Is this THE model for neuropathic pain?

Injury leads to cell death caused by executioner enzymes, which also just happen to accelerate maturation of cytokines which produce reactive oxygen species, or free radicals as they are sometimes called. Free radicals are akin chemically to hydrogen peroxide.

The caspases are enzymes which perform programmed cell death. Their failure has been implicated in cancer.

Enzymes which take apart proteins are called “proteases”. Here we discuss one group, the caspace cascade. Proteins are generally long chains of linked amino acids, much like a very twisted necklace or convoluted and folded ribbon. Cysteine and aspartic acid are amino acids. Caspase has a cysteine residue which cleaves proteins at the aspartic acid residue, hence the combo name of caspase. There are a number of caspaces. Caspase-3 and Caspase-9 have been found in the dorsal horn after chronic constriction injury of peripheral nerves.

In a prior article, following the work of Ramana at UTMB, we emphasized that hyperglycemia and TNF alpha cause dysregulated cell growth and cell death (apoptosis).. We also pointed out that INHIBITION of aldose reductase prevents the oxidative stress by reactive oxygen species and avoids the inflammation. Central Pain is thought to represent; namely, neuroinflammation.

Siniscalco and co researchers in italy have reported in Pharmacol Res. 2007 Feb;55(2):158-66, that Caspase-3 and Caspase-9 can be identified in the dorsal horn of the spinal cord three days after ligation of the sciatic nerve. The dorsal horn or rear area of the cord is where hypersensitization of pain nerves occurs. it is thought the process involves conversion of C fiber excitation to the big A fibers, but this is not proven. There may be an intermediary step via interneurons which descend from the brain to the dorsal horn. These may actually recruit A fibers for pain hypersensitization.

Because several enzymes are going about their business of making reactive oxygen species, Caspase is not the only protein destroying enzyme. Several other proteases do similar work.

Siniscalco found “phenyl-N-tert-butylnitrone (PBN), a potent ROS scavenger, reduced the development of thermal hyperalgesia and mechanical allodynia at 1 and 3 days post-CCI [constriction injury], and decreased the mRNA levels of bax, apaf-1, and caspase-9. [bax and apaf-1* are coworkers in the protein destroying process] PBN also reduced apoptotic and active Caspase-3 positive profiles in the superficial laminae (I-III) of the spinal cord. As you know, pain is carried in the superficial layers of the cord.

Now this may be very important. Acids around nerves cause pain. Cell destruction by caspases and acidification by cytokines such as TNF alpha have a downstream affect on the nuclear transcription factor NF Kappa B, which ultimately leads to more acid, more MAPK/ERK, and more pain.

Gearing up the gene factories for transcription takes a little time, so pro-forms are often present in the body permitting final products to be turned out very rapidly. Pro forms of caspase exist.

There is presently no study to tell us what PBN might do to humans that is bad. However, its mechanism of scavenging reactive oxygen species can be duplicated by a number of other chemicals if PBN is unsafe.

We have to wonder if this is how central pain develops:

1) There is neuron injury,
2) The body’s mechanisms to destroy injured cells kicks in,
3)which liberates inflammatory chemicals,
4)which acidify and cause pain.

One wonders whether a potent ROS scavenger in the central nervous system would prevent or even treat central pain.

As is typical, THIS study was about peripheral nerve injury pain, but more and more there are suspected chemical links between pain in peripheral nerve injury and pain in central nerve injury. You may want to reread the prior article which helps you understand how blocking aldose reductase blocks the action of caspase and TNF alpha, and hence reduces ROS.


*apaf-1 is apoptotic protease-activating factor-1