Katie Lidster

Two Years Later: Journals Are Not Yet Enforcing the ARRIVE Guidelines on Reporting Standards for Pre-Clinical Animal Studies

A study by David Baker and colleagues reveals poor quality of reporting in pre-clinical animal research and a failure of journals to implement the ARRIVE guidelines.

Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis

Progressive multiple sclerosis is associated with metabolic failure of the axon and excitotoxicity that leads to chronic neurodegeneration. Global sodium-channel blockade causes side effects that can limit its use for neuroprotection in multiple sclerosis. Through selective targeting of drugs to lesions we aimed to improve the potential therapeutic window for treatment. This was assessed in the relapsing-progressive experimental autoimmune encephalomyelitis ABH mouse model of multiple sclerosis using conventional sodium channel blockers and a novel central nervous system-excluded sodium channel blocker (CFM6104) that was synthesized with properties that selectively target the inflammatory penumbra in experimental autoimmune encephalomyelitis lesions. Carbamazepine and oxcarbazepine were not immunosuppressive in lymphocyte-driven autoimmunity, but slowed the accumulation of disability in experimental autoimmune encephalomyelitis when administered during periods of the inflammatory penumbra after active lesion formation, and was shown to limit the development of neurodegeneration during optic neuritis in myelin-specific T cell receptor transgenic mice. CFM6104 was shown to be a state-selective, sodium channel blocker and a fluorescent p-glycoprotein substrate that was traceable. This compound was >90% excluded from the central nervous system in normal mice, but entered the central nervous system during the inflammatory phase in experimental autoimmune encephalomyelitis mice. This occurs after the focal and selective downregulation of endothelial p-glycoprotein at the blood-brain barrier that occurs in both experimental autoimmune encephalomyelitis and multiple sclerosis lesions. CFM6104 significantly slowed down the accumulation of disability and nerve loss in experimental autoimmune encephalomyelitis. Therapeutic-targeting of drugs to lesions may reduce the potential side effect profile of neuroprotective agents that can influence neurotransmission. This class of agents inhibit microglial activity and neural sodium loading, which are both thought to contribute to progressive neurodegeneration in multiple sclerosis and possibly other neurodegenerative diseases.

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine) or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment.

Optical Coherence Tomography Detection of Neurodegeneration in Multiple Sclerosis

The pathophysiology of multiple sclerosis (MS) is typically characterised by inflammation and demyelination leading to neurodegeneration, which is associated with disability and the progressive stages of MS. The visual system is a valuable tool for studying neurodegeneration and potential neuroprotection in the central nervous system due to its ease of accessibility. Optical coherence tomography (OCT) is a non-invasive tool, which can be used to measure the thickness of the retinal nerve fibre layer (RNFL). The thickness of RNFL is reduced following the development of MS and optic neuritis and can therefore be used as a correlate of global axonal loss. OCT is currently being investigated as a structural outcome measure for neuroprotective clinical trials of MS. This review describes the relationship between MS and optic neuritis and the associated RNFL thinning, the technology and advancements of OCT, the role of OCT in clinical trials for new neuroprotective therapies in MS and the future role of OCT in MS research.

Imidazol-1-ylethylindazole Voltage-Gated Sodium Channel Ligands Are Neuroprotective during Optic Neuritis in a Mouse Model of Multiple Sclerosis

A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Nav channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis.

Reproducibility: Research-reporting standards fall short.

More than 150 journals and many research-funding charities have endorsed the ARRIVE guidelines for reporting research that uses animal models (C. Kilkenny et al. PLoS Biol. 8, e1000412; 2010), but we find that they are being largely ignored. This could undermine data reproducibility and model credibility, and might obstruct translation into human therapy (S. Landis et al. Nature 490, 187–191; 2012). For example, of 180 papers on multiple sclerosis listed on PubMed in the past 6 months, we found that only 40% used appropriate statistics to compare the effects of gene-knockout or treatment. Appropriate statistics were applied in only 4% of neuroimmunological studies published in the past two years in Nature Publishing Group journals, Science and Cell (details available from D.B. on request). Many journals are therefore failing to ensure that the basics of experimental design and data analysis are respected. Simply introducing guidelines is not enough. The issue requires greater editorial oversight (perhaps using a tick-box questionnaire at submission), stricter refereeing standards and engagement by learned societies. The food industry is rapidly ramping up the production of palm oil, destroying tropical forest at an alarming rate to make way for more oil-palm plantations. Consumers might assume that palm oil is more heart-healthy than animal-based Strength to strength for mouse models Jessica Bolkers emphasis on choosing the right animal model (Nature 491, 31; 2012) should not undermine the validity of the mouse as a model for human disease. Contrary to her implication, mouse researchers do take genetic background and environment into consideration. Mouse models used to test therapies should reproduce closely the human disease being investigated — including the response to genetic and environmental factors. But this need not apply to models for understanding disease mechanisms: Nobel-prizewinning discoveries of embryonic stem cells, the mouse major histocompatibility locus and monoclonal antibodies, for example, all relied on experimental mice and not disease models. Researchers do not use only inbred strains of mice: they use genetically characterized mouse populations and deploy different genetic backgrounds to identify complex inherited traits. There are large collections of recombinant inbred mouse strains, as well as a public database of more than 3,000 traits (E. Collaborative Cross reference panel, representing eight inbred strains of lab and wild-derived mice, contains twice the genetic diversity of the entire human population and allows high-resolution analysis of phenotypic variations (Genetics 190, 389–401; 2012). The full potential of the mouse as a model …

Research-reporting standards fall short

More than 150 journals and many research-funding charities have endorsed the ARRIVE guidelines for reporting research that uses animal models (C. Kilkenny et al. PLoS Biol. 8, e1000412; 2010), but we find that they are being largely ignored. This could undermine data reproducibility and model credibility, and might obstruct translation into human therapy (S. Landis et al. Nature 490, 187–191; 2012). For example, of 180 papers on multiple sclerosis listed on PubMed in the past 6 months, we found that only 40% used appropriate statistics to compare the effects of gene-knockout or treatment. Appropriate statistics were applied in only 4% of neuroimmunological studies published in the past two years in Nature Publishing Group journals, Science and Cell (details available from D.B. on request). Many journals are therefore failing to ensure that the basics of experimental design and data analysis are respected. Simply introducing guidelines is not enough. The issue requires greater editorial oversight (perhaps using a tick-box questionnaire at submission), stricter refereeing standards and engagement by learned societies. The food industry is rapidly ramping up the production of palm oil, destroying tropical forest at an alarming rate to make way for more oil-palm plantations. Consumers might assume that palm oil is more heart-healthy than animal-based Strength to strength for mouse models Jessica Bolkers emphasis on choosing the right animal model (Nature 491, 31; 2012) should not undermine the validity of the mouse as a model for human disease. Contrary to her implication, mouse researchers do take genetic background and environment into consideration. Mouse models used to test therapies should reproduce closely the human disease being investigated — including the response to genetic and environmental factors. But this need not apply to models for understanding disease mechanisms: Nobel-prizewinning discoveries of embryonic stem cells, the mouse major histocompatibility locus and monoclonal antibodies, for example, all relied on experimental mice and not disease models. Researchers do not use only inbred strains of mice: they use genetically characterized mouse populations and deploy different genetic backgrounds to identify complex inherited traits. There are large collections of recombinant inbred mouse strains, as well as a public database of more than 3,000 traits (E. Collaborative Cross reference panel, representing eight inbred strains of lab and wild-derived mice, contains twice the genetic diversity of the entire human population and allows high-resolution analysis of phenotypic variations (Genetics 190, 389–401; 2012). The full potential of the mouse as a model …

Correction to Imidazol-1-ylethylindazole Voltage-Gated Sodium Channel Ligands Are Neuroprotective during Optic Neuritis in a Mouse Model of Multiple Sclerosis

Page 2944. In Table 1, “[3H]sipatrigine” should read “[3H]BW202W93”. Page 2944. In the right column lines 5 and 31, “[3H]sipatrigine” should read “[3H]BW202W93”. Page 2945. In Tables 2 and 3, “[3H]sipatrigine” should read “[3H]BW202W93”. Page 2946. In Table 4, “[3H]sipatrigine” should read “[3H]BW202W93”. Page 2946. In the right column line 9, “[3H]sipatrigine” should read “[3H]BW202W93”.

Research-reporting standards fall short: Reproducibility

More than 150 journals and many research-funding charities have endorsed the ARRIVE guidelines for reporting research that uses animal models (C. Kilkenny et al. PLoS Biol. 8, e1000412; 2010), but we find that they are being largely ignored. This could undermine data reproducibility and model credibility, and might obstruct translation into human therapy (S. Landis et al. Nature 490, 187–191; 2012). For example, of 180 papers on multiple sclerosis listed on PubMed in the past 6 months, we found that only 40% used appropriate statistics to compare the effects of gene-knockout or treatment. Appropriate statistics were applied in only 4% of neuroimmunological studies published in the past two years in Nature Publishing Group journals, Science and Cell (details available from D.B. on request). Many journals are therefore failing to ensure that the basics of experimental design and data analysis are respected. Simply introducing guidelines is not enough. The issue requires greater editorial oversight (perhaps using a tick-box questionnaire at submission), stricter refereeing standards and engagement by learned societies. The food industry is rapidly ramping up the production of palm oil, destroying tropical forest at an alarming rate to make way for more oil-palm plantations. Consumers might assume that palm oil is more heart-healthy than animal-based Strength to strength for mouse models Jessica Bolkers emphasis on choosing the right animal model (Nature 491, 31; 2012) should not undermine the validity of the mouse as a model for human disease. Contrary to her implication, mouse researchers do take genetic background and environment into consideration. Mouse models used to test therapies should reproduce closely the human disease being investigated — including the response to genetic and environmental factors. But this need not apply to models for understanding disease mechanisms: Nobel-prizewinning discoveries of embryonic stem cells, the mouse major histocompatibility locus and monoclonal antibodies, for example, all relied on experimental mice and not disease models. Researchers do not use only inbred strains of mice: they use genetically characterized mouse populations and deploy different genetic backgrounds to identify complex inherited traits. There are large collections of recombinant inbred mouse strains, as well as a public database of more than 3,000 traits (E. Collaborative Cross reference panel, representing eight inbred strains of lab and wild-derived mice, contains twice the genetic diversity of the entire human population and allows high-resolution analysis of phenotypic variations (Genetics 190, 389–401; 2012). The full potential of the mouse as a model …