n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and Amyotrophic-Lateral-Sclerosis

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).. 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.. 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.. 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.

Topics: Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Caspase 8; Cell Count; Disease Models, Animal; fas Receptor; Fas-Associated Death Domain Protein; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Mice; Mice, Transgenic; Motor Neurons; Neuroprotective Agents; Phosphorylation; Rotarod Performance Test; Signal Transduction; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1; Thiazoles; Urea

Glycogen synthase kinase (GSK)-3 has recently been implicated in the pathogenesis of neurodegenerative diseases. Although the neuroprotective effects of GSK-3 inhibitors in Alzheimer's disease have been established, their effects on amyotrophic lateral sclerosis (ALS) have not been well defined. This study was undertaken to evaluate the effects of GSK-3 inhibition in the G93A-SOD1 mouse model of ALS. Groups of G93A-SOD1 mice were treated with varying concentrations of GSK-3 inhibitor VIII, a specific GSK-3 inhibitor that crosses the BBB, intraperitoneally 5 days a week after 60 days of age. The GSK-3 inhibitor VIII treatment significantly delayed the onset of symptoms and prolonged the life span of the animals, and inhibited the activity of GSK-3 in a concentration-dependent manner. Furthermore, this treatment preserved survival signals and attenuated death and inflammatory signals. These data suggest that GSK-3 plays an important role in the pathogenic mechanisms of ALS and that inhibition of GSK-3 could be a potential therapeutic candidate for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Blotting, Western; Caspase 3; Cell Death; Cyclooxygenase 2; Cytochromes c; Cytosol; Disease Progression; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Humans; In Situ Nick-End Labeling; Intercellular Adhesion Molecule-1; Mice; Mice, Transgenic; Motor Neurons; Poly(ADP-ribose) Polymerases; Postural Balance; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1; Thiazoles; Urea