A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice

作者：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^*

来源：Experimental Neurology, 2008, 211(2): 378-386.

DOI：10.1016/j.expneurol.2008.02.004

• amyotrophic lateral sclerosis
• Cu/Zn superoxide dismutase
• transgenic mice
• oxidative stress
• microglia

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 (SOD1(H46R)); 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 SOD1(H46R) 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.

• 出版日期2008-6
• 单位河北医科大学