I would be interested to see an excert showing that hyperforin is a sigma-1 antagonist. I believe that this maybe through indirect means, as i understand hyperforin to competitively inhibt 6-dopamine hydroxilase which would increase sigma-2 agonism, which competitively inhibits sigma-1. This type of inhibition may not be of concern or could be balanced out.
hyperforin is an interesting compound for most
Hyperforin and hypericin inhibit binding to sigma-1, in different concentrations, and apparently the IC50 values are at such high concentrations (both hypericin and hyperforin have IC50 values in the 1-10 micromolar range, which is impossible to reach except by abusive ingestion). This effect, unless I'm misinterpreting the results, is not a direct action on sigma 1, like you stated, although I have not read of any effects on sigma 2, would interested in reading more about this. However, SJW has very complex in vivo action and I have read very much in a short time, and cannot compartmentalize its effects neatly. One particularly confusing bit is that SJW antidpressant effects are abolished by sigma1 antagonists, which suggests to me that hypericum perforatum is actually an indirect sigma1 agonist in vivo, but I guess then I do not understand the difference between a substance that antagonizes by reducing ligand binding at the receptor site, and one that binds to the ligand site, directly blocking any further signal mediation, does that sound sane? Anyways, it seems like the action prevents binding, but does not increase dissasociation, so what is the clinical implication of this?
http://www.sciencedi...2a&searchtype=a"Sigma receptors
In rats rimcazole (a sigma1 receptor antagonist) counteracts the antidepressant effects of the SJW extract, evaluated with the “forced swimming test” (Panocka et al., 2000). However, binding to sigma receptors was not significantly inhibited by two SJW extracts, or by hyperforin, hyperforin analogues or biapigenin (Gobbi et al., 2001). Hypericin and pseudohypericin inhibited ligand binding to sigma receptors with IC50 values of 1.4 μg/mL (Raffa, 1998), although this inhibitory effect of hypericin is partly light-dependent (Gobbi et al., 2001). The hypericin concentration required for these interactions appears to be much higher than the nanomolar plasma concentrations reached in humans after pharmacologically effective doses of SJW extracts (Staffeldt et al., 1994).
In spite of the lack of affinity in vitro, it was recently reported that pre-treatment of rats with pharmacologically active doses of SJW extracts or hyperforin trimethoxybenzoate reduced ligand binding to sigma receptors, measured ex vivo (Pirona et al., 2002 and Cervo et al., 2004). The antidepressant-like activity of hyperforin trimethoxybenzoate was completely antagonized by pre-treating rats with BD 1047, a selective sigma1 antagonist (Cervo et al., 2004). These results, together with the observation that agonists at sigma1 receptors are active in antidepressant models in rats (Matsuno et al., 1996), suggest that the SJW extract's antidepressant effect might be mediated by an indirect action on sigma receptors (i.e. the formation of an un identified metabolite or the release of an endogenous ligand)."
Btw what does that mean, that it is partially light-dependent? That sounds like it means that the antagonism is an indirect effect, mediated by excitation (induced by light).
Then check out this study, on h. trimethoxybenzoate:
http://www.sciencedi...54&searchtype=aAffinity table (IDN 5491 is the trimethoxybenzoate)
SERT DAT BDZ-R SIGMA-R
Vehicle (CMC 1.6%) 100±6 (n=11) 100±8 (n=11) 100±9 (n=11) 100±8 (n=11)
Hypericum extract 111±10 (n=11) 115±8 (n=11) 102±7 (n=11) 66±7**(n=11)
Vehicle (Tween 80 4%) 100±5 (n=6) 100±13 (n=6) 100±4 (n=6) 100±5 (n=29)
IDN 5491 101±9 (n=6) 105±12 (n=6) 105±3 (n=6) 86±4* (n=30)
"
In vivo treatment with H. perforatum L. extract and IDN 5491 did not affect the binding of [3H]citalopram, [3H]WIN-35,428, and [3H]flumazenil to 5-HT transporters, DA transporters and BDZ receptors (Table 4).
[3H]DTG binding to cortical sigma receptors was significantly lower in the brains of rats treated with the extract and IDN 5491 (by 34% and 14%, respectively). Importantly, the decrease of “ex-vivo” [3H]DTG binding was no longer apparent when the samples were treated to favour the dissociation of a previously bound ligand (see Materials and methods). In these conditions, always assayed in parallel, [3H]DTG binding in the brains of extract- or IDN 5491-treated rats was respectively 98±10% (n=5) and 100±5% (n=30) of the corresponding vehicle-treated rats. These data exclude the likelihood of treatment-induced down-regulation of sigma receptors."
Edited by deletethisaccount, 14 October 2010 - 10:27 PM.