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THE LANCET Neurology Vol 1 November 2002 http://neurology.thelancet.com 399

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A third variant of the cyclo-oxygenase(COX) isozyme has been identified as a potential target of paracetamol(acetaminophen). COX-3 is selectivelyinhibited by analgesic and antipyreticdrugs such as paracetamol andphenacetin, and is potently inhibited by some non-steroidal anti-inflammatories. “It seems likely thatinhibition of COX-3 could represent aprimary central mechanism by whichthese drugs decrease pain and possiblyfever”, says Daniel Simmons (BrighamYoung University, Provo, UT, USA).

Simmons and colleagues charac-terised COX-3 and two smaller COX-1derived proteins (PCOX-1 proteins).They showed that COX-3 and one ofthe PCOX-1 proteins are products ofthe COX-1 gene, but they retainintron 1 in their mRNAs. This intron introduces a 30–34 amino-acidinsertion into the hydrophobic signalpeptide that directs COX-1 into thelumen of the endoplasmic reticulumand the nuclear envelope. COX-3, butnot PCOX-1, have glycosylation-dependent cyclo-oxygenase activity.Both proteins are expressed abundantlyin canine cerebral cortex and in thehuman cerebral cortex and heart. Acomparison of canine COX-3 activitywith that of murine COX-1 and COX-2showed that COX-3 is selectivelyinhibited by paracetamol, phenacetin,phenazone, and dipyrone, and ispotently inhibited by diclofenac,aspirin, and ibuprofen. [Proc Natl AcadSci USA; published online Sept 19,2002; DOI/10.1073/pnas.162468699].

Burkhard Hinz at the FriedrichAlexander University (Erlangen-Nuremberg, Germany) points out thatthe mechanism of action of para-cetamol has been debated for morethan three decades. He comments“this is an interesting new findingregarding an old pharmacologicalenigma”. Hinz’s colleague, Kay Brune,agrees and says that, surprisingly, thenew enzyme is derived from the samegene as COX-1. “The induction andmaintenance of hyperalgesia hasrecently been associated with centrallyderived COX-2-dependent prosta-glandins, rather than COX-1”, hecomments.

Regina Botting (The WilliamHarvey Research Institute, London,UK) considers this an important studysince it leads the way to developing newdrugs that selectively inhibit COX-3. “Itshould now be possible to develop morepotent antipyretic analgesics that do nothave the addictive properties of theopiates”, she says. However, Hinz warnsthat more intensive research is neededto clarify the role of COX-3. Inparticular, further experiments withhuman COX isozymes are required to

clarify the effect of paracetamol onCOX-3-dependent prostaglandinproduction. Post mortem analysis ofhuman tissue should help tocharacterise the specific pattern ofCOX-3 expression in both physiologicaland pathophysiological conditions. “Itwill also be important to design somespecific COX-3 inhibitors asexperimental tools, to elucidate the roleof COX-3 in different animal painmodels”, Hinz adds.Kathryn Senior

Homing in on COX-3—the elusive target of paracetamol

Mutant forms of the wild-type prionprotein (PrPC) protect mice fromneurodegeneration after inoculationwith the pathogenic form of the prionprotein (PrPSc). Building on previousin vitro studies, researchers at theUniversity of California at SanFrancisco produced transgenic micewith mutations in the prion gene thatconfer resistance to scrapie in humanbeings. This protective effect, know asdominant-negative inhibition, “occurswhen the mutant or variant formsequesters a (protein) partnerpreventing it from interacting with thewild-type protein”, explains Jiri Safar,one of the investigators.

Safar and colleagues engineeredtransgenic mice that had one of twomutations—Q167R or Q218K—alone or in combination with PrPC.The researchers inoculated transgenicmice with PrPSc and monitored themfor signs of neurological disease. Theyalso analysed the brains of the micefor the presence and location of PrPSc

by immunoblot and histologicalanalysis (Proc Natl Acad Sci USApublished Sept 23, 2002, DOI 10.1073/pnas.182425299).

Transgenic mice that express theQ167R mutation in the absence ofPrPC did not develop any neurologicalsigns, showed no indication ofspontaneous neurodegeneration, andhad no detectable PrPSc in theirbrains. However, Q167R mice thatdid express PrPC had low levels ofPrPSc in the ventral hippocampus,accompanied by widespread vacuo-

lation, and severe astrocytic gliosis at300 days post-inoculation. Thesemice showed signs of neurologicaldysfunction about 450 days afterinoculation compared with 130 daysin control animals. Similarly, five ofnine mice with the Q218K mutationand PrPC (at a ratio of 16/1)developed neurological symptomsafter about 415 days.

These results show that mutationof the prion protein prevents itsconversion to PrPSc. In addition,when expressed alongside normalPrPC, these mutations increase theincubation period of the disease.“The inability of some mutated prionproteins to support prion replicationraises the possibility of identifyingnaturally occuring polymorphisms ordirectly producing prion resistantlivestock”, says Safar.

Anthony Williamson (ScrippsResearch Institute, La Jolla, CA, USA)told The Lancet Neurology that themost significant aspect of this reportis that it provides a solid scientificplatform on which informed choicescan be made regarding theproduction of inherently prion-resistant livestock. Adriano Aguzzi(University Hospital of Zurich,Switzerland) concludes that “[these]results raise the hope that low-molecular weight analogues thatmimic the competing regions of thedominant negative molecule may, atsome point in the future, be exploitedas anti-prion agents”.Rebecca Love

Mutant prions to the rescue