A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice |
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Authors: | Tanaka Kazunori Okada Yoshinori Kanno Takuya Otomo Asako Yanagisawa Yoshiko Shouguchi-Miyata Junko Suga Etsuko Kohiki Eri Onoe Kyuichiro Osuga Hitoshi Aoki Masashi Hadano Shinji Itoyama Yasuto Ikeda Joh-E |
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Affiliation: | aNGP Biomedical Research Institute, Neugen Pharma Inc., Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan;bDepartment of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa 259-1193, Japan;cDepartment of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan;dNeurodegenerative Diseases Research Centre, Graduate School of Medicine, Tokai University, Isehara, Kanagawa 259-1193, Japan;eDepartment of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-0872, Japan;fDepartment of Paediatrics, Faculty of Medicine, University of Ottawa, Ontario, Canada KIH 8M5 |
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Abstract: | Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. It has been shown that oxidative stress plays a pivotal role in the progression of this motor neuron loss. We have previously reported that L-745,870, a dopamine D4 receptor antagonist, selectively inhibits oxidative stress-induced cell death in vitro and exerts a potent neuroprotective effect against ischemia-induced neural cell damage in gerbil. To investigate the efficacy of L-745,870 in the treatment of ALS, we here conducted a chronic administration of L-745,870 to transgenic mice expressing a mutated form of human superoxide dismutase gene (SOD1H46R); a mouse model of familial ALS, and assessed whether the mice benefit from this treatment. The pre-onset administration of L-745,870 significantly delayed the onset of motor deficits, slowed the disease progression, and extended a life span in transgenic mice. These animals showed a delayed loss of anterior horn cells in the spinal cord concomitant with a reduced level of microglial activation at a late symptomatic stage. Further, the post-onset administration of L-745,870 to the SOD1H46R transgenic mice remarkably slowed the disease progression and extended their life spans. Taken together, our findings in a rodent model of ALS may have implication that L-745,870 is a possible novel therapeutic means to the treatment of ALS. |
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Keywords: | Amyotrophic lateral sclerosis Cu/Zn superoxide dismutase Transgenic mice Oxidative stress Microglia |
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