title: The hypnotic bromovalerylurea ameliorates 6-hydroxydopamine-induced dopaminergic neuron loss while suppressing expression of interferon regulatory factors by microglia.
abstract: The low molecular weight organic compound bromovalerylurea (BU) has long been used as a hypnotic/sedative. In the present study, we found that BU suppressed mRNA expression of proinflammatory factors and nitric oxide release in lipopolysaccharide (LPS)-treated rat primary microglial cell cultures. BU prevented neuronal degeneration in LPS-treated neuron-microglia cocultures. The anti-inflammatory effects of BU were as strong as those of a synthetic glucocorticoid, dexamethasone. A rat hemi-Parkinsonian model was prepared by injecting 6-hydroxydopamine into the right striatum. BU was orally administered to these rats for 7 days, which ameliorated the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and alleviated motor deficits. BU suppressed the expression of mRNAs for interferon regulatory factors (IRFs) 1, 7 and 8 in the right (lesioned) ventral midbrain as well as those for proinflammatory mediators. BU increased mRNA expression of various neuroprotective factors, including platelet-derived growth factor and hepatocyte growth factor, but it did not increase expression of alternative activation (M2) markers. In microglial culture, BU suppressed the LPS-induced increase in expression of IRFs 1 and 8, and it reduced LPS-induced phosphorylation of JAK1 and STATs 1 and 3. Knockdown of IRFs 1 and 8 suppressed LPS-induced NO release by microglial cells. These results suggest that suppression of microglial IRF expression by BU prevents neuronal cell death in the injured brain region, where microglial activation occurs. Because many Parkinsonian patients suffer from sleep disorders, BU administration before sleep may effectively ameliorate neurological symptoms and alleviate sleep dysfunction.
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Higaki
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Mohammed Emamussalehin
authors.initials: ME
authors.lastname: Choudhury
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Kawamoto
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Afsana
authors.initials: A
authors.lastname: Islam
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Miyanishi
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Seo
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan; Department of Legal Medicine, Graduate School of Medicine/Faculty of Medicine, Osaka University, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan; Division of Pathophysiology, Faculty of Pharmaceutical Sciences, Hokuriku University, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan. Electronic address: jtanaka@m.ehime-u.ac.jp.
authors.forename: Junya
authors.initials: J
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001968:Bromisovalum / Q000494:pharmacology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D006993:Hypnotics and Sedatives; D050835:Interferon Regulatory Factors; D001968:Bromisovalum; D016627:Oxidopamine
keywords: Cytokine; IRF; NO; Neuroprotective factors; Parkinson; Proinflammatory