Feyza Aricioglu

Agmatine: clinical applications after 100 years in translation.

Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.

Is Agmatine an Endogenous Anxiolytic/Antidepressant Agent?

Abstract: Agmatine, an endogenous cationic amine, exerts a wide range of biologic effects, but its physiologic role is still to be determined. The aim of the present experiments was to investigate the role of agmatine in anxiety and depression. The forced swim test (FST) and the elevated plus maze (EPM) were used to determine the antidepressant and anxiolytic effects of agmatine in comparison with imipramine (30 mg/kg i.p.). Agmatine (10, 20, 40, 80, or 100 mg/kg, i.p.), saline, or imipramine was given 30 minutes before the tests. Agmatine decreased immobility time in the FST and increased the time spent in the open arms in the EPM, as compared with the saline group. As an endogenous substance, agmatine have modulatory effect on anxiety and depression.

Agmatine reduces only peripheral-related behavioral signs, not the central signs, of morphine withdrawal in nNOS deficient transgenic mice

Agmatine inhibits morphine tolerance/dependence and potentiates morphine analgesia. This study was designed to investigate whether neuronal nitric oxide mediates the actions of agmatine in morphine dependence by using mice lacking a functional form of this enzyme. Mice received agmatine just after the morphine pellet implantation for 3 days twice daily or single injection 30 min before naloxone. In both genotypes treated for 3 days with morphine pellets, naloxone administration precipitated clear signs of withdrawal. Both acute and chronic administration of agmatine reduced withdrawal signs in wild type mice and reduced only peripheral signs of morphine dependence in neuronal nitric oxide synthase knockout mice. Withdrawal signs, that are related to central nervous system activity were not affected. These findings indicate that neuronal nitric oxide synthase partly mediates the effects of agmatine in morphine physical dependence.

Effect of Agmatine on Electrically and Chemically Induced Seizures in Mice

Abstract: Agmatine, an amine and organic cation, is formed by the decarboxylation of L‐arginine by arginine decarboxylase. It binds to a2‐adrenergic and imidazoline receptors. It blocks N‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptors and inhibits nitric oxide (NO) synthase. Because the importance of NMDA receptors and the NO system are well known in seizure activity, this study was designed to investigate the effect of agmatine on electrically and chemically induced seizures by using maximal electroshock (MES) and pentilentetrazole (PTZ) models in mice. Initial studies established convulsive current 50 (CC50) for MES and effective dose 50 (ED50) for PTZ to produce seizures. Agmatine (20, 40, 80, and 100 mg/kg intraperitoneally) increased the threshold of seizures in MES dose dependently. In PTZ‐induced convulsions, the highest dose of agmatine (100 mg/kg) increased the seizure onset time and decreased percent survival. The percentage of grade V seizures was found to be increased by agmatine doses greater than 20 mg/kg.

Resveratrol exerts anti-inflammatory and neuroprotective effects to prevent memory deficits in rats exposed to chronic unpredictable mild stress.

A number of studies have recently focused on the neuroprotective and anti-inflammatory effects of resveratrol. In prior studies, we described its beneficial effects on scopolamine-induced learning deficits in rats. The aim of this study was to investigate the effects of resveratrol on emotional and spatial cognitive functions, neurotropic factor expression, and plasma levels of proinflammatory cytokines in rats exposed to chronic unpredictable mild stress (CUMS), which is known to induce cognitive deficits. Resveratrol (5 or 20mg/kg) was administered intraperitoneally for 35 days. Rats in the CUMS group and in the 5mg/kg resveratrol+CUMS group performed poorly in tasks designed to assess emotional and spatial learning and memory. The 20mg/kg resveratrol+CUMS group showed improved performance compared to the CUMS group. In addition, the CUMS procedure induced lower expression of brain-derived neurotrophic factor and c-Fos in hippocampal CA1 and CA3 and in the amygdala of stressed rats. These effects were reversed by chronic administration of resveratrol (20mg/kg). In addition, plasma levels of tumor necrosis factor-alpha and interleukin-1 beta were increased by CUMS, but were restored to normal by resveratrol. These results indicate that resveratrol significantly attenuates the deficits in emotional learning and spatial memory seen in chronically stressed rats. These effects may be related to resveratrol-mediated changes in neurotrophin factor expression in hippocampus and in levels of proinflammatory cytokines in circulation.

Effect of agmatine on acute and mononeuropathic pain.

Abstract: Agmatine is a polycationic amine synthesized from L‐arginine by arginine decarboxylase in brain and several tissues. It binds to N‐methyl‐D‐aspartate (NMDA) subtype of glutamatergic, a2‐adrenergic and imidazoline (I) receptors. The present study was designed to investigate effect of agmatine on acute and mononeuropathic pain after chronic constriction injury (CCI). CCI was created by four loose ligations around the right sciatic nerve. The analgesic threshold in rats was evaluated by using thermal hyperalgesia/allodynia (THA) at 4°C. The evaluations were made preoperatively, on postoperative day 15, and after drug administration. Agmatine (10, 20, 40, 80, and 100 mg/kg) was administered intraperitoneally for 5 days beginning on postoperative day 15. Agmatine significantly reduced the hyperalgesia in all doses applied. When agmatine was injected intraperitoneally (10, 20, 40, 80, and 100 mg/kg), it increased the nociceptive threshold in the tail‐immersion test in a dose‐dependent manner, but it had no effect in the hot‐plate test. This effect of agmatine in the tail‐immersion test was blocked by both yohimbine (1 mg/kg) and idazoxan (0.5 mg/kg). When agmatine was administered intracerebroventricularly (25‐200 mg/10 mL), it increased the nociceptive threshold in the hot‐plate but not in the tail‐immersion test. We conclude that agmatine, an endogenous substance derived from arginine, can modulate both acute and chronic pain.

Inhibition of Neuronal Nitric Oxide Synthase and Soluble Guanylate Cyclase Prevents Depression‐Like Behaviour in Rats Exposed to Chronic Unpredictable Mild Stress

Depression is the most common psychiatric disorder. It is well established that endogenous nitric oxide (NO) contributes to chronic unpredictable mild stress (CUMS)‐induced depression. The aim of this study was to investigate brain‐derived neurotropic factor (BDNF) expression in CUMS‐induced depression‐like behaviour in rats. Rats were exposed to CUMS for 5 weeks. A specific and selective nNOS inhibitor, 3‐bromo‐7‐nitroindazole (3‐Br‐7‐NI; 20 mg/kg/day, i.p.), and a specific soluble guanylate cyclase (sGC) inhibitor, 1H‐(1,2,4)oxadiazolo(4,3‐a)quinoxalin‐1‐one (ODQ; 10 mg/kg/day, i.p.), were administered during CUMS. The forced swimming test (FST) was used to assess despair and sucrose consumption, and sucrose preference test was used to assess anhedonia that are the main symptoms of the depression. We show that both 3‐Br‐7‐NI and ODQ administration during CUMS suppressed CUMS‐induced, depression‐like behavioural changes, including reduced sucrose preference, body‐weight and locomotor activity as well as increased immobility time in the FST. CUMS also significantly decreased BDNF protein levels in the CA1 and CA3 regions of the hippocampus, which was reversed by 3‐Br‐7‐NI and ODQ administration. Our findings suggest a novel role for nNOS and sGC‐cGMP in the development of the CUMS model of depression.

Agmatine Inhibits Naloxone‐Induced Contractions in Morphine‐Dependent Guinea Pig Ileum

Abstract: This study investigates the effects of agmatine on naloxone‐precipitated withdrawal syndrome in morphine‐dependent guinea pig ileum. Male guinea pigs that were starved for 24 hours were decapitated after cervical dislocation, and terminal portions of the ilea were removed. Segments were fixed at a resting tension of 1 g in an organ bath containing 1 3 1026 M morphine in Tyrode solution at 378C, which was bubbled with 95% O2 and 5% CO2. Tissues were incubated in morphine containing Tyrode solution for 4 hours before agmatine was added. Naloxone and agmatine had no effect on naive ilea. Naloxone (1 3 1026 M) contracted morphine‐dependent ilea. Agmatine significantly inhibited the contractile response to naloxone in a dose‐dependent manner (1 3 1027 M, 44%; 1 3 1026 M, 80%; 1 3 1025 M, 95%). This effect of agmatine was partly abolished by pretreatment with yohimbine and was almost completely abolished by idazoxan.

Agmatine, a metabolite of L-arginine, reverses scopolamine-induced learning and memory impairment in rats.

Agmatine (l-amino-4-guanidino-butane), a metabolite of L-arginine through the action of arginine decarboxylase, is a novel neurotransmitter. In the present study, effects of agmatine on cognitive functions have been evaluated by using one trial step-down passive avoidance and three panel runway task. Agmatine (20, 40, 80 mg/kg i.p.) was administered either in the presence or absence of a cholinergic antagonist, scopolamine (1 mg/kg i.p.). Scopolamine significantly impaired learning and memory in both passive avoidance and three panel runway test. Agmatine did not affect emotional learning, working and reference memory but significantly improved scopolamine-induced impairment of learning and memory in a dose dependent manner. Our results indicate that agmatine, as an endogenous substance, may have an important role in modulation of learning and memory functions.

Agmatine Reverses Sub-chronic Stress induced Nod-like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats.

The activation of Nod‐like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)‐1β and IL‐18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant‐like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down‐regulated the gene expressions of all stress‐induced NLRP3 inflammasome components (NLRP3, NF‐κB, PYCARD, caspase‐1, IL‐1β and IL‐18) in the hippocampus and prefrontal cortex (PFC) and reduced pro‐inflammatory cytokine levels not only in both brain regions, but also in serum. Stress‐reduced levels of IL‐4 and IL‐10, two major anti‐inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress‐activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant‐like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression.