Gabapentin-lactam, but not gabapentin, reduces protein aggregates and improves motor performance in a transgenic mouse model of Huntington's disease.
Gabapentin (GBP), an anti-convulsant widely used in the treatment of neuropathic pain syndromes, has been suggested to have neuroprotective properties. There is evidence, however, that the neuroprotective properties attributed to GBP are rather associated with a derivative of GBP, gabapentin-lactam (GBP-L), which opens mitochondrial ATP-dependent K+ channels, in contrast to GBP. We explored whether GBP and GBP-L may attenuate the course of a monogenetic autosomal neurodegenerative disorder, Huntington's disease (HD), using a transgenic mouse model. R6/2 mice treated with GBP-L performed walking on a narrow beam better than mice receiving no treatment, vehicle or GBP, suggesting a beneficial effect of GBP-L on motor function. In addition, a marked reduction of neuronal nuclear and cytoplasmic inclusions was observed in brains of mice treated with GBP-L. The pharmacokinetics of GBP-L yielded a mean plasma concentration near the EC50 of GBP-L to open mitochondrial ATP-dependent K+ channels. These findings support the role of GBP-L as a novel neuroprotective substance in vivo.
Zucker
Birgit
B
Department of Neurology, University Hospital Freiburg, Breisacherstrasse 64, 79106 Freiburg, Germany.
Ludin
Dagmar E
DE
Gerds
Thomas A
TA
Lücking
Carl H
CH
Landwehrmeyer
G Bernhard
GB
Feuerstein
Thomas J
TJ
D000588:Amines / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001372:Aza Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D000077206:Gabapentin; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D013141:Spiro Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015996:Survival Rate; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
D000588:Amines; D000927:Anticonvulsants; D001372:Aza Compounds; D003509:Cyclohexanecarboxylic Acids; D018696:Neuroprotective Agents; D013141:Spiro Compounds; C404763:gabapentin-lactam; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin