Abstract
Agmatine (decarboxylated arginine) exerts numerous central nervous system (CNS) dependent pharmacological effects and may potentially modulate altered neurochemistry seen in neurological disorders. In preclinical studies, injection has been the predominant route of systemic administration. However, a significant translational step would be the use of oral agmatine treatment at therapeutic doses and better understanding of L-arginine metabolic profiles in the CNS post-treatment. The present study systematically investigated the tolerability, safety and brain-plasma neurochemistry following daily oral agmatine sulfate treatment (via gavage) to wild-type (WT) mice up to 900 mg/kg for one week (Experiment 1) or WT and APPswe/PS1ΔE9 transgenic (Tg) mice at 300 mg/kg for fifteen weeks (Experiment 2). Agmatine treatment in both experiments was well tolerated with no marked behavioural impairments, and gross necropsy and organ histology revealed no pathological alterations after 15-week dosing. Moreover, oral treatment increased agmatine levels in the hippocampus and plasma of WT mice (Experiment 1), and in 6 brain regions examined (but not plasma) of WT and Tg mice (Experiment 2), at 30 minutes or 24 hours post-treatment respectively. This study provides fundamental pre-clinical evidence that daily oral delivery of agmatine sulfate to both WT and Tg mice is safe and well tolerated. Exogenous agmatine passes through the blood brain barrier and accumulates in the brain to a greater extent in Tg mice. Furthermore exogenous agmatine has differential actions in the brain and periphery, and its effect on brain putrescine appears to be dependent on the time post-treatment.
Highlights
Agmatine is widely and unevenly distributed in the mammalian brain as a neuromodulator[1,2], and may directly participate in learning and memory processes[3,4,5,6]
Oral agmatine has been shown to be more potent in behavioural models of stress and depression than conventional anti-depressants, and potentiates their effects when co-administered at sub-effective doses via its interactions with N-methyl-D-aspartate (NMDA) receptors and the arginine-nitric oxide (NO) pathway[13,14,15,16,17], illustrating its wide neuromodulatory mechanisms of action
We have previously reported that intraperitoneal (IP) injection of agmatine protects against behavioural deficits in the injectable amyloid-beta (Aβ25–35) model of Alzheimer’s disease (AD)[23], and that L-arginine metabolism in the brain is altered following the intracerebroventricular infusion of pre-aggregated Aβ25–35 and in APPswe/PS1ΔE9 mice with chronic amyloid accumulation and in patients with AD24–27
Summary
Agmatine (decarboxylated arginine) is widely and unevenly distributed in the mammalian brain as a neuromodulator[1,2], and may directly participate in learning and memory processes[3,4,5,6]. It is of interest to note that APPswe/PS1ΔE9 mice at 13 (but not 7) months of age display behavioural deficits in spatial water maze tasks and altered arginine metabolic profiles in the brain, such as reduced agmatine levels in the hippocampus and increased amino acid and polyamine levels in multiple regions, demonstrating the parallel development of altered brain arginine metabolism and behavioural deficits in this mouse model of AD26 These preclinical studies complement findings in post-mortem human brain tissue from AD patients[27], implicating altered arginine metabolism in AD neuropathogenesis and cognitive impairment. The present study was designed to determine the tolerability, safety and brain and plasma arginine metabolic profiles in wild-type and APPswe/PS1ΔE9 (Tg) mice following daily agmatine treatment by oral gavage. The effects of exogenous agmatine on arginine metabolic profiles in the brain and blood were determined, by measuring the levels of L-arginine and its downstream metabolites (L-citrulline, L-ornithine, glutamate, glutamine, γ-aminobutyric acid (GABA), putrescine, spermidine and
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