The neuroprotective effect of the GSK-3β inhibitor and influence on the extrinsic apoptosis in the ALS transgenic mice.
BACKGROUND
Glycogen synthase kinase-3β (GSK-3β) activity plays a central role in motor neuron degeneration. We hypothesized that GSK-3β inhibitor would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS).


METHODS
A total of 40 transgenic mice harboring the human G93A mutated SOD1 gene and 14 wild type mice were used following confirmation of their genotype. The 40 transgenic mice were divided into 2 groups; ALS transgenic mice_control and ALS transgenic mice_GSK-3β inhibitor treatment. The clinical status, rotarod test and survival of the transgenic ALS mice and wild-type mice were evaluated. Additionally, motor neuron counting, GSK-3β activity and extrinsic apoptotic signals in spinal cord were also investigated.


RESULTS
The treatment with GSK-3β inhibitor showed excellent motor ability and delay of the symptom onset and survival in the ALS transgenic mice. However, after clinical symptoms developed, the neuroprotective effect of GSK-3β inhibitor was not significant. And the biochemical results revealed the weakly increased extrinsic apoptotic signals in the ALS transgenic mice by GSK-3β inhibitor treatment.


CONCLUSIONS
The present study suggests that GSK-3β inhibitor would be a novel promising therapeutic strategy in ALS; however neuroprotective effect of GSK-3β inhibitor may be reduced via extrinsic apoptosis or non-neuronal patho-mechanism in late-stage of disease.
Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of medicine, Seoul, Republic of Korea.
Suk-Won
SW
Ahn
Jee-Eun
JE
Kim
Kyung Seok
KS
Park
Won-Jun
WJ
Choi
Yoon-Ho
YH
Hong
Sung-Min
SM
Kim
Seung Hyun
SH
Kim
Kwang-Woo
KW
Lee
Jung-Joon
JJ
Sung
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D002452:Cell Count / Q000379:methods / Q000706:statistics & numerical data; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D045442:Rotarod Performance Test / Q000379:methods / Q000706:statistics & numerical data; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019014:fas Receptor / Q000378:metabolism
C505534:Fadd protein, mouse; C491899:Fas protein, mouse; D053200:Fas-Associated Death Domain Protein; D018696:Neuroprotective Agents; C000606290:SOD1 protein, human; D013844:Thiazoles; D019014:fas Receptor; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053181:Caspase 8