PMID- 29530550 OWN - NLM STAT- MEDLINE DCOM- 20190930 LR - 20211204 IS - 1872-8421 (Electronic) IS - 0165-5728 (Linking) VI - 318 DP - 2018 May 15 TI - Fingolimod inhibits brain atrophy and promotes brain-derived neurotrophic factor in an animal model of multiple sclerosis. PG - 103-113 LID - S0165-5728(17)30519-2 [pii] LID - 10.1016/j.jneuroim.2018.02.016 [doi] AB - Longitudinal brain atrophy quantification is a critical efficacy measurement in multiple sclerosis (MS) clinical trials and the determination of No Evidence of Disease Activity (NEDA). Utilising fingolimod as a clinically validated therapy we evaluated the use of repeated brain tissue volume measures during chronic experimental autoimmune encephalomyelitis (EAE) as a new preclinical efficacy measure. Brain volume changes were quantified using magnetic resonance imaging (MRI) at 7 Tesla and correlated to treatment-induced brain derived neurotrophic factor (BDNF) measured in blood, cerebrospinal fluid, spinal cord and brain. Serial brain MRI measurements revealed slow progressive brain volume loss in vehicle treated EAE mice despite a stable clinical score. Fingolimod (1 mg/kg) significantly ameliorated brain tissue atrophy in the cerebellum and striatum when administered from established EAE disease onwards. Fingolimod-dependent tissue preservation was associated with induction of BDNF specifically within the brain and co-localized with neuronal soma. In contrast, therapeutic teriflunomide (3 mg/kg) treatment failed to inhibit CNS autoimmune mediated brain degeneration. Finally, weekly anti-IL-17A antibody (15 mg/kg) treatment was highly efficacious and preserved whole brain, cerebellum and striatum volume. Fingolimod-mediated BDNF increases within the CNS may contribute to limiting progressive tissue loss during chronic neuroinflammation. CI - Copyright (c) 2018 Elsevier B.V. All rights reserved. FAU - Smith, Paul A AU - Smith PA AD - Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: paul010976@gmail.com. FAU - Schmid, Cindy AU - Schmid C AD - Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: cindy.schmid@novartis.com. FAU - Zurbruegg, Stefan AU - Zurbruegg S AD - Neurosciences, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: stefan.zurbruegg@novartis.com. FAU - Jivkov, Magali AU - Jivkov M AD - Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: magali.jivkov@novartis.com. FAU - Doelemeyer, Arno AU - Doelemeyer A AD - Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: arno.doelemeyer@novartis.com. FAU - Theil, Diethilde AU - Theil D AD - Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: diethilde.theil@novartis.com. FAU - Dubost, Valerie AU - Dubost V AD - Preclinical Safety, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: valerie.dubost@novartis.com. FAU - Beckmann, Nicolau AU - Beckmann N AD - Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland. Electronic address: nicolau.beckmann@novartis.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180303 PL - Netherlands TA - J Neuroimmunol JT - Journal of neuroimmunology JID - 8109498 RN - 0 (Bdnf protein, mouse) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Crotonates) RN - 0 (Hydroxybutyrates) RN - 0 (Il17a protein, mouse) RN - 0 (Immunosuppressive Agents) RN - 0 (Interleukin-17) RN - 0 (Nitriles) RN - 0 (Toluidines) RN - 1C058IKG3B (teriflunomide) RN - G926EC510T (Fingolimod Hydrochloride) SB - IM MH - Animals MH - Atrophy/pathology MH - Brain/*drug effects/metabolism/pathology MH - Brain-Derived Neurotrophic Factor/*drug effects/metabolism MH - Crotonates/pharmacology MH - Encephalomyelitis, Autoimmune, Experimental/metabolism/*pathology MH - Female MH - Fingolimod Hydrochloride/*pharmacology MH - Hydroxybutyrates MH - Immunosuppressive Agents/*pharmacology MH - Interleukin-17/antagonists & inhibitors MH - Magnetic Resonance Imaging MH - Mice MH - Mice, Inbred C57BL MH - Nitriles MH - Toluidines/pharmacology OTO - NOTNLM OT - Brain atrophy OT - Experimental autoimmune encephalomyelitis (EAE) OT - Fingolimod OT - Magnetic resonance imaging (MRI) EDAT- 2018/03/14 06:00 MHDA- 2019/10/01 06:00 CRDT- 2018/03/14 06:00 PHST- 2017/11/13 00:00 [received] PHST- 2018/02/16 00:00 [revised] PHST- 2018/02/26 00:00 [accepted] PHST- 2018/03/14 06:00 [pubmed] PHST- 2019/10/01 06:00 [medline] PHST- 2018/03/14 06:00 [entrez] AID - S0165-5728(17)30519-2 [pii] AID - 10.1016/j.jneuroim.2018.02.016 [doi] PST - ppublish SO - J Neuroimmunol. 2018 May 15;318:103-113. doi: 10.1016/j.jneuroim.2018.02.016. Epub 2018 Mar 3.