Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Abstract

Nitric oxide and excitatory amino acids contribute to hypoxic-ischemic brain injury. Agmatine, an endogenous neurotransmitter or neuromodulator, is an inhibitor of nitric oxide synthase and an antagonist of N-methyl-D-aspartate receptors. Does agmatine reduce brain injury in the rat pup hypoxicischemic model? Seven-day old rat pups had right carotid arteries ligated followed by 2.5 h of hypoxia (8% oxygen). Agmatine or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily thereafter for 3 d. Brain damage was evaluated by weight deficit of the right hemisphere at 22 d after hypoxia by a blinded observer. Agmatine treatments significantly reduced weight loss in the right hemisphere from Ϫ30.5 Ϯ 3.6% in vehicle-treated pups (n ϭ 22) to Ϫ15.6 Ϯ 4.4% in the group treated with 50 mg/kg (n ϭ 18, p Ͻ 0.05) and to Ϫ15.0 Ϯ 3.7% in the group treated with 100 mg/kg (n ϭ 18, p Ͻ 0.05), but the group treated with 150 mg/kg showed no reduction. Other pups received agmatine or vehicle at 5 min after reoxygenation, and brain biochemistry was assessed. Levels of endogenous brain agmatine rose 2-to 3-fold owing to hypoxic-ischemic (3 h), whereas pups treated with agmatine (100 mg/kg) showed 50-fold higher brain agmatine levels (3 h). Agmatine (100 mg/kg) blocked a hypoxia-induced increase in brain nitric oxide metabolites at 6 h (vehicle-treated, ϩ60.2 Ϯ 15.2%; agmatine-treated, ϩ4.2 Ϯ 8.4%; p Ͻ 0.05). Agmatine thus reduces brain injury in the neonatal rat hypoxic-ischemic model, probably by blunting the rise in nitric oxide metabolites normally seen after hypoxia. [11][12][13][14], agmatine is a 4-carbon elongated relative of the synthetic neuroprotective agent, aminoguanidine (12). Agmatine has long been known to exist in plants, bacteria, insects, and invertebrates (13). Only recently was it realized that agmatine is synthesized in mammalian brain (11), where agmatine acts as both a neurotransmitter and neuromodulator (12, 14 -18). From distribution studies of arginine decarboxylase in primary cell cultures, agmatine is thought to be synthesized predominantly by astroglia cells, then released and taken up into neurons by active transport (12,14). Agmatine possesses modest affinities for various receptors, including as an inhibitor of the NMDA subclass of glutamate receptors (19 -21). Agmatine also inhibits all isoforms of NOS (22-25), with highest reported activity (Ki ϭ 29 M) as an irreversible inactivator of neuronal NOS (25). Treatments with agmatine are neuroprotective in vitro (21,22), as well as in gerbil ischemic brain injury, adult rat ischemic brain injury (26), and adult rat spinal cord injury (16,27,28). The effects of agmatine in neonatal HI brain injury have not previously been tested, nor has correlation been studied between the neuroprotective properties of agmatine and NO production in the brain. HI brain injury is a serious cause of death and disability in human newborns. The developmental stage of the brain of the 7-d-old rat pup resembles that of newborn humans (29). As descr...

Agmatine reduces balance deficits in a rat model of third trimester binge-like ethanol exposure

“…Exogenous administration of agmatine attenuates glutamate-induced neurotoxicity in cell cultures of rat cerebellum (Olmos et al, 1999), hippocampus (Wang et al, 2006), and cortex . Additionally, agmatine reduces infarct and loss of cerebellar neurons following in vivo focal or global ischemia (Gilad et al, 1996;Kim et al, 2004) and brain weight loss following ischemia in neonates (Feng et al, 2002). Behaviorally, agmatine dose-dependently attenuates behaviors associated with ethanol withdrawal, including stereotypy, tremor, and wet-dog shakes, without affecting motor coordination in nondependent animals (Uzbay et al, 2000).…”

Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: A potential mechanism for the anticonvulsive effects

“…Moreover, agmatine inhibits the release of vasopressin in neurohypophysis [29] and norepinephrine from perivascular nerve terminals [9], suggesting a pre-synaptic action regulating the release of neuro-transmitters. Functional effects such as protection against ischemic neuronal injury [4,6,8,12,19,32,33] In initial experiments, we administered agmatine to rats (50 mg/kg, i.p.) and measured the levels of agmatine in cortex and hippocampus at different time points.…”

“…Agmatine has been shown to exert several actions that are related to its ability to inhibit NMDA receptors [4,19,30]. The protective effects of agmatine on excitotoxic injury in vitro and ischemic injury in vivo are well documented [4,6,11,12,32,33]. While the centrally administered agmatine potentiates morphine analgesia, peripheral agmatine reduces morphine tolerance and withdrawal symptoms [2,13,14,31].…”

Suppressive effect of electromagnetic field on analgesic activity of tramadol in rats

“…Agmatine also acts as an agonist at imidazoline receptors, inhibits nitric oxide synthase and interacts with alpha-2-adrenoceptors (Berkels et al 2004). Feng et al (2002) have suggested that agmatine reduces brain injury in neonatal rats exposed to hypoxia and ischemia as a result of its inhibitory effect on nitric oxide synthase. Because of its multiple interactions with receptors and enzymes agmatine represents a neurotransmitter that could increase in concentration during conditions such as cardiac arrest to prevent a variety of injurious brain activities.…”