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

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

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

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

Agmatine ; administration & dosage ; pharmacology ; Analgesia ; methods ; Animals ; Injections, Spinal ; Male ; Morphine ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; drug effects

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

Differentiation of neural progenitor cells (NPCs) is important for protecting neural cells and brain tissue during inflammation. Interleukin-1 beta (IL-1beta) is the most common pro- inflammatory cytokine in brain inflammation, and increased IL-1beta levels can decrease the proliferation of NPCs. We aimed to investigate whether agmatine (Agm), a primary polyamine that protects neural cells, could trigger differentiation of NPCs by activating IL-1beta in vitro. The cortex of ICR mouse embryos (E14) was dissociated to culture NPCs. NPCs were stimulated by lipopolysaccharide (LPS). After 6 days, protein expression of stem cell markers and differentiation signal factors was confirmed by using western blot analysis. Also, immunocytochemistry was used to confirm the cell fate. Agm treatment activated NPC differentiation significantly more than in the control group, which was evident by the increased expression of a neuronal marker, MAP2, in the LPS-induced, Agm-treated group. Differentiation of LPS-induced, Agm-treated NPCs was regulated by the MAPK pathway and is thought to be related to IL-1beta activation and decreased expression of TLX, a transcription factor that regulates NPC differentiation. Our results reveal that Agm can promote NPC differentiation to neural stem cells by modulating IL-1beta expression under inflammatory condition, and they suggest that Agm may be a novel therapeutic strategy for neuroinflammatory diseases.
Agmatine* ; Animals ; Blotting, Western ; Brain ; Embryonic Structures ; Encephalitis ; Immunohistochemistry ; Inflammation ; Interleukin-1beta ; Mice ; Mice, Inbred ICR ; Neural Stem Cells ; Neurons* ; Stem Cells ; Transcription Factors

Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-beta-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia.
Aging ; Agmatine* ; Arginine ; Cell Aging* ; Cell Death ; Cytokines ; Decarboxylation ; Diabetes Mellitus ; Diabetic Neuropathies ; Glucose ; Homeostasis ; Hyperglycemia ; Interleukin-6 ; Neurons* ; Reactive Oxygen Species ; Tumor Necrosis Factor-alpha

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

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