title: Transcriptional Regulation of Brain-Derived Neurotrophic Factor (BDNF) by Methyl CpG Binding Protein 2 (MeCP2): a Novel Mechanism for Re-Myelination and/or Myelin Repair Involved in the Treatment of Multiple Sclerosis (MS).
abstract: Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood-brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.
authors.affiliation: College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, Manitoba, Canada.|Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada.
authors.forename: Tina
authors.initials: T
authors.lastname: KhorshidAhmad
authors.affiliation: College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, Manitoba, Canada.|Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada.
authors.forename: Crystal
authors.initials: C
authors.lastname: Acosta
authors.affiliation: College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, Manitoba, Canada.|Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cortes
authors.affiliation: College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, Manitoba, Canada.|Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada.
authors.forename: Ted M
authors.initials: TM
authors.lastname: Lakowski
authors.affiliation: College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, Manitoba, Canada.|Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada.
authors.forename: Surendiran
authors.initials: S
authors.lastname: Gangadaran
authors.affiliation: College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E 0T5, Manitoba, Canada. namakamp@ms.umanitoba.ca.|Manitoba Multiple Sclerosis Research Network Organization (MMSRNO), Winnipeg, Canada. namakamp@ms.umanitoba.ca.|College of Medicine, University of Manitoba, Winnipeg, Canada. namakamp@ms.umanitoba.ca.|School of Medical Rehabilitation, College of Medicine, University of Manitoba, Winnipeg, Canada. namakamp@ms.umanitoba.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Namaka
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000235:genetics* / Q000628:therapy*; D009186:Myelin Sheath / Q000473:pathology*; D014945:Wound Healing / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051783:Methyl-CpG-Binding Protein 2
keywords: Autoimmune disease; Brain-derived neurotrophic factor (BDNF); Epigenetics; Experimental autoimmune encephalomyelitis (EAE); Histone deacetylase (HDAC) inhibitors; Methyl CpG binding protein 2 (MeCP2); Multiple sclerosis (MS)