1.Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation.
Juhyun SONG ; Yumi OH ; Jong Youl KIM ; Kyoung Joo CHO ; Jong Eun LEE
Yonsei Medical Journal 2016;57(6):1461-1467
PURPOSE: Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. MATERIALS AND METHODS: This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. RESULTS: Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. CONCLUSION: Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders.
Agmatine*
;
Biogenic Amines
;
Cell Differentiation
;
Cell Proliferation
;
Central Nervous System
;
MicroRNAs*
;
Neural Stem Cells*
;
Neurogenesis
;
Neurons
2.Suppression of MicroRNA let-7a Expression by Agmatine Regulates Neural Stem Cell Differentiation.
Juhyun SONG ; Yumi OH ; Jong Youl KIM ; Kyoung Joo CHO ; Jong Eun LEE
Yonsei Medical Journal 2016;57(6):1461-1467
PURPOSE: Neural stem cells (NSCs) effectively reverse some severe central nervous system (CNS) disorders, due to their ability to differentiate into neurons. Agmatine, a biogenic amine, has cellular protective effects and contributes to cellular proliferation and differentiation in the CNS. Recent studies have elucidated the function of microRNA let-7a (let-7a) as a regulator of cell differentiation with roles in regulating genes associated with CNS neurogenesis. MATERIALS AND METHODS: This study aimed to investigate whether agmatine modulates the expression of crucial regulators of NSC differentiation including DCX, TLX, c-Myc, and ERK by controlling let-7a expression. RESULTS: Our data suggest that high levels of let-7a promoted the expression of TLX and c-Myc, as well as repressed DCX and ERK expression. In addition, agmatine attenuated expression of TLX and increased expression of ERK by negatively regulating let-7a. CONCLUSION: Our study therefore enhances the present understanding of the therapeutic potential of NSCs in CNS disorders.
Agmatine*
;
Biogenic Amines
;
Cell Differentiation
;
Cell Proliferation
;
Central Nervous System
;
MicroRNAs*
;
Neural Stem Cells*
;
Neurogenesis
;
Neurons
3.Quantitative Analysis of Agmatine by HPLC in Ischemic Brain.
Jong Soon HONG ; Hyug CHUN ; Hyo Seok JEONG ; Jae Hwan KIM ; Won Taek LEE ; Kyung Ah PARK ; Jong Eun LEE
Korean Journal of Anatomy 2003;36(4):257-264
Agmatine, a widely distributed molecule in mammalian tissues, shows neuroprotective effects in brain ischemia. We describe the neuroprotective effects of agmatine in the mouse MCAO model and the quantitative change of agmatine in ischemic injury. Brain ischemic injured mice were injected with agmatine (100 mg/kg of mouse, IP). Agmatine significantly reduced the infarct area after MCAO. Despite the similar patterns of agmatine change observed in control or agmatine injected animals, the agmatine levels of the penumbra were significantly higher than those of the striatum and the cerebral cortex during the early period (<1 hour after 2 hours of MCA occlusion). This suggests that the early period, during which agmatine levels increase in the brain, is the crucial period in terms of neuroprotective effect during ischemia.
Agmatine*
;
Animals
;
Brain Ischemia
;
Brain*
;
Cerebral Cortex
;
Chromatography, High Pressure Liquid*
;
Ischemia
;
Mice
;
Neuroprotective Agents
;
Reperfusion
4.Effects of Intra-articular Injection of Agmatine and Clonidine into the Knee Joint Cavity on the Induction and Maintenance of Arthritic Pain in Rats.
Myeong Jong LEE ; Hyen Soo SHIM ; Geun Hee SEOL ; Pill Joo KIM ; Seung Ho HAN ; Jaeyong YEE ; Chan KIM ; Kyu Chang LEE ; Hye Young KIM ; Sun Seek MIN
Korean Journal of Anesthesiology 2008;54(6):656-661
BACKGROUND: Previous studies suggest that systemic administration of agmatine, endogenous ligand for imidazoline receptors has anti-hypernociceptive effects in experimental animal. However the peripheral effects of agmatine on inflammatory pain have not yet been elucidated. Here we examined the effects of intra-articular injection of agmatine in the induction and maintenance phase of arthritic pain. In addition, we sought to determine the potential contribution of imidazoline and alpha(2)-adrenergic receptors to the antinociceptive effects using clonidine which is mixed alpha(2)-adrenoceptor and imidazoline receptor agonist. METHODS: To induce arthritis in rats, 2% lambda-carrageenan (50microliter, in saline) was injected into the joint of the right hind limb under enflurane anesthesia. Either agmatine (10, 50, 100microgram/40microliter) or clonidine (10, 50, 100microgram/40microliter) was injected into the knee joint cavity immediately before or 4 hr after carrageenan injection. Weight load tests were performed to measure pain-related behavior in freely walking rats. RESULTS: The intraarticular injection of agmatine into the knee joint had no effects in the both phase of induction and maintenance of arthritic pain at any dose tested. However, injection of clonidine reversed arthritic pain, when injected 4 h after carrageenan injection. CONCLUSIONS: In rats, agmatine has no peripheral effect on inflammatory pain and imidazoline receptors in the periphery may not contribute to the anti-inflammatory pain.
Agmatine
;
Anesthesia
;
Animals
;
Arthritis
;
Carrageenan
;
Clonidine
;
Enflurane
;
Extremities
;
Imidazoline Receptors
;
Inflammation
;
Injections, Intra-Articular
;
Joints
;
Knee
;
Knee Joint
;
Rats
;
Walking
5.Agmatine protection against chlorpromazine-induced forebrain cortex injury in rats.
Bratislav DEJANOVIC ; Ivana STEVANOVIC ; Milica NINKOVIC ; Ivana STOJANOVIC ; Irena LAVRNJA ; Tatjana RADICEVIC ; Milos PAVLOVIC
Journal of Veterinary Science 2016;17(1):53-61
This study was conducted to investigate whether agmatine (AGM) provides protection against oxidative stress induced by treatment with chlorpromazine (CPZ) in Wistar rats. In addition, the role of reactive oxygen species and efficiency of antioxidant protection in the brain homogenates of forebrain cortexes prepared 48 h after treatment were investigated. Chlorpromazine was applied intraperitoneally (i.p.) in single dose of 38.7 mg/kg body weight (BW) The second group was treated with both CPZ and AGM (75 mg/kg BW). The control group was treated with 0.9% saline solution in the same manner. All tested compounds were administered i.p. in a single dose. Rats were sacrificed by decapitation 48 h after treatment Treatment with AGM significantly attenuated the oxidative stress parameters and restored antioxidant capacity in the forebrain cortex. The data indicated that i.p. administered AGM exerted antioxidant action in CPZ-treated animals. Moreover, reactive astrocytes and microglia may contribute to secondary nerve-cell damage and participate in the balance of destructive vs. protective actions involved in the pathogenesis after poisoning.
Agmatine/*pharmacology
;
Animals
;
Antioxidants/pharmacology
;
Chlorpromazine/toxicity
;
Oxidative Stress/*drug effects
;
Prosencephalon/*drug effects
;
Rats
;
Rats, Wistar
6.Effects of the spinal cord intrathecal injected to agmatine on intrathecal morphine analgesia.
Zhong-Ping LAN ; Ya-Hui CHEN ; Nan GU ; Li-Ze XIONG ; Yan-Yuan SUN
Chinese Journal of Applied Physiology 2014;30(3):197-203
Agmatine
;
administration & dosage
;
pharmacology
;
Analgesia
;
methods
;
Animals
;
Injections, Spinal
;
Male
;
Morphine
;
pharmacology
;
Rats
;
Rats, Sprague-Dawley
;
Spinal Cord
;
drug effects
7.Agmatine Modulates the Phenotype of Macrophage Acute Phase after Spinal Cord Injury in Rats.
Jae Hwan KIM ; Jae Young KIM ; Chin Hee MUN ; Minah SUH ; Jong Eun LEE
Experimental Neurobiology 2017;26(5):278-286
Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype.
Agmatine*
;
Animals
;
Arginine
;
Contusions
;
Immunohistochemistry
;
Interleukin-10
;
Macrophages*
;
N-Methylaspartate
;
Neuralgia
;
Neuroprotection
;
Neuroprotective Agents
;
Nitric Oxide Synthase
;
Phenotype*
;
Rats*
;
RNA, Messenger
;
Spinal Cord Injuries*
;
Spinal Cord*
8.Endogenous Agmatine Induced by Ischemic Preconditioning Regulates Ischemic Tolerance Following Cerebral Ischemia.
Jae Hwan KIM ; Jae Young KIM ; Jin Young JUNG ; Yong Woo LEE ; Won Taek LEE ; Seung Kon HUH ; Jong Eun LEE
Experimental Neurobiology 2017;26(6):380-389
Ischemic preconditioning (IP) is one of the most important endogenous mechanisms that protect the cells against ischemia-reperfusion (I/R) injury. However, the exact molecular mechanisms remain unclear. In this study, we showed that changes in the level of agmatine were correlated with ischemic tolerance. Changes in brain edema, infarct volume, level of agmatine, and expression of arginine decarboxylase (ADC) and nitric oxide synthases (NOS; inducible NOS [iNOS] and neural NOS [nNOS]) were analyzed during I/R injury with or without IP in the rat brain. After cerebral ischemia, brain edema and infarct volume were significantly reduced in the IP group. The level of agmatine was increased before and during ischemic injury and remained elevated in the early reperfusion phase in the IP group compared to the experimental control (EC) group. During IP, the level of plasma agmatine was increased in the early phase of IP, but that of liver agmatine was abruptly decreased. However, the level of agmatine was definitely increased in the ipsilateral and contralateral hemisphere of brain during the IP. IP also increased the expression of ADC—the enzyme responsible for the synthesis of endogenous agmatine—before, during, and after ischemic injury. In addition, ischemic injury increased endogenous ADC expression in the EC group. The expression of nNOS was reduced in the I/R injured brain in the IP group. These results suggest that endogenous increased agmatine may be a component of the ischemic tolerance response that is induced by IP. Agmatine may have a pivotal role in endogenous ischemic tolerance.
Agmatine*
;
Animals
;
Arginine
;
Brain
;
Brain Edema
;
Brain Ischemia*
;
Ischemic Preconditioning*
;
Liver
;
Neuroprotection
;
Nitric Oxide
;
Nitric Oxide Synthase
;
Plasma
;
Rats
;
Reperfusion
;
Reperfusion Injury
9.Agmatine Improves Cognitive Dysfunction and Prevents Cell Death in a Streptozotocin-Induced Alzheimer Rat Model.
Juhyun SONG ; Bo Eun HUR ; Kiran Kumar BOKARA ; Wonsuk YANG ; Hyun Jin CHO ; Kyung Ah PARK ; Won Taek LEE ; Kyoung Min LEE ; Jong Eun LEE
Yonsei Medical Journal 2014;55(3):689-699
PURPOSE: Alzheimer's disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterations similar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigated whether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model. MATERIALS AND METHODS: We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateral ventricle (5 microL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day. RESULTS: Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunction in the STZ-Agm group was observed compared with the EC group. Western blot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and gamma-glutamyl cysteine synthetase, in the STZ-Agm group. CONCLUSION: Our results showed that Agm is involved in the activation of antioxidant signaling pathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuating apoptosis in AD.
Agmatine/*therapeutic use
;
Alzheimer Disease/*chemically induced/*drug therapy
;
Animals
;
Cognition Disorders/*chemically induced/*drug therapy
;
Disease Models, Animal
;
Male
;
Rats
;
Streptozocin/*toxicity
10.Effects of Agmatine on GABAA Receptor Antagonist-induced Tactile Allodynia.
Youn Woo LEE ; Toshizo ISHIKAWA
The Korean Journal of Pain 2008;21(3):173-178
BACKGROUND: The intrathecal (IT) GABAA receptor antagonist, bicuculline (BIC), results in tactile allodynia (TA) through disinhibition in the spinal cord. Such disinhibition is considered to be an important mechanism for neuropathic pain. Agmatine, an endogenous polyamine, has a neuro-protective effect in the central nervous system. We investigated the analgesic effects and mechanisms of agmatine action on BIC-induced TA. METHODS: Male Sprague-Dawley rats, weighting 250-300 g, were subjected to implantations of PE-10 into the lumbar subarachnoid space for IT drug injection. Five days after surgery, either 10 microliter of normal saline (NS) or agmatine (30 microgram or 10 microgram) in 10 microliter NS were injected 10 min prior to BIC (10 microgram) or NMDA (5 microgram). We assessed the degree of TA (graded 0: no response, 1: mild response, 2: moderate response, 3: strong response) every 5 min for 30 min. Areas under curves and degree of TA were expressed as mean +/- SEM. Results were analyzed using one-way ANOVA followed by a Tukey test for multiple comparisons. P < 0.05 was considered significant. RESULTS: IT BIC-induced strong TA reached its peak and plateaued between 10 to 15 min. IT NS-NMDA induced mild transient TA for up to 15 min. Preemptive IT AG attenuated IT BIC-induced TA dose dependently and preemptive IT AG10 completely abolished the IT NMDA-induced TA. CONCLUSIONS: Preemptive IT AG attenuated the IT BIC-induced TA through inhibitory actions on postsynaptic NMDA receptor activation. AG might be a viable therapeutic option in the treatment of neuropathic pain.
Agmatine
;
Bicuculline
;
Central Nervous System
;
Humans
;
Hyperalgesia
;
Male
;
N-Methylaspartate
;
Neuralgia
;
Nitrogen Mustard Compounds
;
Rats, Sprague-Dawley
;
Spinal Cord
;
Subarachnoid Space