1.The Effect of Halothane and Isoflurane on KCNK2 Transfected HEK-293 Cells.
Woo Jong SHIN ; Hyun Jung KIM ; Jae Hang SHIM ; Woo Jae JEON ; Sang Yoon CHO ; Jong Hoon YEOM ; Kyung Hun KIM ; Kyo Sang KIM
Korean Journal of Anesthesiology 2005;49(6):S20-S25
BACKGROUND: According to the report that KCNK activity in transfected COS-7 and HEK-293 cells was modulated by volatile anesthetics and activation of KCNK channels by neuroprotectants, the importance of KCNK2 were emphasized. In this study, we studied the effect of halothane and isoflurane on KCNK2 in the KCNK2 transfected HEK-293 cells. METHODS: Multiple patch clamp experiments with halothane and isoflurane were conducted to characterize KCNK2 in the KCNK2 transfected HEK-293 cells. KCNK2 cDNA were transiently transfected with FuGENE6 transfection reagents and whole cell recordings were made using predesigned pulse protocol. RESULTS: KCNK2 transfected HEK cells exhibited rapid rising, a time-independent, non-inactivating, outward-rectifying currents and had no threshold for activation by voltage. Multiple patch clamp experiments showed the presence of outward-rectifying K+ selective channels with a conductance of 1.31 +/- 0.59 nS (n = 16) at positive potentials. Recordings of halothane 448microM (-2 MAC) increased outward currents from control by 218% in standard saline perfusate (n = 4, P<0.05, paired t-test) and that of isoflurane 822microM (-3 MAC) increased outward currents by 172% in standard saline perfusate (n = 12, P<0.05, paired t-test). Channel activity enhanced during the duration of the exposure to volatile anesthetics returned to the baseline quickly upon wash. CONCLUSIONS: Considering the activation of KCNK2 by neuroprotectants such as riluzole and PUFA, we might think of the possibility of halothane and isoflurane as neuroprotectants because these anesthetics activated background K+ channels in KCNK2 transfected HEK-293 cells.
Anesthetics
;
DNA, Complementary
;
Halothane*
;
Indicators and Reagents
;
Isoflurane*
;
Neuroprotective Agents
;
Riluzole
;
Transfection
2.The Effect of Methylprednisolone and Riluzole on Axonal Growth after Acute Spinal Cord Injury in Rats.
Chang Hwa HONG ; Jun Young YANG ; June Kyu LEE ; Ho Sup SONG
The Journal of the Korean Orthopaedic Association 2008;43(6):783-790
PURPOSE: To determine the effect of methylprednisolone (MP) and riluzole administration on axonal growth after spinal cord injury (SCI) in rats. MATERIALS AND METHODS: Three Sprague Dawley rats (SD rat) served as controls (average 24 weeks of age) and 24 SCI SD rats scoring below 7 points on on Basso, Beattie, and Bresnahan open field test served as test subjects (total 27 SD rats; mean weight 581 g, range=427-613 g). Test subjects were divided into two groups of 12 subjects each. Group I was injected with saline (1 ml/kg) and group II was injected with MP (300 mg/kg) and riluzole (5 mg/kg) intraperitoneally. Four SD rats were sacrificed in each group at the following time points after SCI: days 1, 4, and 7. We completed behavioral testing, immunohistochemical staining and RT-PCR for chondroitin sulfate proteoglycans (CSPG), and microarrays for c-JUN, ATF-2, p53, and Elk-1. RESULTS: On behavioral testing, group II showed superior results at only day 4 after SCI (p<0.05). On RT-PCR for CSPG, optical densities were 2.06 (ratio=Group I/Group II) and 2.11 at days 4 and 7, respectively. Microarray showed that lower expression of c-JUN in group II during the entire period (p< 0.05). ATF-2 showed lower expression in group II at days 4 and 7 (p<0.05). p53 showed lower expression in group I at day 1 (p<0.05). Elk-1 showed lower expression in group I at day 1 (p<0.05) and in group II at day 7 (p<0.05). CONCLUSION: Simultaneous administration of MP and riluzole led to various changes in the MAPK pathway, and decreased CSPG. Therefore, this method has a protective effect on axonal regeneration after SCI in an SD rat model.
Animals
;
Axons
;
Chondroitin Sulfate Proteoglycans
;
Methylprednisolone
;
Rats
;
Rats, Sprague-Dawley
;
Regeneration
;
Riluzole
;
Spinal Cord
;
Spinal Cord Injuries
3.Update of Therapeutic Clinical Trials for Amyotrophic Lateral Sclerosis.
Korean Journal of Clinical Neurophysiology 2015;17(1):1-16
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by progressive death of motor neurons in the cortex, brainstem, and spinal cord. Until now, many treatment strategies have been tested in ALS, but so far only Riluzole has shown efficacy of slightly slowing disease progression. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. Other motor neuron disease such as spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA) are also progressive neurodegenerative disease with loss of motor neuron as ALS. This common thread of motor neuron loss has provided a target for the development of therapies for these motor neuron diseases. A better understanding of these pathogenic mechanisms and the potential pathological relationship between the various cellular processes have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS.
Amyotrophic Lateral Sclerosis*
;
Brain Stem
;
Disease Progression
;
Hope
;
Motor Neuron Disease
;
Motor Neurons
;
Muscular Atrophy, Spinal
;
Muscular Disorders, Atrophic
;
Neurodegenerative Diseases
;
Riluzole
;
Spinal Cord
;
Stem Cells
4.The Effects of Riluzole and Trolox in Transient Retinal Ischemia.
Soon Il KWON ; Yong Eun KIM ; Hyung Chan KIM ; Ha Kyoung KIM
Journal of the Korean Ophthalmological Society 2003;44(3):712-720
PURPOSES: To evaluate the effect of riluzole (water soluble vitamin E, antioxidant) and trolox(glutamatergic neurotransmission antagonist) in transient retinal ischemia. METHODS: The effects of two drugs were investigated in a gerbil model of retinal ischemic injury. Retinal ischemia was induced by clipping both common carotid arteries for 15 minutes. In group I (10 eyes), 10 gerbils received an intraperitoneal injection of the saline, and in group II (10 eyes), riluzole was injected 30 minutes before ischemia and 30 minutes after the end of the ischemic insult and once daily during the recovery period. In group III (10 eyes), trolox was injected and in group IV (10 eyes), riluzole and trolox were injected in a same manner. Electroretinograms were recorded before ischemia and after 1 hour, 2 days, and 7days of reperfusion. Retinas were harvested for histopathology (hematoxyline-eosin staining and Tdt-dUTP terminal nick-end labeling method). RESULTS: Ischemia for 15 minutes caused reduction of a- and b- waves of the electroretinogram. Treatments with riluzole or trolox significantly enhanced the recovery of the reduced a-and b-waves after reperfusion. Combined treatment with riluzole and trolox also enhanced the recovery of the reduced a-and b-waves, but synergistic effect was not observed. Riluzole and trolox also prevented or attenuated ischemia induced cell death (necrosis and apoptosis). CONCLUSIONS: Riluzole and trolox acted in vivo as a potent neuroprotective agents against transient retinal ischemic model. Therefore, riluzole and trolox may be a major drug for use in the protection against retinal ischemic injury.
Apoptosis
;
Carotid Artery, Common
;
Cell Death
;
Gerbillinae
;
Injections, Intraperitoneal
;
Ischemia*
;
Necrosis
;
Neuroprotective Agents
;
Reperfusion
;
Retina
;
Retinaldehyde*
;
Riluzole*
;
Synaptic Transmission
;
Vitamin E
;
Vitamins
5.Rosmarinic Acid Alleviates Neurological Symptoms in the G93A-SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.
Ji Seon SEO ; Juli CHOI ; Yea Hyun LEEM ; Pyung Lim HAN
Experimental Neurobiology 2015;24(4):341-350
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons in the brain and spinal cord, resulting in paralysis of voluntary skeletal muscles and eventually death, usually within 2~3 years of symptom onset. The pathophysiology mechanism underlying ALS is not yet clearly understood. Moreover the available medication for treating ALS, riluzole, only modestly improves neurological symptoms and increases survival by a few months. Therefore, improved therapeutic strategies are urgently needed. In the present study, we investigated whether rosmarinic acid has a therapeutic potential to alleviate neurological deterioration in the G93A-SOD1 transgenic mouse model of ALS. Treatment of G93A-SOD1 transgenic mice with rosmarinic acid from 7 weeks of age at the dose of 400 mg/kg/day significantly extended survival, and relieved motor function deficits. Specifically, disease onset and symptom progression were delayed by more than one month. These symptomatic improvements were correlated with decreased oxidative stress and reduced neuronal loss in the ventral horns of G93A-SOD1 mice. These results support that rosmarinic acid is a potentially useful supplement for relieving ALS symptoms.
Amyotrophic Lateral Sclerosis*
;
Animals
;
Brain
;
Horns
;
Mice
;
Mice, Transgenic*
;
Motor Neurons
;
Muscle, Skeletal
;
Neurodegenerative Diseases
;
Neurons
;
Oxidative Stress
;
Paralysis
;
Riluzole
;
Spinal Cord
6.Agonistforthe Control of Apotosis through the Study of Cytokine Expression after Spinal CordInjuryin Rats.
Jun Young YANG ; K Daniel RIEW
The Journal of the Korean Orthopaedic Association 2007;42(1):106-114
Purpose: To analyze the cytokines that appear after a spinal cord injury in rats and to determine the agonists that regulate apoptosis. Materials and Methods: Sixty female Sprague-Dawley rats were anesthetized, and a laminectomy was performed at the 9th thoracic vertebra. The spinal cord injury was induced by dropping a 10 gm weight at a height of 20 mm. The subjects were divided into 5 groups. Group I was administered aminoguanidine, group II was administered GM-CSF, group III was administered riluzole, group IV was administered erythropoietin, and group V was administered methylprednisolone. A control group was administered normal saline. The results were assessed using the Tarlov motor grading method. In 1, 3, 5 and 7 days after the spinal cord injury, the rats were sacrificed and evaluated using the syringomyelic cavity size. Immunohistochemical staining for e-NOS and RT-PCR for XIAP were also performed. Results: Groups I, III, and V showed significantly different results in terms of the motor recovery and inhibition of increase in the syringomyelic cavity compared with the other groups (p<0.05). The e-NOS activity was observed in groups I, III, and V. The other groups showed almost no e-NOS activity. On the RT-PCR, groups I, III, and V showed significantly different results in terms of XIAP expression with time compared with the other groups. Conclusion: Steroids, NOS inhibitors and sodium channel inhibitors appear to be important factors for regulating apoptosis in the early stage of a spinal cord injury. Further study will be needed to develop new pharmaceuticals with synergic effects on spinal cord injuries.
Animals
;
Apoptosis
;
Cytokines
;
Erythropoietin
;
Female
;
Granulocyte-Macrophage Colony-Stimulating Factor
;
Humans
;
Laminectomy
;
Methylprednisolone
;
Rats*
;
Rats, Sprague-Dawley
;
Riluzole
;
Sodium Channel Blockers
;
Spinal Cord Injuries
;
Spine
;
Steroids
7.Riluzole Selective Antioxidant Effects in Cell Models Expressing Amyotrophic Lateral Sclerosis Endophenotypes
Gessica SALA ; Alessandro AROSIO ; Elisa CONTI ; Simone BERETTA ; Christian LUNETTA ; Nilo RIVA ; Carlo FERRARESE ; Lucio TREMOLIZZO
Clinical Psychopharmacology and Neuroscience 2019;17(3):438-442
OBJECTIVE: Until recently, riluzole was the only drug licensed for amyotrophic lateral sclerosis (ALS). In spite of its efficacy, the mechanism of action remains elusive, and both blocking of glutamate release and antioxidant properties have been postulated. Here we characterized human SH-SY5Y neuroblastoma cell lines, taking advantage of their insensitivity to excitotoxic insults, in order to selectively assess the presence of a direct antioxidant effect of riluzole. METHODS: SH-SY5Y cells, either parental or overexpressing the G93A SOD1 mutation, were exposed for 24 hours to the selected stimuli. RESULTS: Riluzole (1–10 μM) was able to counteract the effects of H₂O₂ exposure (200 μM/24 hr), limiting both cell death and whole-cell reactive oxygen species (ROS) increase. The same experiments were repeated using SH-SY5Y cells carrying the familial ALS-related G93A-SOD1 mutation and constitutively expressing two-fold increased whole-cell ROS levels with respect to wild-type cells: riluzole was ineffective in this paradigm. Analogously, riluzole was ineffective in preventing cell death induced by exposing SH-SY5Y cells to 3-morpholino-sydnonimine (SIN-1, 1.5 mM/24 hr), a reactive nitrogen species (RNS) donor. CONCLUSION: Our data support a direct antioxidant action of riluzole. Furthermore, the lack of efficacy of riluzole observed in the SOD1 cell model mirrors the lack of efficacy already demonstrated in cognate mouse models of ALS, plausibly reflecting differences in the underlying pathogenic mechanisms. Finally, riluzole inefficacy against nitrosative stress might support the idea that a combined therapeutic intervention may result more effective in ALS patients, as in the case of co-administration of edaravone, a drug known to reduce RNS.
Amyotrophic Lateral Sclerosis
;
Animals
;
Antioxidants
;
Cell Death
;
Cell Line
;
Endophenotypes
;
Glutamic Acid
;
Humans
;
Mice
;
Neuroblastoma
;
Parents
;
Reactive Nitrogen Species
;
Reactive Oxygen Species
;
Riluzole
;
Tissue Donors
8.Psychopharmacotherapy in Bipolar Depression, Present and Future.
Jong Hyun JEONG ; Young Seop WOO ; Won Myong BAHK
Korean Journal of Psychopharmacology 2008;19(3):125-135
This article reviews the characteristics and major pharmacological treatment modalities of bipolar depression, which is distinguished from unipolar depression by etiologic differences, symptomatic features, clinical courses, and treatment responses. Bipolar depression is often disabling and very challenging to treat. In acute and prophylactic phases, mood stabilizers such as lithium, divalproex, and lamotrigine are used as first-line treatment, unless the patient is psychotic or markedly dysfunctional. Carbamazepine and oxcarbazepine can be used as a second-line treatment or in a combination regimen. Depressive episodes that do not respond to mood stabilizers, as well as relapsing episodes despite prophylactic therapy, justify treatment with antidepressants. Many clinicians also advocate the early use of antidepressants and antipsychotics when depressive episodes are severe or psychotic. Selective serotonin reuptake inhibitors and bupropion are considered the first choices for use in combination with a mood stabilizer. Bupropion in particular yields stability against manic switches or cycle acceleration. Traditionally, clinicians have used antipsychotics as a combination option when treating patients with bipolar depression who exhibit psychotic features. However, extensive and well controlled recent studies have shown that atypical antipsychotics such as quetiapine, olanzapine, and an olanzapine/fluoxetine combination can yield therapeutic efficacy and good tolerability for treating bipolar depression with or without psychotic features. In particular, a randomized controlled trial (RCT) using quetiapine monotherapy to treat patients with bipolar depression yielded significantly reduced depressive symptomatology. Other atypical antipsychotics such as amisulpride, aripirazole, risperidone, and ziprasidone have yielded antidepressive efficacy, but no RCT trials have been conducted on patients with bipolar depression. Some preliminary studies have shown that newly developed agents such as dopamine agonist, agomelatine, riluzole, mefepristone, and uridine effectively improve mood symptoms among patients with bipolar depression. More extensive clinical trials are needed.
Acceleration
;
Acetamides
;
Antidepressive Agents
;
Antipsychotic Agents
;
Benzodiazepines
;
Bipolar Disorder
;
Bupropion
;
Carbamazepine
;
Depressive Disorder
;
Dibenzothiazepines
;
Dopamine Agonists
;
Humans
;
Lithium
;
Piperazines
;
Riluzole
;
Risperidone
;
Serotonin Uptake Inhibitors
;
Sulpiride
;
Thiazoles
;
Triazines
;
Uridine
;
Valproic Acid
;
Quetiapine Fumarate
9.Psychopharmacotherapy in Bipolar Depression, Present and Future.
Jong Hyun JEONG ; Young Seop WOO ; Won Myong BAHK
Korean Journal of Psychopharmacology 2008;19(3):125-135
This article reviews the characteristics and major pharmacological treatment modalities of bipolar depression, which is distinguished from unipolar depression by etiologic differences, symptomatic features, clinical courses, and treatment responses. Bipolar depression is often disabling and very challenging to treat. In acute and prophylactic phases, mood stabilizers such as lithium, divalproex, and lamotrigine are used as first-line treatment, unless the patient is psychotic or markedly dysfunctional. Carbamazepine and oxcarbazepine can be used as a second-line treatment or in a combination regimen. Depressive episodes that do not respond to mood stabilizers, as well as relapsing episodes despite prophylactic therapy, justify treatment with antidepressants. Many clinicians also advocate the early use of antidepressants and antipsychotics when depressive episodes are severe or psychotic. Selective serotonin reuptake inhibitors and bupropion are considered the first choices for use in combination with a mood stabilizer. Bupropion in particular yields stability against manic switches or cycle acceleration. Traditionally, clinicians have used antipsychotics as a combination option when treating patients with bipolar depression who exhibit psychotic features. However, extensive and well controlled recent studies have shown that atypical antipsychotics such as quetiapine, olanzapine, and an olanzapine/fluoxetine combination can yield therapeutic efficacy and good tolerability for treating bipolar depression with or without psychotic features. In particular, a randomized controlled trial (RCT) using quetiapine monotherapy to treat patients with bipolar depression yielded significantly reduced depressive symptomatology. Other atypical antipsychotics such as amisulpride, aripirazole, risperidone, and ziprasidone have yielded antidepressive efficacy, but no RCT trials have been conducted on patients with bipolar depression. Some preliminary studies have shown that newly developed agents such as dopamine agonist, agomelatine, riluzole, mefepristone, and uridine effectively improve mood symptoms among patients with bipolar depression. More extensive clinical trials are needed.
Acceleration
;
Acetamides
;
Antidepressive Agents
;
Antipsychotic Agents
;
Benzodiazepines
;
Bipolar Disorder
;
Bupropion
;
Carbamazepine
;
Depressive Disorder
;
Dibenzothiazepines
;
Dopamine Agonists
;
Humans
;
Lithium
;
Piperazines
;
Riluzole
;
Risperidone
;
Serotonin Uptake Inhibitors
;
Sulpiride
;
Thiazoles
;
Triazines
;
Uridine
;
Valproic Acid
;
Quetiapine Fumarate
10.Enhanced Expression of TREK-1 Is Related with Chronic Constriction Injury of Neuropathic Pain Mouse Model in Dorsal Root Ganglion.
Hyo Jo HAN ; Seung Wook LEE ; Gyu Tae KIM ; Eun Jin KIM ; Byeonghun KWON ; Dawon KANG ; Hyun Jeong KIM ; Kwang Suk SEO
Biomolecules & Therapeutics 2016;24(3):252-259
Neuropathic pain is a complex state showing increased pain response with dysfunctional inhibitory neurotransmission. The TREK family, one of the two pore domain K+ (K2P) channel subgroups were focused among various mechanisms of neuropathic pain. These channels influence neuronal excitability and are thought to be related in mechano/thermosensation. However, only a little is known about the expression and role of TREK-1 and TREK-2, in neuropathic pain. It is performed to know whether TREK-1 and/or 2 are positively related in dorsal root ganglion (DRG) of a mouse neuropathic pain model, the chronic constriction injury (CCI) model. Following this purpose, Reverse Transcription Polymerase Chain Reaction (RT-PCR) and western blot analyses were performed using mouse DRG of CCI model and compared to the sham surgery group. Immunofluorescence staining of isolectin-B4 (IB4) and TREK were performed. Electrophysiological recordings of single channel currents were analyzed to obtain the information about the channel. Interactions with known TREK activators were tested to confirm the expression. While both TREK-1 and TREK-2 mRNA were significantly overexpressed in DRG of CCI mice, only TREK-1 showed significant increase (~9 fold) in western blot analysis. The TREK-1-like channel recorded in DRG neurons of the CCI mouse showed similar current-voltage relationship and conductance to TREK-1. It was easily activated by low pH solution (pH 6.3), negative pressure, and riluzole. Immunofluorescence images showed the expression of TREK-1 was stronger compared to TREK-2 on IB4 positive neurons. These results suggest that modulation of the TREK-1 channel may have beneficial analgesic effects in neuropathic pain patients.
Animals
;
Blotting, Western
;
Constriction*
;
Diagnosis-Related Groups
;
Fluorescent Antibody Technique
;
Ganglia, Spinal*
;
Humans
;
Hydrogen-Ion Concentration
;
Mice*
;
Neuralgia*
;
Neurons
;
Polymerase Chain Reaction
;
Reverse Transcription
;
Riluzole
;
RNA, Messenger
;
Spinal Nerve Roots*
;
Synaptic Transmission