed up the process of  finding agents to deal with progression and repair. It is clear that clinical trials will take too long, and whilst we have developed some animal models they are not quick either. Many of the test tube models are quick but lack a lot of the complexity of the central nervous system with an immune response in action

This study takes an slice of spinal cord tissue and then keeps it alive, you can then stimulate cells to do things like damage nerves. You then have a potential to use it to screen drugs to see if they are neuroprotective and potentially useful for MSers. These could be done in isolation or combination. This study looked at resveratrol an anti-oxidant-flavinoid in red wine and black currants. 

There have been many brain slice cultures that have been used in studies of myelination, this moves this into spinal cords. This is the place were animals with EAE get most of the pathology, so maybe you can take spinal cord with chronic lesions and keep them alive and then try an repair demyelinated and gliotic lesions, which you cannot properly re-create in test tube cultures. You could see if stem cells can repair them or hopefully show that you can use the cultures to slow nerve damage. Alternatively you could develop ways of demyelinating the slices and looking from repair. This is being done in Edinburgh  to look for factors promoting repair

Zhang H, Jarjour AA, Boyd A, Williams A. Central nervous system remyelination in culture--a tool for multiple sclerosis research. Exp Neurol. 2011;230:138-48.

Multiple sclerosis is a demyelinating disease of the central nervous system which only affects humans. This makes it difficult to study at a molecular level, and to develop and test potential therapies that may change the course of the disease. The development of therapies to promote remyelination in multiple sclerosis is a key research aim, to both aid restoration of electrical impulse conduction in nerves and provide neuroprotection, reducing disability in patients. Testing a remyelination therapy in the many and various in vivo models of multiple sclerosis is expensive in terms of time, animals and money. We report the development and characterisation of an ex vivo slice culture system using mouse brain and spinal cord, allowing investigation of myelination, demyelination and remyelination, which can be used as an initial reliable screen to select the most promising remyelination strategies. We have automated the quantification of myelin to provide a high content and moderately-high-throughput screen for testing therapies for remyelination both by endogenous and exogenous means and as an invaluable way of studying the biology of remyelination. 


Now if you can then move this from rodents to human tissue slices....I know this is a bit grizzly.....but remember people donate to brain banks (Here is the link to the UK MS Bankbank site website) and if you get it quick enough....then you may be able to get at MS directly, without needing animals and it will provide even bigger clues about useful drugs for MSers.

This would be exciting.... I need to learn some new techniques.

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