1. Okay it is relevant to the thread. USP have got an adaptogen which could well moderate the cortisol response. If its low they pick it up (preventing crashes), I dunno how effective adaptogens are at capping extremes of cortisol.
As Vat Attack!'s MOA is through 11b-HSD1R mRNA reduction, its cortisol-mitigating properties are well-stated. From the research:
"The presence of coffee extract at a final concentration of 1% almost completely inhibited the 11b-HSD1-dependent oxoreduction of cortisone in cell lysates...Coffee extract similarly inhibited 11b-HSD1 activity in fully differentiated mouse 3T3-L1 adipocytes and in mouse C2C12 myotubes (not shown), two metabolically relevant endogenous cell models."
The fact the assay was taken from fully differentiated cells is important, insofar as suggesting these activities will have a dose-dependent crossover effect
in vivo. The same results in preadipocytes, for example, are not as compelling due to the intricacy of the 11B-H6P-IL6 pathway of glucocorticoid-related pre-differentiated cell metabolism.
3. The specific question is 1-carboxy-2-amino-3-pyrobenzol(3,4 diol) - 1-C, an analogue of L-dopa. What you seem to be saying is that dopa decarboxylase will not turn this into dopamine in the blood stream, but it will do so in the brain. My question is how? If I take an oral dose of Mucana and swallow I get a heap of dopamine in my blood stream - which always worries my kidneys, but makes my body feel great! [massive excess l-dopa will collapse the kidneys].
Without a dopa decarboxylase inhibitor in the blood stream (which can't get into the brain) how's it work?
Various pieces from the literature:
"Compared with standard LD/CD, the 30 g mucuna preparation led to a considerably faster onset of effect (34.6 v 68.5 min; p = 0.021), reflected in shorter latencies to peak L-dopa plasma concentrations. Mean on time was 21.9% (37 min) longer with 30 g mucuna than with LD/CD (p = 0.021); peak L-dopa plasma concentrations were 110% higher and the area under the plasma concentration v time curve (area under curve) was 165.3% larger (p = 0.012)."
Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study. (2004).Katzenschlager R, et al.
"Oral administration of Mucuna pruriens endocarp in the form of HP-200 had a significant effect on dopamine content in the cortex with no significant effect on levodopa, norepinephrine or dopamine, serotonin, and their metabolites- HVA, DOPAC and 5-HIAA in the nigrostriatal tract. The failure of Mucuna pruriens endocarp to significantly affect dopamine metabolism in the striatonigral tract along with its ability to improve Parkinsonian symptoms in the 6-hydorxydopamine animal model and humans may suggest that its antiparkinson effect may be due to components other than levodopa or that it has an levodopa enhancing effect."
Effect of antiparkinson drug HP-200 (Mucuna pruriens) on the central monoaminergic neurotransmitters. (2004). Bala V. Manyam et al.,
"Oral administration of the 5.0g/kg Mucuna pruriens cotyledon powder significantly restored the endogenous levodopa content in the substantia nigra (p < 0.03) and striatum (p < 0.004) while an equivalent amount (by weight present in Mucuna pruriens cotyledon powder) of synthetic levodopa treatment (250 and 500mg/kg) and a lower dose Mucuna pruriens cotyledon powder (2.5g/kg) did not have any effect....In conclusion, the present study shows that Mucuna pruriens cotyledon powder significantly restored the monoaminergic neurotransmitter levels in the substantia nigra and had a better neuroprotective effect compared with levodopa."
Neuroprotective effects of the antiparkinson drug Mucuna pruriens. (2004) Manywam et al.,
"MPCP also significantly restored the levels of dopamine in substantia nigra and norepinephrine in the nigrostriatal tract of parkinsonian animal model (Manyam et al., 2004a). Thus, these studies showed that Mucuna pruriens, in addition to levodopa, had numerous unknown compounds with neuroprotective effects. Although the mechanism of action of Mucuna pruriens in Parkinson’s disease is not fully understood, it appears to have multiple pharmacological actions at more than one site in the central nervous system. One such important mechanism may be by protecting the biologically important molecules such as DNA."
Anti-Parkinson botanical Mucuna pruriens prevents levodopa induced plasmid and genomic DNA damage. (2007) Tharakan B et al.,
So, what do we have here? Primarily, two postulates: a) that MP preparations contain DCIs and/or independent, unknown l-DOPA enhancing adjuvants, and; b) that MP preparations contain antioxidants such as NADP and COQ10 that limit l-DOPA-induced oxidative DNA damage and lipid peroxidation to the dopaminergic neurons, thereby improving dopamine sensitivity. Let us review the plausibility of each postulate.
a)
MP contains DCIs
The most valid reasoning in this regard is the presence and expression of key monamine neurotransmitters in the various regions of the so-called, "cortico-basal ganglia-loop" that is responsible for the synthesis and transmission of dopamine. Let's briefly examine the key players.
The region of the mid-brain known as the "substantia nigra" is the key dopaminergic production center, due to the vast expression of dopaminergic ions in the sector of the brain; as a dopamine hotbed, it is very highly involved in the mediation of risk-reward scenarios, pleasure, learning, memory consolidation [in concert with the hippocampus], motor planning and execution, and mediation of sensory inputs.
The corpus striatum is another key portion of the inner-brain, basal-ganglia structure, and works in tandem with the substantia nigra to coordinate movement, emotion, addiction, and memory in response to monamine inputs. The dopaminergic input from the substantia nigra is the nigrostitial tract, which I will discuss next.
The nigrostriatal tract is the determinant link between substantia nigra and
corpus striatum, and it is a complex of nerve-fiber bundles with high neuronal conductivity. While it expresses dopaminergic neurons, the activation by dopamine in this region is low, as its primary role is transmission.
The prefrontal cortex, as you know, is the region of the front-brain that is highly regulated by monoamine neurotransmitter levels [serotonin, dopamine, norepinephrine] and carries out so-called, "executive functions": the mediation of conflicting thoughts, interpretation of consolidated memories from the hippocampus, consolidating risk-reward sense-datum from the mid-brain and so forth.
Now, the expression of l-DOPA, dopamine, and norepinephrine in these respective regions of the brain in response to PDS therapies is critical to understanding the MOAs at foot here. The massively increased l-DOPA/dopamine peak concentrations, AUC peak lengths, and decreased latency to peak and onset times of MP preparations v., synthetic l-DOPA in the substantia nigra, corpus striatum and PFC alone are not indicative of MP containing DCIs. As stated, this could very well be due to l-DOPA-independent adjuvants or the aforementioned antioxidant properties of MP improving dopamine "reception" in these key portions of the brain. The most encouraging bit of information in this regard is the expression of norepinephrine, and the complete lack of dopamine expression, in the nigrostriatal tract, in response to MP therapy. The massive increases in dopamine in dopamine-expressive tissues and the lack of expression in the distribution pathway suggests that MP is inducing dopamine expression only in necessary tissues. Without a localized DCI content, we would see high dopamine expression in the nigrostriatal tract, which is common with synthetic l-DOPA monotherapy. The second point of contention which leads one to believe this postulate is true, is the complete lack of dyskinesia in MP-therapy. As you know, dyskinesia is a random fluctuation of motor coordination due to l-DOPA therapy, most likely due to the "dopamine flux" hypothesis: the notion that a lack of PDCIs causes random stimulation of dopamine neurons in peripheral tissues; as you also know, this side-effect is several reduced in LD/CD combined therapies. The lack of dyskinesias in combination with low dopamine expression in the nigrostriatal tract very strongly suggests that MP contains native DCIs.
b)
MP preparations have high ORAC values, and thereby prevent l-DOPA-mediated genomic damage.
The primary issues with l-DOPA therapy is the degeneration of the nigrostriatal tract, and the DNA damage and lipid peroxidation to dopaminergic ions in the important brain regions discussed above. The decarboxylation of l-DOPA into dopamine is an oxidative process, and the result is often high levels of DNA and protein content reduction in dopamine ions [seen in animal models], damaging of the lipid membrane [lipid peroxidation] and copper-induced chelation; taken together, these effects can severely limit the long-term tolerability and effective response to l-DOPA therapies. In turn, a postulate for MP's 2-3fold effectiveness over synthetic preparations of l-DOPA is its incredible neuroprotective activities, limiting cell damage and death. The viability of this postulate is seen in the 2004 Manywam study quoted above, where endogenous levels of dopamine, serotonin, and norepinephrine were increased post-administration: the enhancement of monoamine neurostransmitter metabolism and distribution post-administration highly suggests that MP preparations have lasting effects on the brain, not readily explainable by DCI content alone. The post-administrative effects suggest neuroprotection and repair via oxidative stress reduction.
The most likely culprit: a combination of the two.
4. Everyone says Powerfull makes them sleepy and appears to promote deep sleep - great, excellent in fact because I don't know any drug that does - well a few might decrease REM. A break through IMO. If dopamine is produced you'll not feel sleepy anything but. Is this tripping into melatonin? How's this happening. Whats going on?
Dopamine's effect on neural activity is not unilinear - that is, in certain amounts it is neurostimulative, while in lesser amounts it is a neurorelaxant. Given the fact that increased sleep is seen in neither MP or LD/CD therapies [due to the fact that the dopaminergic pathway highly regulates circadian rhythms and REM patterns] the most likely explanation is that the dose of l-DOPA present within PowerFULL is such that a neurorelaxant effect is produced in most. This is obviously dependent on individual dopamine metabolism.
