Role of Oxidative Stress in Neurodegenerative Diseases and Ischemic Stroke, and Prospects of Antioxidant Therapies as a New Therapeutic Strategy / 한양의대학술지

Roles of oxidative stress have recently been emphasized in the pathogenic mechanisms of neurodegenerative diseases and ischemic stroke. Many recent increasing evidence support that oxidative stress induces neuronal death related to neurodegenerative diseases and stroke. There fore, identification of cellular targets affected by oxidative stress and development or discovery of antioxidants relieving oxidative stress-induced damage would be extremely beneficial to reduce or postpone disability from neurodegenerative diseases and stroke. Here we discuss the roles of oxidative stress in neuronal cell death, known until now, and the possibility of antioxidants as a new therapeutic strategy. Oxidative stress and reactive oxygen species (ROS) have been confirmed to cause neuronal cell death by affecting several intracellular signals, such as phosphatidylinositol 3-kinase/Akt, Wnt, glycogen synthase kinase-3beta, c-Jun N-terminal kinase, signals associated with mitochondrial dysfunction, caspase-3, poly (ADP-ribose) polymerase, etc. And, many antioxidants, including epigallocatechin gallate, diallyl disulfide, several kinds of vitamin, etc, have been clarified to protect neuronal cells from oxidative stress and ROS by affecting various intracellular signals. Therefore, appropriate use of antioxidants may be a new and good therapeutic strategy that can modulate and treat neurodegenerative disease.

Role of Glycogen Synthase Kinase-3 in Motor Neuronal Cell Death Mechanism of in Vitro Familial ALS Model (G94A, A4V mutant motoneuron)

BACKGROUND: G93A or A4V mutations in the human Cu/Zn- superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). However, it has not yet clearly understood how these bring about fALS. We investigated the effects of the G93A or A4V mutations in hSOD1 on the phosphatydilinositol-3-kinase (PI3K)/Akt and glycogen synthase kinase-3 (GSK-3) pathway, and effects of GSK-3 inhibitor on the G93A- or A4V-mutant cells. METHODS: To evaluate those effects, VSC4.1 motoneuron cells were transfected with G93A- or A4V-mutant types of hSOD1 (G93A and A4V cells, respectively) with/without GSK-3 inhibitor were compared with them transfected with wild type (wild cells) in cell viability and intracellular signals, including PI3K/Akt, GSK-3, and caspase-3, 24 hours after neuronal differentiation. RESULTS: Compared with wild cells, MTT assay revealed a greatly reduced viability in G93A and A4V cells without GSK-3 inhibitor. However, treatment with GSK-3 inhibitor increased the viability of G93A and A4V cells. Western blotting showed that PI3K and pAkt were decreased, and GSK-3 and caspase-3 were increased in G93A and A4V cells, and that GSK-3 inhibitor treatment reduced caspase-3 but did not affected PI3K, Akt and GSK-3. CONCLUSIONS: These results suggest that the G93A or A4V mutations induce inhibition of PI3K/Akt and activation of GSK-3 and caspase-3 resulting the vulnerability to oxidative stress, and that GSK-3 mediated cell death mechanism is important in G93A and A4V cell death.