The neuroprotective effect of the GSK-3 beta inhibitor and influence on the extrinsic apoptosis in the ALS transgenic mice

Abstract

Background: Glycogen synthase kinase-3 beta (GSK-3 beta) activity plays a central role in motor neuron degeneration. We hypothesized that GSK-3 beta 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-3 beta 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-3 beta activity and extrinsic apoptotic signals in spinal cord were also investigated. Results: The treatment with GSK-3 beta 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-3 beta inhibitor was not significant. And the biochemical results revealed the weakly increased extrinsic apoptotic signals in the ALS transgenic mice by GSK-3 beta inhibitor treatment. Conclusion: The present study suggests that GSK-3 beta inhibitor would be a novel promising therapeutic strategy in ALS; however neuroprotective effect of GSK-3 beta inhibitor may be reduced via extrinsic apoptosis or non-neuronal patho-mechanism in late-stage of disease.