The discovery of a link between hyperglycemia and inflammation was unexpected, but it appears to be extremely important.
To abbreviate some of the prior articles here, TNF alpha leads to BDNF, which leads to blockade of GABA B, an important suppressor of pain.
Having said that, we focus now on TNF alpha, or tumor necrosis factor alpha. TNF alpha, despite its name, is mainly a transcriptional factor,w hich leads to production of cytokines, which are integral parts of the inflammatory process. Chronic neuroinflammation of cells in the central nervous system IS central pain. The earliest parts of the cascade actually occur in the glia (microglia) which surround neurons. They manufacture and release the growth factors which are designed to clear away old cells and produce new ones. The clearing away of old cells involves acidic compounds and the generation of reactive oxygen species (ROS) in cells which store them in order to act as part of the immune system.
In an earlier article we referred to work by Ramana, whose primary interest is in diabetes. He is attempting to determine exactly how hyperglycemia can cause inflammation and the damage secondary to diabetes. Many diabetics have a “mild” burning on the skin and/or loss of sensation, which is called “diabetic neuropathy”. The burning of diabetic neuropathy is nothing close to the horrors of severe central pain, but it is pain, and the patients dislike it intensely. This is in fact, the biggest market for drugs for nerve injury pain. We can participate in the research being done on diabetic neuropathy, a PNI nerve pain.
It would appear that high glucose levels somehow encourage cell growth and so it is not such a reach to conceive how hyperglycemia could become linked to growth factors (nerve and otherwise), and in fact we now know this is the case. What is odd is that glucose seems to specifically be involved in EXCESS growth of, and inflammation of smooth muscle cells in the walls of blood vessels, but the mechanism is similar and possibly almost identical to the way growth and inflammation are linked in nerve cells.
Ramana has now completed a new series of investigations on aldose reductase and TNF alpha. One possibility of course is that ANY sugar would do the same thing. However, Ramana found that ONLY glucose, ie. hyperglycemia raised the TNF alpha. Neither mannitol, nor 3-methyl glucose were capable of increasing the level of cytokines (proinflammatory molecules). Ramana then blocked the elevated TNF alpha with Actinomycin D and cycloheximide. That he was able to do so indicated that high TNF alpha levels are the result of some transcriptional factor acting on the TNF alpha gene.
TNF-alpha attenuates NF-kappaB activation. NF Kappa B is another transcriptional factor, so there is competition, more properly dysfunction, going on between transcription factors, in pain.
Transcription factors are like switches to turn genes on and off. Obviously, growth factors and transcription factors are directly linked. Transcription means that a gene or group of genes will begin to make a product, or series of amino acids, which will become part of a peptide, which may then congregate to make a protein. Transcription means to make the genes start “writing” or copying their genetic code into amino acid sequences.
As you recall from the prior article, aldose reductase and TNF alpha are “partners in crime”. Ramana found, not surprisingly, that the TNF alpha elevation could be blocked by administration of an aldose reductase inhibitor. This is interesting because blockers of aldose reductase (AR) are well known and include -sorbinil and tolrestate and as well as antisense AR mRNA.
Antibodies to TNF alpha also worked but antibodies to normal bodily chemicals often raiae problems, since they have some normal function, particularly in initiating cell death in cells which ought to die (apoptosis). TNF alpha antibodies would therefore seem not to hold much therapeutic promise, but then you never know.
Ramana went so far as to declare, “These data indicate that AR is required for high glucose-induced TNF-alpha synthesis and release.”
More puzzling was the finding that protein kinase C (delta variety) if blocked with Rottlerin (blocks PKC delta), specifically inhibited high glucose induced TNF alpha release; however, inhibition of PKC-beta2 did NOT block the high glucose effects.
We seems a little clearer now on which PKC we need to worry about (delta) and maybe are a little closer to some sort of therapy. Ramana is NOT a pain researcher. However, he works at UTMB, where our old friends associated with Wm Willis Jr practice, such as Claire Hulsebosch. We are certain Ramana’s work will be interesting to them and if some sort of cross benefit to pain research is possible, there are good people in pain to incorporate Ramana’s research.
Hope grows daily for greater understanding of central pain. The experts are not just casting around with nothing much to go on. They are doing VERy elegant and specific work. If ONLY the NIH would allocate more money, we might be very close to an effective treatment.
In the interest of mankind, we need a thousand Ramana’s to work the pathways of neuroinflammation through, and then, to block them.