The prostaglandins are one of the acid related chemicals in injured nerves. Their role in nerve injury in acute situations such as stroke is leading to better understanding of nerve injury in general. (The current dilemma in treating stroke is that COX(2) inhibitors block prostaglandin neurotoxicity but lead to adverse cardiovascular effects.)
Prostaglandins and prostanoids have already been discussed at this site under the article on Eicosanoids, of which prostaglandins are one. Review of that article may illuminate the relevance of this article.
When dealing with prostaglandins, one must be extremely careful to designate WHICH prostanoid chemical is being discussed. There is a cascade of prostaglandins, and even more importantly, of their receptors. We emphasize again that it is the nature of the receptor which determines the result of neuroactive drugs, NOT necessrily the nature of the neuromodulator.
Nowhere is this better illustrated than in the case of the prostaglandins. Arachidonic acid is the first important acid step in the formation of prostaglandins. Cyclo-oxygenase 2 enzyme production (COX-2) is the rate limiting step in the formation of prostaglandins. Of the various prostaglandins, prostaglandin E is thought to be most intimately related to neuropathic pain. The receptor for Prostaglandin E (known as EP1 (or E Prostanoid receptor 1) has downstream effects which DAMAGE nerve. These products are neurotoxic and blocking their action is hoped to prevent the neurotoxic effects of ischemia (oxygen deprival). Ischemic or oxygen deprival damage is seen both in stroke and traumatic spinal cord injury.
In cord injury this can result either from swelling which compresses the arterial supply to the cord, or much more commonly by compression of the thinner walled veins which drain the cord, preventing further blood from entering that area of the cord. This has been called the “watershed effect” or cord tourniquet. In this situation, blood can get into the cord, but swelling or pressure by surrounding bone prevents exit via the veins, so the whole circulation backs up or ceases. The compression releases certain chemicals which cause expanding nerve damage. This expanded chemical damage may be MORE IMPORTANT in long term cord injury than the actual focus of cord trauma. A similar situation occurs in clots to the lung. The clot itself is usually small, but it releases vasoactive amines which cause constriction of blood vessels in a wide area, making the area of lung damage perhaps ten or twenty times the size of the initial clot. This then is what makes the clot fatal. A similar mechanism is thought to be relevant in cord injury, although the actual mechanisms are probably different, since the chemicals produced are different.
The ischemic injury to nerve may be partially preventable by either pharmacologic blockade or inhibition of the EP1 gene. See Kawano T, et al Nat Methods. 2006 Jan 6
By comparison, the E4 receptor has downstream products which PROTECT against nerve damage. See eg. Ahmad et al in Brain Res Dec 2005 1066 (1-2)71-7 have shown at Johns Hopkins that EP4 is NEUROPROTECTIVE. EP1 interferes with the Na+-Ca2++ exchange, which leads to BUILDUP of Ca2+, which activates both pain production in the genetic protein factories AND facilitates activity of pain exciters already manufactured. It is important to get rid of excess Ca2+, which can set off a cascade of pain exciters, (as discussed in other articles at this site). Blocking E4 is harmful. In a very nice piece of work, Ahmad and coworkers have shown that pretreatment with ONO-AE1-329 in fractional O.1 nanomolar concentrations (this compound being an antagonist of blocker of EP4) facilitates nerve injury. Frequently in chemistry, anything active at nanomolar concentrations, which is very, very dilute is considered to be THE or at least A main chemical activator at that site. Thus, EP4 is an important preventer of neurotoxicity, presumably via the prevention of the buildup of excess calcium. The calcium channels are important in the activation of pain neurons. The TRPV-1 channel is Ca2++ dependent.
Once again, an important avenue for pain therapy has been suggested. We hope the NIH has sufficient funding to pursue at least some of these avenues. This particular article may be of more benefit to those in the future who suffer injuries that lead to central pain, ie. by providing treatment within a few hours after injury, the development of central pain may be avoided. Nevertheless, the knowledge of how the acid forming and acid relating chemicals behave in pain should also eventually lead to better methods of treatment for existing central pain.
