Effect of Cholera Toxin Administered Supraspinally or Spinally on the Blood Glucose Level in Pain and D-Glucose Fed Animal Models

심윤범,박수현,강유정,김성수,김채하,김수진,정준섭,류옥현,최문기,최성수,서홍원 대한약리학회 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.2

In the present study, the effect of intrathecal (i.t.) or intracerebroventricular (i.c.v.) administration with cholera toxin (CTX) on the blood glucose level was examined in ICR mice. The i.t. treatment with CTX alone for 24 h dose-dependently increased the blood glucose level. However, i.c.v. treatment with CTX for 24 h did not affect the blood glucose level. When mice were orally fed with D-glucose (2 g/kg), the blood glucose level reached to a maximum level at 30 min and almost returned to the control level at 120 min after D-glucose feeding. I.c.v. pretreatment with CTX increased the blood glucose level in a potentiative manner, whereas i.t. pretreatment with CTX increased the blood glucose level in an additive manner in a D-glucose fed group. In addition, the blood glucose level was increased in formalin-induced pain animal model. I.c.v. pretreatment with CTX enhanced the blood glucose level in a potentiative manner in formalin-induced pain animal model. On the other hand, i.t. pretreatment with CTX increased the blood glucose level in an additive manner in formalin-induced pain animal model. Our results suggest that CTX administered supraspinally or spinally differentially modulates the regulation of the blood glucose level in D-glucose fed model as well as in formalin-induced pain model.

Various pain stimulations cause an increase of the blood glucose level

심윤범,서홍원,박수현,강유정,정준섭,류옥현,최문기 한국통합생물학회 2012 Animal cells and systems Vol.16 No.5

The relationship between pain stimulation and the blood glucose level was studied in ICR mice. We examined the possible change of the blood glucose level after the pain stimulation induced by acetic acid injected intraperitoneally (i.p.),, formalin injected subcutaneously (s.c.) into the hind paw, or substance P (SP), glutamate, and proinflammatory cytokines (TNF-a and IFN-g) injected intrathecally (i.t.). We found in the present study that acetic acid, formalin, SP, TNF-a, and IFN-g increased the blood glucose level. The blood glucose level reached at maximal state 30 min and returned to normal level 2 h after the pain stimulation in a fasting group. Furthermore, acetic acid,formalin, SP, TNF-a, and IFN-g caused the elevation of the blood glucose level in D-glucose-fed group only in an additive manner. However, i.t. injection of glutamate did not alter the blood glucose level in a fasting group. In contrast, i.t. injection of glutamate enhanced the blood glucose level in the D-glucose-fed group. Our results suggest that the blood glucose level appears to be differentially regulated by various pain stimulation induced by acetic acid,formalin, SP, glutamate, and pro-inflammatory cytokines.

Spinal β-adrenergic receptors’ activation increases the blood glucose level in mice

심윤범,서홍원,박수현,김성수,임수민,정준섭,Naveen Sharma 한국통합생물학회 2017 Animal cells and systems Vol.21 No.4

We examined the role of spinally located β-adrenergic receptors in the regulation of the blood glucose level. The intrathecal (i.t.) injections with dobutamine (β1-adrenergic receptor agonist) or terbutaline (β2-adrenergic receptor agonist) caused an elevation of the blood glucose level, whereas metoprolol (β1-adrenergic receptor antagonist) or butoxamine (β2-adrenergic receptor antagonist) did not. In addition, i.t. pretreatment with pertussis toxin (PTX) attenuated the hyperglycemic effect induced by dobutamine or terbutaline. Moreover, plasma insulin level was increased by dobutamine but not by terbutaline, and PTX reduced dobutamine-induced upregulation of the plasma insulin level. Terbutaline significantly increased plasma corticosterone level, and PTX further enhanced terbutaline-induced corticosterone level. Furthermore, intraperitoneal (i.p.) pretreatment with hexamethonium- (a preganglionic blocker) attenuated dobutamine- and terbutaline-induced hyperglycemic effects. Our results suggest that activation of spinal β1- and β2-adrenergic receptors produces hyperglycemic effects in a different manner. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by terbutaline. Furthermore, dobutamine- or terbutaline-induced hyperglycemia appears to be mediated through the spinal nerves.

Islet Amyloid Polypeptide에 의해 유도되는 췌장 RINm5F 세포의 세포사기전 : Superoxide radical의 연관성

심윤범,이명원,권혁일 한국노화학회 2007 한국노화학회지 Vol.17 No.3

Islet amyloid polypeptide (LAPP) is the major component of amyloid aggregates found in the extracellular spaces of the pancreatic islets of patients with non-insulin dependent diabetes (NIDDM). The increase in these aggregates correlate with the gradual destruction of β-cells of individuals with NIDDM. However, the underlying molecular mechanism by which LAPP evokes β-cells apoptosis is not yet fully characterized. The aim of this study is to determine whether reactive oxygen species and nitic oxide are involved in LAPP-induced cell death in a pancreatic β-cell line, RINm5F cell. LAPP significantly inhibited RINm5F cell proliferation and evoked cell death. The intracellular level of superoxide radical was significantly increased in a dose-dependent manner, whereas intracellular production of nitric oxide was not changed by treatment of LAPP. The LAPP-induced cell death, superoxide production and lipid peroxidation were significantly inhibited by pretreatment with antioxidants (trolox, quercetin, EGCG) and a cell-permeable HIV-1 Tat-Cu,Zn-superoxide dismutase fusion protein. Taken together, these results suggest that LAPP-induced cell death of RINm5F islet β-cell is associated with increased intracellular superoxide radical, but not nitric oxide.

Repaglinide, but Not Nateglinide Administered Supraspinally and Spinally Exerts an Anti-Diabetic Action in D-Glucose Fed and Streptozotocin-Treated Mouse Models

심윤범,박수현,강유정,김성수,김채하,김수진,임수민,정준섭,류옥현,최문기,서홍원 대한약리학회 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.6

We have recently demonstrated that some anti-diabetic drugs such as biguanide and thizolidinediones administered centrally modulate the blood glucose level, suggesting that orally administered anti-diabetic drugs may modulate the blood glucose level by acting on central nervous system. The present study was designed to explore the possible action of another class of anti-diabetic drugs,glinidies, administered centrally on the blood glucose level in ICR mice. Mice were administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with 5 to 30 μg of repaglinide or nateglinide in D-glucose-fed and streptozotocin (STZ)-treated models. We found that i.c.v. or i.t. injection with repaglinide dose-dependently attenuated the blood glucose level in D-glucose-fed model, whereas i.c.v. or i.t. injection with nateglinide showed no modulatory action on the blood glucose level in D-glucose-fed model. Furthermore, the effect of repaglinide administered i.c.v. or i.t. on the blood glucose level in STZ-treated model was studied. We found that repaglinide administered i.c.v. slightly enhanced the blood glucose level in STZ-treated model. On the other hand, i.t. injection with repaglinide attenuated the blood glucose level in STZ-treated model. The plasma insulin level was enhanced by repaglinide in D-glucose-fed model, but repaglinide did not affect the plasma insulin level in STZ-treated model. In addition, nateglinide did not alter the plasma insulin level in both D-glucose-fed and STZ-treated models. These results suggest that the anti-diabetic action of repaglinide appears to be, at least,mediated via the brain and the spinal cord as revealed in both D-glucose fed and STZ-treated models.

The Modulatory Role of Spinally Located Histamine Receptors in the Regulation of the Blood Glucose Level in D-Glucose-Fed Mice

심윤범,박수현,김성수,김채하,김수진,임수민,정준섭,류옥현,최문기,서홍원 대한약리학회 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.1

The possible roles of spinal histamine receptors in the regulation of the blood glucose level werestudied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist(2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) orantagonist (ranitidine), histamine 3 (H3) receptor agonist (α -methylhistamine) or antagonist (carcinine)and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the bloodglucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection withα -methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. Inaddition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the bloodglucose level in D-glucose-fed model. In addition, α-methylhistamine, but not carcinine, slightly but significantlyenhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120,but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptorsthemselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, ourresults suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the bloodglucose level in D-glucose fed model.

The Regulation of Blood Glucose Level in Physical and Emotional Stress Models: Possible Involvement of Adrenergic and Glucocorticoid Systems

심윤범,박수현,Yu-Jung Kang,Seon-Mi Kim,이진구,Jun-Sub Jung,서홍원 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.10

This study was done to determine the effect of stress on blood glucose regulation in ICR mice. The stress was induced by the electrical foot shock-witness model. Blood glucose level was found to be increased in the electrical foot shock-induced physical stress group. Furthermore, the blood glucose levels were also elevated in the emotional stress group in both physical and emotional stress groups. The blood glucose level reached maximum 30 min after stress stimulation and returned to normal level 2 h after stress stimulation in both physical and emotional stress groups. Subsequently,we observed that intraperitoneal injection of phentolamine (an α1-adrenergic receptor antagonist), yohimbine (an α2-adrenergic receptor antagonist) or RU486 (a glucocorticoid receptor blocker) significantly inhibited blood glucose level induced by both physical and emotional stress. The results of our study suggest that physical and emotional stress increases blood glucose level via activation of adrenergic and glucocorticoid system.

Antinociceptive Profiles and Mechanisms of Orally Administered Vanillin in the Mice

박수현,심윤범,Seung-Min Choi,서영준,권민수,이진구,서홍원 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.11

In the present study, the antinociceptive profiles of vanillin were examined in ICR mice. Vanillin administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dosedependent manner as measured in the acetic acid-induced writhing test. Duration of antinociceptive action of vanillin maintained at least for 30 min. But, the cumulative response time of nociceptive behaviors induced by a subcutaneous (s.c.) formalin injection, intrathecal (i.t.) substance P (0.7 μg) or glutamate (20 μg) injection was not affected by vanillin. Intraperitoneal (i.p.) pretreatment with yohimbine (α2-adrenergic receptor antagonist) or naloxone (opioid receptor antagonist) attenuated antinociceptive effect induced by vanillin in the writhing test. However, phentolamine (α1-adrenergic receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) did not affect antinociception induced by vanillin in the writhing test. Our results suggest that vanillin exerts a selective antinociceptive property in the acetic acidinduced visceral inflammatory pain model. Furthermore, this antinociceptive effect of vanillin may be mediated by α2-adrenergic and opioid receptors, but not α1-adrenergic and serotonergic receptors.

Effects of 5,7-dihroxytryptamine administered supraspinally or spinally on the blood glucose level in D-glucose-fed and immobilization stress models

박수현,심윤범,김성수,이재령,Naveen Sharma,서홍원 한국통합생물학회 2016 Animal cells and systems Vol.20 No.5

5,7-Dihydroxytryptamine (5,7-DHT) is a neurotoxin which causes the depletion of serotonin. Moreover, the serotonergic system is the regulator of the blood glucose level. However, the role of centrally located serotonergic system in blood glucose regulation after D-glucose feed and immobilization (IMO) stress was not clearly characterized yet. Thus the present study was designed to examine the effect of 5,7-DHT administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) on the blood glucose level in D-glucose-fed and immobilization stress models. Mice were pretreated once i.c.v. or i.t. with 5,7-DHT (from 10 to 40 μg) for 3 days and D-glucose (2 g/kg) was fed orally. The blood glucose level was measured at 0, 30, 60 and 120 min after Dglucose feeding and immobilization stress initiation. We found that i.c.v. or i.t. pretreatment with 5,7-DHT attenuated the blood glucose level in both animal models. D-glucose feeding causes an increase in plasma insulin level, whereas the plasma corticosterone level was downregulated in the D-glucose-fed model. The i.c.v. or i.t. pretreatment with 5,7-DHT alone slightly increased the plasma corticosterone level. In addition, the i.c.v. or i.t. pretreatment with 5,7-DHT caused a reversal of the downregulation of plasma corticosterone level induced by D-glucose feeding, whereas immobilization stress causes an increase in plasma corticosterone and insulin levels. The i.c.v or i.t. pretreatment with 5,7-DHT attenuated the immobilization stress-induced plasma corticosterone and plasma insulin levels. Our results suggest that supraspinal and spinal depletion of serotonin appears to be responsible for the downregulation of blood glucose level in both D-glucose-fed and immobilization stress models.

Mechanisms involved in the antinociceptive effects of orally administered oleanolic acid in the mouse

박수현,심윤범,Yu-Jung Kang,김성수,김채하,김수진,서홍원 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.7

The antinociceptive effects of oleanolic acid wereexamined in ICRmice. Oleanolic acid administered orally (1, 5and 10 mg/kg) showed an antinociceptive effect in a dosedependentmanner as measured in the acetic acid-inducedwrithing test. In the time- course study, duration of antinociceptiveaction of oleanolic acidmaintained at least for 60 min. In addition, the cumulative nociceptive response time forintraplantar formalin injection (2nd phase), intrathecal injectionof substance P (0.7 lg) or glutamate (20 lg) was diminishedby oleanolic acid. Intraperitoneal (i.p.) pretreatmentwithnaloxone (opioid receptor antagonist) or methysergide (5-HTserotonergic receptor antagonist) attenuated antinociceptiveeffect induced by oleanolic acid in the writhing test. However,yohimbine (adrenergic receptor antagonist) did not affect antinociceptioninduced by oleanolic acid. The results indicatethat oleanolic acid shows an antinociceptive property in variouspain models such as writhing, formalin, substance P andglutamate pain tests. Furthermore, this antinociceptive effectof oleanolic acid may be mediated by opioidergic and serotonergicreceptors, but not adrenergic receptors.