A more effective inhibitor of NF-kB might also be more effective in the prevention of migraine.
A number of different medications and medication classes have been found to be at least somewhat effective in the prevention of acute migraine.
However, because upstream events triggering acute migraine are poorly understood, identification of these agents has largely been the result of serendipitous observations combined with presumed class effects (e.g. anticonvulsants).
A better understanding of migraine would allow for a more rational approach to the discovery and development of medications to prevent migraine attacks.
On investigation, a number of existing migraine preventatives are found to inhibit NF-kB.
It is proposed that chronic over-activation of NF-kappaB (though some as yet unknown mechanism) predisposes to acute migraine attacks (headaches, et al) and that effective migraine prevention can (best) be achieved through the use of NF-kappaB inhibitors. Of particular value might be those natural NF-kappaB inhibitors which have been proven safe by extensive human use over the course of several millenia.
Banjo is designed to be an effective inhibitor of NF-kappaB.
The proposed ‘stream’ of events in migraine is as follows:
NF-kappaB activation => Nitric Oxide (NO) production => CGRP production & release => Migraine
Based on that proposed series of events in migraine, an inhibitor of NF-kappaB should be effective in preventing or lessening acute attacks.
Indeed, as will be seen below, several pharmaceuticals known to be effective in the prevention of migraine appear to act, at least in part, by inhibiting NF-kappaB activation.
The fact that each of the discussed pharmaceuticals has been shown to inhibit NF-kappaB is remarkable – especially given that these drugs are of entirely different types (e.g. antidepressant, anti-convulsant, calcium channel blocker.) The ‘unexpected’ overlap in mechanism strongly suggests that said ‘overlap’ (NF-kB inhibition) may in fact define their means of efficacy in the prevention of migraine. If nothing else, the observed mechanism provides evidence in support of:
- The proposed mechanism of migraine.
- The proposed method of prevention – by inhibition of NF-kappaB.
- The general safety of NF-kappaB inhibition.
However, if NF-kB inhibition is in fact the key to effective migraine prevention, then the use of agents not designed for that purpose is likely to be inefficient (each drug is designed for other purposes, and as such migraine prevention is essentially a side effect, albeit a beneficial one.) Such agents are likely to be only weak inhibitors of NF-kB, but may have significant (other) side effects that are harmful. In fact even those effects not generally considered ‘side effects’ would be so for the migraine patient (unless they have need of an anti-depressant, and anti-convulsant or a calcium channel blocker.)
Banjo combines a number of natural plant extracts – each a known inhibitor of NF-kappaB and each with at least a thousand year history of safe use – and delivers those extracts in a form designed to ensure maximum bio-availability.
Because Banjo is specifically designed to inhibit NF-kappaB, it may be substantially more effective than those agents inadvertently discovered to reduce migraine, and may have substantially fewer and far less serious side effects.
Many existing migraine preventatives inhibit NF-kappaB.
Anti-depressants, especially the tricyclic anti-depressants, have been shown to inhibit NF-kB.
The anti-convulsant valproic acid (valproate) has been shown to inhibit NF-kB.
The calcium channel blocker verapamil has been shown to inhibit NF-kB.
Tricyclic anti-depressants inhibit NF-kB.
In the study briefly summarized below, several tricyclic antidepressants were shown to exert general anti-inflammatory effects in glial cells. Nitric oxide (NO) levels were reduced, tumor necrosis factor (TNF) levels were reduced, and inducible nitric oxide synthase (iNOS) expression was reduced, as was that of interleukin-1 (IL-1).
NO, iNOS, TNF, and IL-1 have all been proposed as important elements in migraine.
NO, iNOS, TNF, and IL-1 are all under the control of NF-kB.
Not surprising in light of the above, expression of NF-kB was found to be diminished by the tricyclic antidepressants clomipramine and imipramine.
Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants.
Summary of the abstract
Neuronal inflammation with glial activation plays an important role in a number of degenerative conditions affecting the central nervous system. Alzheimer’s disease, Parkinson’s disease, and HIV dementia all relate to neuronal inflammation with glial activation. Activated glial cells are believed to be most important because they secrete, or can, various pro-inflammatory cytokines.
The anti-inflammatory effects of tricyclic antidepressants have been investigated.
- Clomipramine and imipramine were found to reduce substantially the production of nitric oxide and TNF generated by microglia.
- Those two drugs also reduced inducible nitric oxide synthase expression, along with that of pro-inflammatory cytokines such as IL-1 and TNF.
- Significantly, clomipramine and imipramine both were found to be effective inhibitors of NF-kB, which is their presumed mechanism of action in reducing the production of pro-inflammatory cytokines.
Valproate, an anti-convulsant, inhibits NF-kB.
Valpoic acid is used in the treatment of seizure disorders and bipolar disorders, as well as in the prevention of migraine. Its mechanism of action is not known.
In the study briefly summarized below, the effects of long-term valproate administration were investigated.
Valproate was found to decrease the expression of COX-2, presumably through the observed inhibition of NF-kB. As commented by the authors, this inhibition of NF-kB is likely to inhibit other NF-kB regulated genes. That is, NF-kB inhibition by valproate could be expected to decrease TNF, IL-1, IL-6, NO and iNOS, any or all of which might be important in the initiation and progression of migraine attacks.
One obvious implication of this study is that valproate may be effective in the prevention of migraine, at least in part, because it inhibits NF-kB.
Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-kappaB DNA binding activity and COX-2 mRNA.
Summary of the abstract
Valproic acid (valproate) is used to treat bipolar disorder, but its mechanism of action is not clear.
The effect of chronic valproate administration on transcription factors was examined. The finding was of down-regulation of the COX-2 gene and of NF-kB. Valproic acid was found to significantly reduce NF-kB activity.
It is concluded that valproate down-regulates NF-kB activity, and that the effect on NF-kB explains the decrease in COX-2. The decrease in NF-kB activity by chronic valproate administration would be expected to also affect other NF-kB regulated genes, including those responsible for the production of other cytokines.
Verapamil, a calcium channel blocker, inhibits NF-kB.
While the study briefly summarized below looked at the effect of verapamil in the liver, it is reasonable to suspect that verapamil may exert the same effect at other locations, especially as it is known to cross the blood-brain barrier and to act on the central nervous system.
Verapamil was found to inhibit NF-kB activation, most likely leading to the observed decrease in TNF and IL-6.
Verapamil modulates LPS-induced cytokine production via inhibition of NF-kappa B activation in the liver.
Summary of the abstract
This study investigated the effect of verapamil on LPS-induced cytokines TNF, IL-6, and IL-10, each in relation to NF-kB. LPS was found sufficient to stimulate TNF, IL-6 and IL-10 production, probably through its effect in activating NF-kB.
Pretreatment with verapamil reduced the ability of LPS to stimulate pro-inflammatory cytokine release (TNF and IL-6) but increased the production of the anti-inflammatory cytokine IL-10. it also inhibited NF-kB activation.
Verapamil therefore seems able to reduce inflammation by means of NF-kB inhibition, which subsequently alters the cytokine profile in a manner which inhibits the ongoing inflammatory response.