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THE LANCETNeurology Vol 2 February 2003 http://neurology.thelancet.com70

Newsdesk

In the current study, Montal andLilia Koriazova found that the heavychain is crucial to the movement of thelight chain metalloprotease across theendosomal membrane; it acts as achaperone protein to prevent aggreg-

ation and allow the protease to enterthe cytosol as an active enzyme withoutexpending any of the cell’s energy.That, he told The Lancet Neurology,creates the possibility of discoveringmolecules directed against the channel.

“If you block that channel, you willbe able to abrogate the action of thetoxin, not by touching the enzyme, butby precluding it from entering the

cytosol from the acidic endosome”,says Montal. Although such blockingagents are still at the conceptual stage,his team has a grant to screen knownmolecules for blocking properties—asort of prophylactic strategy against thetoxin’s activity that could one day beapplied to other metalloproteasetoxins, such as tetanus and anthrax.

Bernhard Rupp (LawrenceLivermore National Laboratory,Livermore, CA, USA) said the study“provides additional understanding ofthe complex, multistep mechanism ofclostridial neurotoxicity and host cellinvasion”. Rupp, who has studied thestructure of the toxin, told The LancetNeurology that an approach to drugdiscovery, in which screening targetseach step in a pathway rather than justthe toxic step, is becoming morecommon. For botulinum toxin “this isof particular interest, as targeteddelivery of a inhibitor to the actualplace of action of the light chain insidethe neuron poses a major difficulty ineffective drug development”.Ivan Oransky

Although the cosmetic uses ofClostridium botulinum neurotoxinenjoy tremendous popularity, thetoxin’s negative effects—as an agent offood poisoning and, potentially, ofbioterrorism—remain untamed. In astep that could help to identifyantitoxin agents, scientists at theUniversity of California at San Diegohave discovered how the toxin movesfrom endosomes into the cytosol (NatStruct Biol 2002; 10: 13–18).

The toxin, which blocks neuro-transmitter release at presynapticmotor-neuron terminals, is made oftwo parts: a light chain metalloproteasethat exerts its toxic action and a heavychain channel that allows the proteaseto cross the endosomal membrane afterthe toxin is taken up into neurons.Attempts to block the protease havebeen successful in vitro but have beenless successful in vivo, according to thelead author Mauricio Montal. But thechannel, thought an “interesting featurebut probably an epiphenomenon”, hadbeen largely ignored, according toMontal.

Ironing out the wrinkles in the botulinum toxin intracellular pathway

Calm down, it’s not cannabis. . .

Clostridium botulinum

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Tetrahydrocannabinol, the psycho-active constituent of cannabis, acts viaCB1 cannabinoid receptors and hasvarious effects, including a lowering ofanxiety. Researchers have nowdeveloped drugs that amplify theeffects of endogenous cannabinoidsby preventing their inactivation.“Inhibitors of anandamide hydrolysissuch as those identified in our studymay provide an innovative mechanismto treat anxiety and depression, onethat may offer advantages in terms ofefficacy and/or side-effect profile overexisting therapies”, comments seniorauthor Daniele Piomelli (University ofCalifornia, Irvine, CA, USA).

Piomelli and colleagues developedcompounds that are potent, selective,and systemically active inhibitors offatty acid amide hydrolase (FAAH),which degrades the endogenouscannabinoid ananamide. In rats, theinhibitors showed benzodiazepine-likeproperties in standard behavioural

tests of anxiety. The behaviouraleffects were accompanied by increasedbrain concentrations of anandamideand were prevented by blocking theCB1 receptor with antagonists (NatMed 2003: 9: 76–81).

Maurice Elphick (School ofBiological Sciences, Queen Mary,University of London, UK) thinks thatinhibitors of FAAH could be used inthe future for treatment of humandisorders such as chronic anxiety andpain. “However”, he says, “theselectivity of this approach may bedependent on endogenous productionof endocannabinoids in relevant brainregions.” At the moment, he stressesthat whether endocannabinoidsynthesis is increased in human beingsas a consequence of anxiety or pain isunknown. “Relevant to this study isthe recent paper by Sipe and co-workers (Proc Natl Acad Sci USA 200299: 8394–99 ) reporting that humanswith a mutated version of FAAH have

an increased likelihood of street druguse and problem drug/alcohol use.This provides further importantevidence that in humans, FAAH playsan important role in normal humanbrain function”, he adds.

“There is much basic research stillto be done and, of course, ourhypothesis needs to be validated inphase II clinical studies”, warnsPiomelli. Important open questionsinclude: What regions of the brain areinvolved in the anxiolytic actions ofthe FAAH inhibitors? What additionalneurotransmitter systems might beengaged? And how are anxiolysis andanalgesia connected? “Moreover, froma translational perspective, we need toidentify specific therapeutic targets aswell as clinical candidates forpreclinical toxicology and, eventually,human testing. Optimistically, thismay happen within 2 years”, heconcludes.Kathryn Senior

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