Neuropharmacokinetic and Dynamic Studies of Agmatine (Decarboxylated Arginine)

Abstract

Agmatine has been previously proposed to represent a novel neurotransmitter. One of the criteria required to test that hypothesis is that the exogenously administered chemical produces pharmacological effects similar to the physiological effects of the putative neurotransmitter. Since agmatine was first identified in brain, approximately sixty studies of the in vivo effects of exogenously administered agmatine have been reported. Despite the assertion that agmatine functions as a neuromodulator/neurotransmitter, the vast majority of experiments have administered agmatine through systemic (rather than central) routes of administration. Systemic delivery of agmatine for studies of centrally mediated phenomenon (e.g., pain, spinal cord injury, cardiovascular responses) relies on the presumption that agmatine (a polar compound) gains appreciable access to the CNS. The mechanism by which agmatine crosses the blood-brain barrier is not well understood. A number of studies have examined the in vivo effects of agmatine following central administration (e.g., intracerebroventricular and intrathecal). This paper summarizes and provides a comparison between the systemic versus central routes of administration for delivery of agmatine in experimental subjects.

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

“…Findings from the central effects of agmatine on functional/behavioral parameters in vivo have not been consistent and vary with the route of administration and doses used (see review [18]). The major unanswered issues are the penetration of agmatine into brain and its biological half-life after peripheral injection.…”

“…Since all these conditions involve higher glutamate release and excessive NMDA receptor activation, agmatine could be acting by reducing glutamatergic transmission. While the blockade of NMDA receptors by agmatine have been reported in neuronal cells [30], effects on in vivo glutamate release have not been investigated.Findings from the central effects of agmatine on functional/behavioral parameters in vivo have not been consistent and vary with the route of administration and doses used (see review [18]). The major unanswered issues are the penetration of agmatine into brain and its biological half-life after peripheral injection.…”

Pharmacodynamic and Pharmacokinetic Studies of Agmatine after Spinal Administration in the Mouse

“…Furthermore, an agmatinergic blood-brain barrier transport system has yet to be definitively characterized. In support of the proposal that agmatine exerts its effects through a central site of action, a number of studies have applied agmatine through central routes of administration, including intracerebroventricular (for a complete list, see Nguyen et al, 2003) and intrathecal (Fairbanks and Wilcox, 1997;Horvath et al, 1999;Fairbanks et al, 2000;Hou et al, 2003). Although these pharmacological studies provide proof-of-principle for agmatinergic modulation of many centrally mediated plasticity-requiring phenomena, minimal information is available regarding the pharmacokinetics of agmatine in the serum or the CNS.…”

“…Although these pharmacological studies provide proof-of-principle for agmatinergic modulation of many centrally mediated plasticity-requiring phenomena, minimal information is available regarding the pharmacokinetics of agmatine in the serum or the CNS. Two preliminary studies report mouse spinal cord (Nguyen et al, 2003) and brain (Piletz et al, 2003) recovery of agmatine after systemic administration of agmatine. Piletz et al (2003) also reported a preclinical study of CSF agmatine recovery after systemic administration (30 mg/kg i.v.)…”

“…The doses, species, dependent measures, and outcomes from greater than 50 such in vivo studies have recently been reviewed (Nguyen et al, 2003). The effective systemic agmatine doses that elicit therapeutic results in these animal models exhibit a wide range (10 -400 mg/kg); 100 mg/kg has been the most frequently applied effective systemic dose of agmatine.…”