A novel acylaminoimidazole derivative, WN1316, alleviates disease progression via suppression of glial inflammation in ALS mouse model.
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron degenerative disease. Given that oxidative stress and resulting chronic neuronal inflammation are thought to be central pathogenic, anti-oxidative agents and modulators of neuronal inflammation could be potential therapies for ALS. We report here that the novel small molecular compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316) selectively suppresses oxidative stress-induced cell death and neuronal inflammation in the late-stage ALS mice. WN1316 has high blood-brain-barrier permeability and water solubility, and boosts both neuronal apoptosis inhibitory protein (NAIP) and NF-E2-related factor 2 (Nrf2) which governed glutathione (GSH)-related anti-oxidation pathway protecting motor neurons against oxidative injuries. Post-onset oral administration of low dose (1-100 µg/kg/day) WN1316 in ALS(SOD1(H46R)) and ALS(SOD1(G93A)) mice resulted in sustained improved motor function and post onset survival rate. Immunohistochemical analysis revealed less DNA oxidative damage and motor neuronal inflammation as well as repression of both microgliosis and astrocytosis, concomitant down regulation of interleukin-1β and inducible nitric oxide synthase, and preservation of the motoneurons in anterior horn of lumbar spinal cord and skeletal muscle (quadriceps femoris). Thus, WN1316 would be a novel therapeutic agent for ALS.
NGP Biomedical Research Institute, Neugen Pharma Inc., Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Kazunori
K
Tanaka
NGP Biomedical Research Institute, Neugen Pharma Inc., Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Takuya
T
Kanno
NGP Biomedical Research Institute, Neugen Pharma Inc., Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Yoshiko
Y
Yanagisawa
NGP Biomedical Research Institute, Neugen Pharma Inc., Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Kaori
K
Yasutake
Wakunaga Pharmaceutical Co. Ltd., Akitakada, Hiroshima, Japan.
Satoshi
S
Inoue
Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Noriaki
N
Hirayama
NGP Biomedical Research Institute, Neugen Pharma Inc., Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan ; Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan ; Department of Molecular Neurology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan ; Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Joh-E
JE
Ikeda
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D007093:Imidazoles; D009419:Nerve Tissue Proteins