Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, incoordination, and shortened life-span, and by huntingtin inclusions and neurodegeneration. We previously screened the 1040 FDA-approved compounds from the NINDS compound library and found that a compound, nipecotic acid, significantly reduced mutant huntingtin aggregations and blocked cell toxicity in an inducible cell model of HD. Because nipecotic acid does not cross the blood-brain barrier (BBB), we studied its analogue, tiagabine, which is able to cross the BBB, in both N171-82Q and R6/2 transgenic mouse models of HD. Tiagabine was administered intraperitoneally at 2 and 5 mg/kg daily in HD mice. We found that tiagabine extended survival, improved motor performance, and attenuated brain atrophy and neurodegeneration in N171-82Q HD mice. These beneficial effects were further confirmed in R6/2 HD mice. The levels of tiagabine at effective doses in mouse serum are comparable to the levels in human patients treated with tiagabine. These results suggest that tiagabine may have beneficial effects in the treatment of HD. Because tiagabine is an FDA-approved drug, it may be a promising candidate for future clinical trials for the treatment of HD.
Masuda
Naoki
N
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Peng
Qi
Q
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Li
Qing
Q
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Jiang
Mali
M
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Liang
Yideng
Y
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Wang
Xiaofang
X
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Zhao
Ming
M
Oncology Analytical Pharmacology core, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Wang
Wenfei
W
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Ross
Christopher A
CA
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Duan
Wenzhen
W
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, CMSC 8-121, 600 N. Wolfe Street, Baltimore, MD 21287, USA. Electronic address: wduan2@jhmi.edu.
D000818:Animals; D001120:Arginine / Q000235:genetics; D001216:Asparagine / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005973:Glutamine / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009557:Nipecotic Acids / Q000627:therapeutic use*; D016716:PC12 Cells; D051381:Rats; D000078308:Tiagabine
D018696:Neuroprotective Agents; D009557:Nipecotic Acids; D005973:Glutamine; D001216:Asparagine; D001120:Arginine; D000078308:Tiagabine