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Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis.
Brain. 2014 Jan; 137(Pt 1):92-108.B

Abstract

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.

Authors+Show Affiliations

1 Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24287115

Citation

Al-Izki, Sarah, et al. "Lesional-targeting of Neuroprotection to the Inflammatory Penumbra in Experimental Multiple Sclerosis." Brain : a Journal of Neurology, vol. 137, no. Pt 1, 2014, pp. 92-108.
Al-Izki S, Pryce G, Hankey DJ, et al. Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain. 2014;137(Pt 1):92-108.
Al-Izki, S., Pryce, G., Hankey, D. J., Lidster, K., von Kutzleben, S. M., Browne, L., Clutterbuck, L., Posada, C., Edith Chan, A. W., Amor, S., Perkins, V., Gerritsen, W. H., Ummenthum, K., Peferoen-Baert, R., van der Valk, P., Montoya, A., Joel, S. P., Garthwaite, J., Giovannoni, G., ... Baker, D. (2014). Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. Brain : a Journal of Neurology, 137(Pt 1), 92-108. https://doi.org/10.1093/brain/awt324
Al-Izki S, et al. Lesional-targeting of Neuroprotection to the Inflammatory Penumbra in Experimental Multiple Sclerosis. Brain. 2014;137(Pt 1):92-108. PubMed PMID: 24287115.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lesional-targeting of neuroprotection to the inflammatory penumbra in experimental multiple sclerosis. AU - Al-Izki,Sarah, AU - Pryce,Gareth, AU - Hankey,Deborah J R, AU - Lidster,Katie, AU - von Kutzleben,Stephanie M, AU - Browne,Lorcan, AU - Clutterbuck,Lisa, AU - Posada,Cristina, AU - Edith Chan,A W, AU - Amor,Sandra, AU - Perkins,Victoria, AU - Gerritsen,Wouter H, AU - Ummenthum,Kim, AU - Peferoen-Baert,Regina, AU - van der Valk,Paul, AU - Montoya,Alexander, AU - Joel,Simon P, AU - Garthwaite,John, AU - Giovannoni,Gavin, AU - Selwood,David L, AU - Baker,David, Y1 - 2013/11/27/ PY - 2013/11/30/entrez PY - 2013/11/30/pubmed PY - 2014/3/13/medline KW - animal models KW - experimental allergic encephalomyelitis KW - multiple sclerosis KW - neural repair SP - 92 EP - 108 JF - Brain : a journal of neurology JO - Brain VL - 137 IS - Pt 1 N2 - 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. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/24287115/Lesional_targeting_of_neuroprotection_to_the_inflammatory_penumbra_in_experimental_multiple_sclerosis_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awt324 DB - PRIME DP - Unbound Medicine ER -