A clue to a drug's neurotoxicity?: The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered brain damage. As an initial step in investigating whether inhibition of off-target proteins by BIA 10-2474 might contribute to its clinical neurotoxicity, van Esbroeck et al. used activity-based proteomic assays to identify proteins targeted by the drug. Studying human cells and brain samples from subjects not associated with the trial, they found that BIA 10-2474 targeted several different lipases in addition to FAAH. It also substantially altered lipid metabolism in cultured neurons. Science , this issue p. 1084

Moringa oleifera Lam. is a tropical plant widely used in traditional medicines and as a food supplement. It is characterized by the presence of glucosinolates and isothiocyanates; the stable isothiocyanate 4-[(α-l-rhamnosyloxy)benzyl]isothiocyanate (moringin) has been widely studied for its bioactivity as hypoglycemic, antimicrobial, anticancer and in particular for its involvement in nociception and neurogenic pain. Moringa extracts and pure moringin were submitted to in vitro assays with the somatosensory TRPA1 ion channel, proving that moringin is a potent and effective agonist of this receptor involved in nociceptive function and pain states. Moringin do not activate or activates very weakly the vanilloids somatosensory channels TRPV1,2,3 and 4, and the melastatin cooling receptor TRPM8. The comparison of moringin’s activity with other known agonists of natural origin is also discussed.

The transient receptor potential vanilloid-1 cat ion channel (TRPV1) is a nonspecific cation channel that can be activated by multiple endogenous stimuli and is expressed predominantly in sensory neurons, where it serves as a key nodal point in pain transmission pathways. In mammals, TRPV1 displays a wide tissue and cellular expression including both the peripheral and central nervous system, and in the latter it is now recognized to have a broader distribution and function. The pharmacological modulation of TRPV1 represents a strategy for the treatment of a variety of disease states, particularly those requiring chronic pain management. The validation of the TRPV1 channel as a therapeutic target for the control of pain and inflammatory conditions in a variety of diseases and injury states, has prompted the development of several TRPV1 agonists and antagonists that have entered clinical trials. Studies comparing the analgesic effects of TRPV1 antagonists with and without significant CNS penetration demonstrated that a dual (both peripheral and central) action is required to produce broad-spectrum analgesia. TRPV1 can be considered as a target for next generation analgesics. However, although a number of compounds are in clinical trials, the therapeutic utility of TRPV1 agonist and antagonists is yet to be validated unequivocally. This review summarizes current clinical trials and recent patents with small molecule TRPV1 agonists and antagonists with a focus on neurological conditions.