Table of Contents

October 2004; 4 (5)

Speaking of Pharmacology



  • Mechanisms that underlie persistent (i.e., chronic) pain are different from those that underlie acute pain. Recent findings seem to indicate that superoxide (SO) is a mediator of persistent pain that accompanies inflammation. Other reactive oxygen species (ROS) might also participate in persistent pain. Wang and colleagues, in the Journal of Pharmacology and Experimental Therapeutics, found that SO contributes to hyperalgesic responses that can be ameliorated by the addition of a compound that mimics the enzymatic function of superoxide dismutase (SOD). SO can also combine with nitric oxide to form peroxynitrite, which inhibits the catalytic function of SOD. Expanded research on ROS as pain mediators should lead to better drugs for the management of chronic pain and help further elucidate the different mechanisms involved in chronic vs acute pain.

  • The advent of clinically useful immunosuppressive drugs that block T-cell activation has given hope to many with autoimmune disorders or organ transplants. These drugs, however, are not without potentially life-threatening side effects, including kidney disease and increased incidence of infection or cancer. The identification of ion channels in T cells has raised the possibility that channel blockers exhibiting high specificity might become new therapeutics in the never-ending search for better immunosuppressants. Recent results published in Molecular Pharmacology have characterized new psoralen-derived compounds that specifically block the Kv3.1 channel in T effector (TEM) cells while sparing with the activation of naïve or T central memory cells. Thus, TEM cell–mediated autoimmune diseases such as multiple sclerosis or Type I diabetes mellitus might be successfully treated by these new compounds.

  • The development of atherosclerosis can, in the absence of intervention, lead to cardiovascular disease, which is responsible for the demise of more Americans per year than any other disease. Beyer and colleagues report, in the Journal of Pharmacology and Experimental Therapeutics, that treating mice with a liver X receptor (LXR) agonist increases not only the concentration of circulating high-density lipoprotein (HDL) but also, unfortunately, that of circulating triglycerides. When doubly treated with LXR agonists together with peroxisome proliferator–activated receptor α(PPARα) agonists, mice exhibited reduced concentrations of circulating triglycerides (but interestingly, triglyceride concentrations in the liver were not reduced) while their HDL concentrations remained elevated. The authors suggest that activation of both receptors, through the development and use of LXRα–PPARα dual agonists, might become a useful therapy to bolster HDL levels while simultaneously suppressing circulating triglycerides in patients.


  • Although the usefulness of lithium in the treatment of bipolar affective disorder was discovered over fifty years ago, only recently have many of the molecular targets for lithium’s action been identified, including glycogen synthase kinase-3 (GSK-3) and neurotrophic signaling cascades. These observations may lead to a new understanding of the underpinnings of bipolar disorder and will likely support the use of lithium in the management and treatment of neurodegenerative disorders. Multiple lines of investigation have established lithium’s direct effects on several phosphatases, kinases, and other enzymes, and have also indicated lithium’s indirect effects on downstream targets, including adenylate cyclase, the phosphoinositol cascade and protein kinase C, and arachidonic acid metabolism. There is also experimental momentum behind the hypothesis that lithium mediates neurotrophic effects.

  • Owing to the difficulty of getting drugs across the blood–brain barrier, the treatment of various cancers of the brain range from tumor resection (where possible) to radiation therapy. Unfortunately, irradiation of tumors also involves the irradiation of surrounding normal brain tissue, and radiation injury of the central nervous system (CNS) has severe clinical consequences. Clonogenic apoptosis is not the only mode of cell death in the CNS after radiation therapy; secondary injury leading to neural cell death arises from alterations to the microenvironment as mediated by hypoxia/ischemia and inflammation. New research now raises the possibility of reversible components in the injury response and may lead the way to novel neuroprotective interventions. In particular, cytokine cascades and stress responses associated with radiation-associated damage provide important targets for further investigations.

  • Although neuropharmacologists have fervently sought ligands to target most classes of neuroreceptors, the cholinergic systems have for the past few decades been relatively exempt from therapeutically biased investigations. This unfortunate situation now seems to be improving, however, particularly with the discovery of multiple subtypes of nicotinic cholinergic receptors. Several nicotine-derived compounds have been synthesized, and their efficiency in modulating nicotinic receptor subtypes has led to the development of several experimental drugs for treatment of pain, neurodegenerative diseases, and psychiatric conditions that involve cognitive impairment. Beyond the race that has been initiated to bring nicotinic drugs to market, these new compounds have in some instances established themselves as experimental tools in the study of cholinergic functions.

Beyond the Bench

Net Results