This article is really good, and the authors discuss the discrepancies in past research on the antagonism (or negative allosteric modulation) of NMDA receptor (NMDA-R) activation by agmatine [Gibson et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12363406)]. I've seen authors of some articles make statements that agmatine doesn't bind to "the polyamine binding site" on NMDA receptors, but Gibson et al. (2002) point out the fact that a minimum of three polyamine binding sites are known to exist on different NMDA-R subunits. Gibson et al. (2002) found that agmatine displaced spermidine from binding to NMDA-Rs and antagonized the spermidine-mediated positive allosteric activation of MK-801-induced NMDA-R activation. I'm going to refer to this effect of spermidine as positive allosteric modulation, even though Gibson et al. (2002) discuss the inchoate understanding of the mechanism by which spermidine potentiates ligand-induced NMDA-R activation. The research Gibson et al. (2002) discuss, in relation to the precise mechanisms, is just crazy, and so I have to use *some* term to refer to the effect. But the research of Gibson et al. (2002) just shows that spermidine, a polyamine that can be produced from putrescine (and, by extension, agmatine and its precursor, arginine), potentiated the excitatory effects of NMDA-R activation (which would occur in vivo in response to the binding of glutamate, rather than MK-801). Agmatine produced essentially "mild" NMDA-R antagonism (by acting as an antagonist of the binding of spermidine to one of the polyamine binding sites on NMDA-Rs or to one of the "crazy-mystery-non-polyamine-binding-sites" that binds polyamines) at remarkably low concentrations (5 uM and above, with a Ki value for inhibition of spermidine-induced MK-801 potentiation of 14.8 uM). The Ki value is lower than the Ki value for irreversible inhibition of nNOS activity by agmatine aldehyde (29 uM). Gibson et al. (2002) note that researchers may have been looking for direct antagonism of NMDA-R ligands in past assays, and those different ligand-receptor binding assays produced a bizarre range of Ki values for the antagonism or negative modulation of NMDA-Rs by agmatine (12 uM to 1000 uM, or 1 mM).
The results of Gibson et al. (2002) suggest, in my opinion, that agmatine, derived from exogenous agmatine or arginine, could produce direct antagonistic effects (i.e. not mediated by inhibition of nNOS activity) on NMDA-R activation by glutamate, and those effects could help to account for the antidepressant (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=agmatine+antidepressant) and antihyperalgesic (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=agmatine+pain)/cognition-enhancing (http://scholar.google.com/scholar?q=agmatine+cognitive&hl=en&lr=) effects of agmatine in animal models. The newer NMDA-R antagonists, such as memantine, have been tested for the antidepressant effects that they can produce, but my sense is that they're more useful as strategies to augment or restore the effectiveness of other treatments. The authors of many articles discuss the fact that mild NMDA-R antagonism can sometimes enhance cognitive functioning and produce antidepressant effects, but more potent inhibition of NMDA-R activation can easily impair cognition and worsen depression, etc. This article by Gibson et al. (2002) helps explain the complex and conflicting dose-response relationships that researchers have found for arginine in animal models of depression or chronic stress or pain (http://hardcorephysiologyfun.blogspot.com/2009/03/arginine-agmatine-and-nitric-oxide-in.html), given that arginine is a precursor of glutamate (and, by extension, GABA), agmatine, putrescine, spermidine, and spermine. Each of those compounds can produce different effects on NMDA-R activation. I tend to think that lower doses of arginine would produce lower levels of agmatine and produce mainly inhibitory effects at NMDA-Rs, but, under conditions of inflammation or chronic stress, the excitatory effects of spermidine or spermine (or the supposed capacity of agmatine to induce glutamate release at high concentrations) might begin to predominate. The articles on polyamines tend to be really confusing for everyone, including the researchers writing them, seemingly. It's really a strange area of research, and polyamine metabolism is very dynamic and context-specific. There's a whole area of research on the effects of MAO inhibitors on polyamine metabolism, given that MAO inhibitors can inhibit the recycling of polyamines by producing inhibition of diamine oxidase, evidently (and the N-acetylpolyamines are substrates for MAO-B). But there's the initial effect and then there's the long-term response to the accumulation of N-acetylspermine and N-acetylspermidine, etc., etc. I don't need to say that MAO-B inhibitors have been used for cognitive enhancement and Parkinson's disease and depression and everything else under the sun, and some of those effects are thought to be due to the changes, produced by MAO-B inhibition, in the polyamine-dependent modulation of glutamatergic transmission [Youdim et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8302308); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22MAO-B%22+polyamine)].
No comments:
Post a Comment