A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice.
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.
Tanaka
Kazunori
K
NGP Biomedical Research Institute, Neugen Pharma Inc., Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Okada
Yoshinori
Y
Kanno
Takuya
T
Otomo
Asako
A
Yanagisawa
Yoshiko
Y
Shouguchi-Miyata
Junko
J
Suga
Etsuko
E
Kohiki
Eri
E
Onoe
Kyuichiro
K
Osuga
Hitoshi
H
Aoki
Masashi
M
Hadano
Shinji
S
Itoyama
Yasuto
Y
Ikeda
Joh-E
JE
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D013116:Spinal Cord / Q000166:cytology* / Q000187:drug effects / Q000502:physiology
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D018492:Dopamine Antagonists; D011725:Pyridines; D011758:Pyrroles