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For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Neurology Vol 1 November 2002 http://neurology.thelancet.com 399 Newsdesk A third variant of the cyclo-oxygenase (COX) isozyme has been identified as a potential target of paracetamol (acetaminophen). COX-3 is selectively inhibited by analgesic and antipyretic drugs such as paracetamol and phenacetin, and is potently inhibited by some non-steroidal anti- inflammatories. “It seems likely that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever”, says Daniel Simmons (Brigham Young University, Provo, UT, USA). Simmons and colleagues charac- terised COX-3 and two smaller COX-1 derived proteins (PCOX-1 proteins). They showed that COX-3 and one of the PCOX-1 proteins are products of the COX-1 gene, but they retain intron 1 in their mRNAs. This intron introduces a 30–34 amino-acid insertion into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and the nuclear envelope. COX-3, but not PCOX-1, have glycosylation- dependent cyclo-oxygenase activity. Both proteins are expressed abundantly in canine cerebral cortex and in the human cerebral cortex and heart. A comparison of canine COX-3 activity with that of murine COX-1 and COX-2 showed that COX-3 is selectively inhibited by paracetamol, phenacetin, phenazone, and dipyrone, and is potently inhibited by diclofenac, aspirin, and ibuprofen. [Proc Natl Acad Sci USA; published online Sept 19, 2002; DOI/10.1073/pnas.162468699]. Burkhard Hinz at the Friedrich Alexander University (Erlangen- Nuremberg, Germany) points out that the mechanism of action of para- cetamol has been debated for more than three decades. He comments “this is an interesting new finding regarding an old pharmacological enigma”. Hinz’s colleague, Kay Brune, agrees and says that, surprisingly, the new enzyme is derived from the same gene as COX-1. “The induction and maintenance of hyperalgesia has recently been associated with centrally derived COX-2-dependent prosta- glandins, rather than COX-1”, he comments. Regina Botting (The William Harvey Research Institute, London, UK) considers this an important study since it leads the way to developing new drugs that selectively inhibit COX-3. “It should now be possible to develop more potent antipyretic analgesics that do not have the addictive properties of the opiates”, she says. However, Hinz warns that more intensive research is needed to clarify the role of COX-3. In particular, further experiments with human COX isozymes are required to clarify the effect of paracetamol on COX-3-dependent prostaglandin production. Post mortem analysis of human tissue should help to characterise the specific pattern of COX-3 expression in both physiological and pathophysiological conditions. “It will also be important to design some specific COX-3 inhibitors as experimental tools, to elucidate the role of COX-3 in different animal pain models”, Hinz adds. Kathryn Senior Homing in on COX-3—the elusive target of paracetamol Mutant forms of the wild-type prion protein (PrP C ) protect mice from neurodegeneration after inoculation with the pathogenic form of the prion protein (PrP Sc ). Building on previous in vitro studies, researchers at the University of California at San Francisco produced transgenic mice with mutations in the prion gene that confer resistance to scrapie in human beings. This protective effect, know as dominant-negative inhibition, “occurs when the mutant or variant form sequesters a (protein) partner preventing it from interacting with the wild-type protein”, explains Jiri Safar, one of the investigators. Safar and colleagues engineered transgenic mice that had one of two mutations—Q167R or Q218K— alone or in combination with PrP C . The researchers inoculated transgenic mice with PrP Sc and monitored them for signs of neurological disease. They also analysed the brains of the mice for the presence and location of PrP Sc by immunoblot and histological analysis (Proc Natl Acad Sci USA published Sept 23, 2002, DOI 10.1073 /pnas.182425299). Transgenic mice that express the Q167R mutation in the absence of PrP C did not develop any neurological signs, showed no indication of spontaneous neurodegeneration, and had no detectable PrP Sc in their brains. However, Q167R mice that did express PrP C had low levels of PrP Sc in the ventral hippocampus, accompanied by widespread vacuo- lation, and severe astrocytic gliosis at 300 days post-inoculation. These mice showed signs of neurological dysfunction about 450 days after inoculation compared with 130 days in control animals. Similarly, five of nine mice with the Q218K mutation and PrP C (at a ratio of 16/1) developed neurological symptoms after about 415 days. These results show that mutation of the prion protein prevents its conversion to PrP Sc . In addition, when expressed alongside normal PrP C , these mutations increase the incubation period of the disease. “The inability of some mutated prion proteins to support prion replication raises the possibility of identifying naturally occuring polymorphisms or directly producing prion resistant livestock”, says Safar. Anthony Williamson (Scripps Research Institute, La Jolla, CA, USA) told The Lancet Neurology that the most significant aspect of this report is that it provides a solid scientific platform on which informed choices can be made regarding the production of inherently prion- resistant livestock. Adriano Aguzzi (University Hospital of Zurich, Switzerland) concludes that “[these] results raise the hope that low- molecular weight analogues that mimic the competing regions of the dominant negative molecule may, at some point in the future, be exploited as anti-prion agents”. Rebecca Love Mutant prions to the rescue

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

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For personal use. Only reproduce with permission from The Lancet Publishing Group.

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

Newsdesk

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