title: Efficacy of N-Acetylserotonin and Melatonin in the EAE Model of Multiple Sclerosis.
abstract: Melatonin and N-acetylserotonin (NAS) are tryptophan metabolites that have potent anti-oxidant, anti-inflammatory and neuroprotective properties in several animal models of neurological injury and disease including multiple sclerosis (MS). The therapeutic effect of NAS has not been reported previously in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS. Using a MOG-peptide induced EAE mouse model we examined the effects of melatonin and NAS on clinical score, inflammatory markers, free radical generation, and sparing of axons, oligodendrocytes and myelin. We found that NAS and melatonin reduced clinical scores when administered prior to or after symptom onset. This effect was more pronounced when melatonin and NAS were administrated prior to symptom onset whereby the appearance of motor symptoms was significantly delayed. Activated microglia and CD4+T-cells were increased in the white matter of untreated EAE mice, with a return to near control levels after melatonin or NAS treatment. The expression of the NADPH oxidase component p67phox and inducible nitric oxide synthase (iNOS) was increased in the EAE mice as compared with controls, and both drug treated groups had significant reductions in their expression. Melatonin and NAS treatment significantly reduced the loss of mature oligodendrocytes, demyelination and axonal injury. Both compounds also significantly attenuated iNOS induction and reactive oxygen species (ROS) generation in lipopolysaccharide-activated microglia in culture. Our results show for the first time the therapeutic effects of NAS and confirm previous reports on the effectiveness of melatonin in the EAE model of MS.
authors: Department of Anatomy, Physiology and Genetics, Neuroscience Program, Bldg. C, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
authors: Jie
authors: J
authors: Wen
authors: Molecular Diagnostics Div., Department of Medical Oncology, Amrita Institute of Medical Sciences, Amrita University, Kochi, India.
authors: Prasanth S
authors: PS
authors: Ariyannur
authors: Department of Anatomy, Physiology and Genetics, Neuroscience Program, Bldg. C, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
authors: Rachel
authors: R
authors: Ribeiro
authors: Department of Anatomy, Physiology and Genetics, Neuroscience Program, Bldg. C, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
authors: Mikiei
authors: M
authors: Tanaka
authors: Department of Anatomy, Physiology and Genetics, Neuroscience Program, Bldg. C, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
authors: John R
authors: JR
authors: Moffett
authors: Epilepsy Center, Department of Neurology, Scott and White Hospital, Texas A&M University, Temple, TX, USA.
authors: Batool F
authors: BF
authors: Kirmani
authors: Department of Anatomy, Physiology and Genetics, Neuroscience Program, Bldg. C, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA. anamboodiri@usuhs.edu.
authors: Aryan M A
authors: AM
authors: Namboodiri
authors: Department of Anatomy, Physiology and Genetics, Neuroscience Program, Bldg. C, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA. yumin.zhang@usuhs.edu.
authors: Yumin
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D008550:Melatonin / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D012701:Serotonin; D008550:Melatonin; C006389:N-acetylserotonin
keywords: Demyelination; Experimental autoimmune encephalomyelitis; Indoleamine 2,3 dioxygenase; Inflammation; Microglia; Neuroprotection; Reactive oxygen species