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THE LANCET Neurology Vol 1 September 2002 http://neurology.thelancet.com 273

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results reported by Rothwell andLevison may simply reflect thedifferent outcome parameters used bythe two groups. Nevertheless, for nowRothwell cautions against looking formolecules targeted specifically at IL-1R1 for therapeutic use and notesthat she is initiating early clinical trialsof an IL-1 blocker. Levison agrees thatit will be important to know more

about potential additional receptorsbefore going down the IL-1R1 route,but notes that “targeting IL-1 itself, aswell as damping down theinflammatory response, would alsoremove adaptive effects of IL-1 such asinduction of nerve growth factor,which did not require IL-1R1 in ourexperiments”.Jane Bradbury

Mounting evidence indicates thatinterleukin-1 (IL-1) is involved in thedevelopment of brain damage afterinjury. Now, Anirban Basu andcolleagues (Pennsylvania StateUniversity College of Medicine,Hershey, PA, USA) report that thetype 1 IL-1 receptor (IL-1R1) isnecessary for the activation of micro-glia and induction of proinflam-matory mediators in response to apenetrating brain injury. “On thebasis of our results”, says seniorresearcher Steven Levison, “we believethat IL-1R1 could be a key drug targetfor reduction of brain damage afterinjury.”

IL-1 concentrations in brain arenormally low. However, in responseto experimental or clinical insults suchas traumatic brain injury and stroke,IL-1 brain concentrations increase. 10years ago, Nancy Rothwell (Universityof Manchester, UK) showed thattreatment with a naturally occuring IL-1 receptor antagonist preventedneuronal death in a rat model ofischaemia. Since then, much has beenlearnt about IL-1, but how blockingIL-1 action provides neuroprotectionremains unclear.

To discover more, Levison’s teamlooked at cellular and molecularresponses to penetrating brain injuryin wild-type mice and mice null for IL-1R1. Fewer microglia andmacrophages collected next todamaged tissue in IL-1R1-null mice,and expression of the proinflam-matory mediators cyclooxygenase 2and IL-6 was reduced in the null micecompared with the wild-type mice (J Neurosci 2002: 22: 6071–82). Theteam now plans to look at a strokemodel in the two types of mice, and,says Levison, “I predict that we will getsimilar results”.

“This is a nicely done paper”, saysRothwell, “that once again shows theimportance of IL-1 in the inflam-matory response to brain injury.However, we recently reported thatthe IL-1R1-null mice do not have areduced response to ischaemic braindamage (J Neurosci 2002; 22: 38–43)and suggested that there might beadditional IL-1 receptors in thebrain.” The apparently contradictory

The IL-1 type 1 receptor: a drug target for treating brain injury?

Fear becomes first emotion to yield tomolecular neuroscienceIndividual genes can influence howwe feel about our environment,according to research published inJuly. “Our data are the firstdemonstration of a mechanism bywhich a gene can affect the functionof a system in the brain involved inemotional processing”, notes leadresearcher Daniel Weinberger(National Institute on Mental Health,Bethesda, MD, USA).

The group is exploring the geneticarchitecture of fear processing bystudying links between single-genevariants and the responsiveness of theamygdala, a region involved inexperience of fear. Their recentScience publication further implicatespolymorphisms in the serotonintransporter (5-HTT) gene as a likelykey factor in the complex interplay ofanxiogenic and anxiolytic processesthat results in individual anxietystates (Science 2002; 297: 400–03).

The 5-HTT gene has either a long(l) or short (s) promoter region, andindividuals with one or two s alleleshave an increased risk of variouspsychological and behavioural traits,such as neuroticism and alcoholabuse. However, studies attemptingto relate gene variants to anxietydisorders have produced conflictingresults.

Weinberger’s team hypothesisedthat a direct assay of brain activitymight highlight differences betweenpeople with an s allele (group S) andthose without (group L). So theyinvestigated the response of amygdalaactivity to facial-emotion processingtasks, using functional magnetic

resonance imaging to measure localblood-oxygen level. Group S wasmore responsive to fearful stimuli,most likely reflecting increasedneuronal excitability, the teamspeculate, although they have not yetproven that this is linked withincreased synaptic serotonin.

Anxiety has been linked withseveral neurotransmitter systems,although most experts agree thatserotonin plays a central role. “Whilea single gene cannot be heldaccountable for complex emotionalstates, such as anxiety disorders,we’re beginning to pinpoint whichgenetic traits may make a person susceptible to developingpsychological disorders”, saysNorman Schmidt of Ohio StateUniversity, USA. According toSchmidt, most experts believe fearand anxiety are regulated by “quite afew genes. Until we can adequatelymodel more complex geneinteractions, it’s unlikely that we willbe able to tell the complete story”.

The Weinberger team’s findingsmay help resolve some contradictoryfindings, such as those previouslyreported by Schmidt’s team, whichshowed increased misperception ofphysical symptoms as anxiety inl carriers, especially in those who alsohad the psychological trait of anxietysensitivity. Schmidt concludes from“converging lines of evidence” that“adults with anxiety disorders mayhave an underlying constitutionalvulnerability that is partly genetic andvariably expressed over time”.Kelly Morris