Kwang Woo Lee

The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice

Epigallocatechin gallate (EGCG) is a constituent of green tea, and increasing evidence suggests that EGCG has neuroprotective effects on oxidative stress-injured neuronal cells, especially motoneurons. Although the neuroprotective effects of EGCG have been demonstrated in Parkinsons and Alzheimers diseases and ischemic stroke models, there has been no report on the effect of EGCG on an in vivo model of amyotrophic lateral sclerosis (ALS). This study was undertaken to evaluate the effect of EGCG on ALS model mice with the human G93A mutated Cu/Zn-superoxide dismutase (SOD1) gene. We treated each group of 11 ALS model mice with EGCG (1.5, 2.9, and 5.8 microg/g body weight), dissolved in 0.5 ml of 0.9% sterile NaCl, and one group of 11 with 0.5 ml of 0.9% sterile NaCl (control group) intraorally every day after 60 days of age (presymptomatic treatment). The treatment of more than 2.9 microg EGCG/g body weight significantly prolonged the symptom onset and life span, preserved more survival signals, and attenuated death signals. These data suggest that EGCG could be a potential therapeutic candidate for ALS as a disease-modifying agent.

Role of GSK-3β activity in motor neuronal cell death induced by G93A or A4V mutant hSOD1 gene

Point mutations such as G93A and A4V in the human Cu/Zn‐superoxide dismutase gene (hSOD1) cause familial amyotrophic lateral sclerosis (fALS). In spite of several theories to explain the pathogenic mechanisms, the mechanism remains largely unclear. Increased activity of glycogen synthase kinase‐3 (GSK‐3) has recently been emphasized as an important pathogenic mechanism of neurodegenerative diseases, including Alzheimers disease and ALS. To investigate the effects of G93A or A4V mutations on the phosphatidylinositol‐3‐kinase (PI3‐K)/Akt and GSK‐3 pathway as well as the caspase‐3 pathway, VSC4.1 motoneuron cells were transfected with G93A‐ or A4V‐mutant types of hSOD1 (G93A and A4V cells, respectively) and, 24 h after neuronal differentiation, their viability and intracellular signals, including PI3‐K/Akt, GSK‐3, heat shock transcription factor‐1 (HSTF‐1), cytochrome c, caspase‐3 and poly(ADP‐ribose) polymerase (PARP), were compared with those of wild type (wild cells). Furthermore, to elucidate the role of the GSK‐3β‐mediated cell death mechanism, alterations of viability and intracellular signals in those mutant motoneurons were investigated after treating the cells with GSK‐3β inhibitor. Compared with wild cells, viability was greatly reduced in the G93A and A4V cells. However, the treatment of G93A and A4V cells with GSK‐3β inhibitor increased their viability by activating HSTF‐1 and by reducing cytochrome c release, caspase‐3 activation and PARP cleavage. However, the treatment did not affect the expression of PI3‐K/Akt and GSK‐3β. These results suggest that the G93A or A4V mutations inhibit PI3‐K/Akt and activate GSK‐3β and caspase‐3, thus becoming vulnerable to oxidative stress, and that the GSK‐3β‐mediated cell death mechanism is important in G93A and A4V cell death.

Intraoperative neurophysiologic monitoring: basic principles and recent update.

The recent developments of new devices and advances in anesthesiology have greatly improved the utility and accuracy of intraoperative neurophysiological monitoring (IOM). Herein, we review the basic principles of the electrophysiological methods employed under IOM in the operating room. These include motor evoked potentials, somatosensory evoked potentials, electroencephalography, electromyography, brainstem auditory evoked potentials, and visual evoked potentials. Most of these techniques have certain limitations and their utility is still being debated. In this review, we also discuss the optimal stimulation/recording method for each of these modalities during individual surgeries as well as the diverse criteria for alarm signs.

Comparison between Clinical Disabilities and Electrophysiological Values in Charcot-Marie-Tooth 1A Patients with PMP22 Duplication

Background and Purpose Charcot-Marie-Tooth disease (CMT) type 1A (CMT1A) is the demyelinating form of CMT that is significantly associated with PMP22 duplication. Some studies have found that the disease-related disabilities of these patients are correlated with their compound muscle action potentials (CMAPs), while others have suggested that they are related to the nerve conduction velocities. In the present study, we investigated the correlations between the disease-related disabilities and the electrophysiological values in a large cohort of Korean CMT1A patients. Methods We analyzed 167 CMT1A patients of Korean origin with PMP22 duplication using clinical and electrophysiological assessments, including the CMT neuropathy score and the functional disability scale. Results Clinical motor disabilities were significantly correlated with the CMAPs but not the motor nerve conduction velocities (MNCVs). Moreover, the observed sensory impairments matched the corresponding reductions in the sensory nerve action potentials (SNAPs) but not with slowing of the sensory nerve conduction velocities (SNCVs). In addition, CMAPs were strongly correlated with the disease duration but not with the age at onset. The terminal latency index did not differ between CMT1A patients and healthy controls. Conclusions In CMT1A patients, disease-related disabilities such as muscle wasting and sensory impairment were strongly correlated with CMAPs and SNAPs but not with the MNCVs or SNCVs. Therefore, we suggest that the clinical disabilities of CMT patients are determined by the extent of axonal dysfunction.

Sera from amyotrophic lateral sclerosis patients reduce high-voltage activated Ca2+ currents in mice dorsal root ganglion neurons.

This study investigated the effects of sera from amyotrophic lateral sclerosis (ALS) patients on high voltage activated (HVA) Ca2+ current in mice dorsal root ganglion (DRG) cells using whole-cell voltage-clamp method. Mice were injected with sera from healthy adults, from patients with other neurological diseases, and from patients with the sporadic form of ALS, for a period of 3 days. Sera from five of six ALS patients reduced HVA Ca2+ current amplitude. The peak Ca2+ current was significantly reduced by ALS sera while the sera from healthy adults and patients with other diseases did not alter Ca2+ current. The inactivation kinetics was altered by ALS sera, and the half-inactivation voltage shifted to more negative potential in ALS group. These results suggest that sporadic ALS serum factors may exert interactions with the HVA Ca2+ channel in DRG cells to reduce the Ca2+ current.