• Journal of Korean Neurosurgical Society
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• 제39권2호
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• pp.130-135
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• 2006

Objective : After ischemic stroke, partial recovery of function frequently occurs and may depend on the plasticity of axonal connections. Here, we examine whether blockade of the Nogo/NogoReceptor[NgR] pathway might enhance axonal sprouting and thereby recovery after focal brain infarction. Methods : Adult male Sprague Dawley rats weighing $250{\sim}350g$ were used. Left middle cerebral artery occlusion[MCAO] was induced with a intraluminal filament. An osmotic mini pump [Alzet 2ML4, Alza Scientific Products, Palo Alto, CA] for the infusion of NgR-Ecto[310]-Fc to block Nogo/NgR pathway was implanted 1 week after cerebral ischemia. Prior to induction of ischemia, all animals received training in the staircase and rotarod test. Two weeks after biotin dextran amine injection, animals were perfused transcardially with PBS, followed by 4% paraformadehyde/PBS solution. Brain and cervical spinal cord were dissected. Eight coronal sections spaced at 1mm intervals throughout the forebrain of each animal with cresyl violet acetate for determination of infarction size. Images of each section were digitized and the infarct area per section was measured with image analysis software. Results : Histological examination at 11 weeks post-MCAO demonstrates reproducible stroke lesions and no significant difference in the size of the stroke between the NgR[310]Ecto-Fc protein treated group and the control group. Behavioral recovery is significantly better and more rapid in the NgR-Ecto[310]-Fe treated group. Blockade of NgR enhances axonal sprouting from the uninjured cerebral cortex and improves the return of motor task performance. Conclusion : Pharmacological interruption of NgR allows a greater degree of axonal plasticity in response this is associated with improved functional recovery of complicated motor tasks.

• Journal of Yeungnam Medical Science
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• 제8권2호
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• pp.95-105
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• 1991

흰쥐 적출소장의 수축성에 미치는 GABA의 영향을 관찰하여 다음과 같은 결과를 얻었다. 1. GABA는 소장을 이완시켰으며 그 이완 작용은 십이지장, 공장 그리고 회장의 순이었다. GABA A수용체 효현제인 muscimol 역시 소장을 이완시켰으며, 그 효능의 강도는 십이지장, 공장 그리고 회장의 순이었다. 그러나 GABA B수용체 효현제인 baclofen은 소장의 운동성에 유의한 영향을 미치지 못하였다. 2. 상경적 GABA A수용체 길항제인 bicuculline과 비 상경적 GABA A수용체 길항제인 picrotoxin은 십이지장에 대한 GABA와 muscimol의 이완 작용을 현저히 억제시켰다. 그리고 bicuculline의 억제 작용이 picrotoxin 보다 강하였다. 3. Sodium channel blocker인 tetrodotoxin은 GABA의 이완 작용을 봉쇄하였다. 4. 신경절 봉쇄적인 hexamethonium은 십이지장에 대한 GABA의 이완작용을 길항하지 못하였다. 이상의 실험 결과로 볼 때 흰쥐 소장의 자발 수축운동에 대한 GABA의 이완작용은 소장이 부위에 따라 다르게 나타나며, 그 작용은 postganglionic presynaptic neuron에 존재하는 GABA A 수용체에 작용함으로써 나타나는 것으로 사료된다.

• Journal of Acupuncture Research
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• 제22권2호
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• pp.19-32
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• 2005

Objectives : to evaluate the analgesic effect of bee venom acupuncture on Choksamni (ST36) in the collagen-induced arthritis rats and investigate the role played by serotonergic receptor subtypes (5-HT1a, 5-HT2a) in the antinociceptive effect of bee venom acupuncture in a thermal hyperalgesia test Methods : Experiments were performed on 5 week-aged 60 male Sprague-Dawley rats according to National Institute of Health guidelines and the ethical guidelines of the International Association for the Study of Pain (IASP). Arthritis was induced with arthrogenic collagen emulsion (Bovine type II collagen ${\mu}g$ with incomplete Freund's adjuvant $100\;{\mu}g$). The onset of arthritis was considered to be present when erythema and swelling were detected in at least one joint. The thermal hyperalgesia was evaluated weekly with tail flick test in the rats of severity grade 3 without any injury at tail and foot (including inflammation, ulceration, snap). In the fourth week after first immunization, the analgesic effect of bee venom acupuncture (Choksamni, ST36) was measured with consecutive tail flick latency after intraperitoneal injection of spiroxatrine (1mg/kg) and spiperone (1mg/kg). Results : Chronic inflammatory pain was induced as time elapsed after the immunization of arthrogenic collagen and the maximum value was reached from third to fifth week. Chronic inflammatory pain induced by CIA was inhibited by bee venom acupuncture on the left ST36. The analgesic effect of bee venom acupuncture was inhibited by intraperitoneal injection of 5-HT1a antagonist spiroxatrine and 5-HT2a antagonist spiperone. Conclusions : Therefore, a conclusion. that the analgesic effect of bee venom acupuncture in the chronic inflammatory pain is partially mediated by 5-HT1a and 5-HT2a receptors can be made.

• The Korean Journal of Pain
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• 제22권1호
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• pp.58-64
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• 2009

Background: Magnesium is a noncompetitive antagonist of the N-methyl-D aspartate (NMDA) receptor. Magnesium is thought to be involved in opioid tolerance by way of inhibiting calcium entry into cells. Methods: The patients were randomly assigned to three groups according to the anesthetic regimens: Group M received magnesium sulfate and Group C received saline intravenously under remifentanil-based anesthesia. Group S received saline intravenously under sevoflurane based anesthesia in place of remifentanil. The patients in the group M received 25% magnesium sulfate 50 mg/kg in 100 ml of saline, and those patients in groups C and S received an equal volume of saline before induction of anesthesia; this was followed by 10 mg/kg/h infusion of either magnesium sulfate (group M) or an equal volume of saline (groups C and S) until the end of surgery. Pain was assessed on a visual analog scale at 1, 6, 12, 24, and 36 hours after the operation. The time to the first postoperative analgesic requirement and the cumulative analgesic consumption were evaluated in the three groups. Results: The visual analog scales for pain and the cumulative analgesic consumption were significantly greater in group C than in other groups. The time to first postoperative analgesic requirement was significantly shorter in group C than that in the other groups. There were no differences between group M and S for side effects. Conclusions: A relatively high dose and continuous remifentanil infusion is associated with clinically relevant evidence of acute opioid tolerance. NMDA-receptor antagonist, magnesium sulfate as an adjuvant analgesic prevents opioid tolerance in patients who are undergoing major abdominal surgery under high dose and continuous remifentanil infusion-based anesthesia.

• 대한약리학회지
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• 제29권1호
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• pp.9-22
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• 1993

허혈성 뇌손상시 칼슘길항제, 항산화제와 산소라디칼 제거제 그리고 흥분성 아미노산 수용체 길항제의 보호효과를 검토하기 위해 본 연구에서는 랫트 뇌 해마조직 절편을 산소와 포도당을 제거한 반응액에 노출시켜 실험적 허혈상태를 유도하였다. 그리고 여러 약물을 처리한 상태에서 허혈시의 뇌세포 손상정도를 생화학적 지표들(절편내 ATP와 반응액내 lactate 및 malondialdehyde (MDA)유리량)을 측정하여 검토하였다. 60분까지 허혈상태를 유발시킨 경우 시간에 따라 절편내 ATP 함량이 감소하였고 lactate 유리량이 증가하였다. 그 후 산소와 포도당이 든 반응액으로 바꿔주니 이들 생화학적 변화들이 회복되는 양상을 보였다. 그러나 본 실험조건에서 허혈상태로부터 완전히 회복되지는 않았다. 동일한 허혈조건에서 verapamil과 비타민 E는 ATP 함량 감소와 절편으로부터의 lactate 유리량의 증가에 대해 보고효과를 보였다. 그리고 verapamil과 diltiazem은 반응액내로의 MDA유리를 감소시켰다. Superoxide dismutase (SOD), glutathione과 MK-801 (NMDA 수용체 길항제)은 20분 허혈조건에서 ATP 함량을 증가시켰으나 그외 다른 조건에서 보호효과를 보이지 않았다. 허혈 후 20분간 산소와 포도당을 재공급한 경우 verapamil은 ATP 함량과 lactate 유리에 보호효과를 보였다. 한편 비타민 E는 20분 허혈 조건에서의 lactate 유리와 60분 허혈시의 MDA 유리 증가에 대해 감소효과를 보였다. 이상의 결과는 칼슘길항제와 비타민 E가 랫트 뇌절편에서의 허혈성 생화학적 손상을 방지함으로 나타난 결과로 해석되며, 칼슘갈항제의 효과가 비타민 E보다 우수함으로 미루어 칼슘길항제는 허혈성 뇌손상에 예방 및 보고효과를 보일 것으로 믿어졌다.

• The Korean Journal of Physiology and Pharmacology
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• 제1권5호
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• pp.565-572
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• 1997

In the freshly isolated rat nephron, the effect of endothelin-1, -2 and -3 (ET-1, -2 and -3) on cytosolic free calcium concentration ($[Ca^{2+}]_i$) was determined using the fluorescent indicator Fura-2/AM. $[Ca^{2+}]_i$ increase was investigated in 9 parts of the single nephron including glomerulus (Glm), $S_1,\;S_2,\;S_3$, cortical and medullary thick ascending limb and cortical (CCT) and outer medullary collecting tubule (OMCT). Endothelins increased $[Ca^{2+}]_i$ in Glm (ET-1; $127{\pm}17%$, ET-2; $93{\pm}5%$, ET-3; $169{\pm}17%$), CCT (ET-1; $30{\pm}6%$, ET-2; $38{\pm}19%$, ET-3; $158{\pm}18%$) and OMCT (ET-1; $197{\pm}11%$, ET-2; $195{\pm}11%$, ET-3; $215{\pm}37%$) at 10-7 M. In OMCT, ET-1 and ET-2 increased $[Ca^{2+}]_i$ in a dose-dependent manner ($10^{-10}{\sim}10^{-6}$ M). To the contrary, ET-3-induced $[Ca^{2+}]_i$ rise was begun from $10^{-12}$ M. BQ-123Na, an antagonist of ETA receptor, at $10^{-4}$ M inhibited about 30% of $[Ca^{2+}]_i$ rise induced by ET-1 and -3. Binding experiments using $[^{125}I]ET-3$ showed the existence of $ET_B$ receptor in OMCT. This binding was replaced by ET-1, ET-2 or ET-3 by the almost same degree but not by angiotensin II or vasopressin.

• The Korean Journal of Physiology and Pharmacology
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• 제3권4호
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• pp.383-391
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• 1999

This study was carried out to determine whether the effects of an ${\alpha}_2-adrenoceptor$ agonist, clonidine, on mean arterial pressure (MAP) and heart rate (HR) are influenced by mild hypothermia. Experiments were performed in respiration-controlled and spontaneously breathing pentobarbital-anesthetized rats. Rectal temperature was maintained at $37.5{\pm}0.3^{circ}C$ for normothermic groups or at $35.2{\pm}0.3^{circ}C$ for mild hypothermic groups. Intravenous injection of clonidine (1 and 2 ${\mu}g/kg)$ produced depressor and bradycardic responses in spontaneously breathing rats under both normothermic and mild hypothermic condition: a decrease in MAP was not altered but bradycardic response was significantly augmented in the mild hypothermic group as compared with the normothermic group. Under the respiration-controlled condition, the hypotensive effect of clonidine $(2\;{\mu}g/kg)$ was reduced, whereas the bradycardic effect was increased in mild hypothermic rats as compared with normothermic rats. Both hypotensive and bradycardic effects of clondine $(2\;{\mu}g/kg)$ were blocked by pretreatment with an ${\alpha}_2-adrenoceptor$ antagonist, yohimbine (0.5 mg/kg), in both thermal conditions. Yohimbine (0.5 mg/kg, i.v.) alone produced signifcantly an increase in heart rate in the mild hypothermic group than in the normothermic group. Pretreatment with a muscarinic receptor antagonist, atropine methylnitrate (1 mg/kg, i.v.), attenuated the bradycardic effect of clonidine in the mild hypothermic group but not in the normothermic group. These results suggest that clonidine- induced bradycardia is amplified by mild hypothermia probably through an increased parasympathetic activity.

• The Korean Journal of Physiology and Pharmacology
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• 제6권1호
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• pp.27-31
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• 2002

${\gamma}-Aminobutyric$ Acid (GABA) is contained in pancreatic islet ${\beta}-cells$ although its physiological role in pancreatic exocrine function is completely unknown at the present time. Recently, we have reported that exogenous GABA enhances secretagogue-evoked exocrine secretion in the isolated, perfused rat pancreas. This study was aimed to investigate an effect of exogenous GABA on pancreatic exocrine secretion in vivo evoked by intestinal stimulation. Rats were anesthetized with urethane (1.4 g/kg) after 24-h fast with free access to water. GABA $(10,\;30\;and\;100\;{\mu}mol/kg/h),$ given intravenously, did not change spontaneous pancreatic amylase secretion but dose-dependently elevated the amylase secretion evoked by intraduodenal sodium oleate (0.05 mmol/h). GABA $(30\;{\mu}mol/kg/h)$ also further increased the amylase secretion stimulated by CCK (30 pmol/kg/h) plus secretin (20 pmol/kg/h) but failed to modify the amylase secretion induced by secretin alone. GABA $(10,\;30\;and\;100\;{\mu}mol/kg/h)$ also dose-dependently elevated pancreatic amylase secretion evoked by CCK alone. Bicuculline $(100\;{\mu}mol/kg/h),$ a $GABA_A-receptor$ antagonist, markedly reduced the GABA-enhanced pancreatic responses to sodium oleate, CCK plus secretin or CCK alone. The results indicate that GABA enhances the sodium oleate-evoked pancreatic amylase secretion via $GABA_A-receptor$ in anesthetized rats, which may account for elevating the action of CCK released by sodium oleate.

• The Korean Journal of Pain
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• 제28권1호
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• pp.4-10
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• 2015

Etifoxine (etafenoxine, $Stresam^{(R)}$) is a non-benzodiazepine anxiolytic with an anticonvulsant effect. It was developed in the 1960s for anxiety disorders and is currently being studied for its ability to promote peripheral nerve healing and to treat chemotherapy-induced pain. In addition to being mediated by $GABA_A{\alpha}2$ receptors like benzodiazepines, etifoxine appears to produce anxiolytic effects directly by binding to ${\beta}2$ or ${\beta}3$ subunits of the $GABA_A$ receptor complex. It also modulates $GABA_A$ receptors indirectly via stimulation of neurosteroid production after etifoxine binds to the 18 kDa translocator protein (TSPO) of the outer mitochondrial membrane in the central and peripheral nervous systems, previously known as the peripheral benzodiazepine receptor (PBR). Therefore, the effects of etifoxine are not completely reversed by the benzodiazepine antagonist flumazenil. Etifoxine is used for various emotional and bodily reactions followed by anxiety. It is contraindicated in situations such as shock, severely impaired liver or kidney function, and severe respiratory failure. The average dosage is 150 mg per day for no more than 12 weeks. The most common adverse effect is drowsiness at the initial stage. It does not usually cause any withdrawal syndromes. In conclusion, etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired psychomotor performance, and withdrawal syndromes than those of benzodiazepines. It potentiates $GABA_A$ receptor-function by a direct allosteric effect and by an indirect mechanism involving the activation of TSPO. It seems promising that non-benzodiazepine anxiolytics including etifoxine will replenish shortcomings of benzodiazepines and selective serotonin reuptake inhibitors according to animated studies related to TSPO.

• Journal of Yeungnam Medical Science
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• 제36권1호
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• pp.26-35
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• 2019

Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner