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Calm down, it's not cannabis…
Newsdesk Ironing out the wrinkles in the botulinum toxin intracellular pathway In the current study, Montal and Lilia Koriazova found that the heavy chain is crucial to the movement of the light chain metalloprotease across the endosomal membrane; it acts as a chaperone protein to prevent aggreg-
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Clostridium botulinum
ation and allow the protease to enter the cytosol as an active enzyme without expending any of the cell’s energy. That, he told The Lancet Neurology, creates the possibility of discovering molecules directed against the channel. “If you block that channel, you will be able to abrogate the action of the toxin, not by touching the enzyme, but by precluding it from entering the
Dr Gary Gaugler/Science Photo Library
Although the cosmetic uses of Clostridium botulinum neurotoxin enjoy tremendous popularity, the toxin’s negative effects—as an agent of food poisoning and, potentially, of bioterrorism—remain untamed. In a step that could help to identify antitoxin agents, scientists at the University of California at San Diego have discovered how the toxin moves from endosomes into the cytosol (Nat Struct Biol 2002; 10: 13–18). The toxin, which blocks neurotransmitter release at presynaptic motor-neuron terminals, is made of two parts: a light chain metalloprotease that exerts its toxic action and a heavy chain channel that allows the protease to cross the endosomal membrane after the toxin is taken up into neurons. Attempts to block the protease have been successful in vitro but have been less successful in vivo, according to the lead author Mauricio Montal. But the channel, thought an “interesting feature but probably an epiphenomenon”, had been largely ignored, according to Montal.
cytosol from the acidic endosome”, says Montal. Although such blocking agents are still at the conceptual stage, his team has a grant to screen known molecules for blocking properties—a sort of prophylactic strategy against the toxin’s activity that could one day be applied to other metalloprotease toxins, such as tetanus and anthrax. Bernhard Rupp (Lawrence Livermore National Laboratory, Livermore, CA, USA) said the study “provides additional understanding of the complex, multistep mechanism of clostridial neurotoxicity and host cell invasion”. Rupp, who has studied the structure of the toxin, told The Lancet Neurology that an approach to drug discovery, in which screening targets each step in a pathway rather than just the toxic step, is becoming more common. For botulinum toxin “this is of particular interest, as targeted delivery of a inhibitor to the actual place of action of the light chain inside the neuron poses a major difficulty in effective drug development”. Ivan Oransky
Calm down, it’s not cannabis. . . Tetrahydrocannabinol, the psychoactive constituent of cannabis, acts via CB1 cannabinoid receptors and has various effects, including a lowering of anxiety. Researchers have now developed drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. “Inhibitors of anandamide hydrolysis such as those identified in our study may provide an innovative mechanism to treat anxiety and depression, one that may offer advantages in terms of efficacy and/or side-effect profile over existing therapies”, comments senior author Daniele Piomelli (University of California, Irvine, CA, USA). Piomelli and colleagues developed compounds that are potent, selective, and systemically active inhibitors of fatty acid amide hydrolase (FAAH), which degrades the endogenous cannabinoid ananamide. In rats, the inhibitors showed benzodiazepine-like properties in standard behavioural
70
tests of anxiety. The behavioural effects were accompanied by increased brain concentrations of anandamide and were prevented by blocking the CB1 receptor with antagonists (Nat Med 2003: 9: 76–81). Maurice Elphick (School of Biological Sciences, Queen Mary, University of London, UK) thinks that inhibitors of FAAH could be used in the future for treatment of human disorders such as chronic anxiety and pain. “However”, he says, “the selectivity of this approach may be dependent on endogenous production of endocannabinoids in relevant brain regions.” At the moment, he stresses that whether endocannabinoid synthesis is increased in human beings as a consequence of anxiety or pain is unknown. “Relevant to this study is the recent paper by Sipe and coworkers (Proc Natl Acad Sci USA 2002 99: 8394–99 ) reporting that humans with a mutated version of FAAH have
an increased likelihood of street drug use and problem drug/alcohol use. This provides further important evidence that in humans, FAAH plays an important role in normal human brain function”, he adds. “There is much basic research still to be done and, of course, our hypothesis needs to be validated in phase II clinical studies”, warns Piomelli. Important open questions include: What regions of the brain are involved in the anxiolytic actions of the FAAH inhibitors? What additional neurotransmitter systems might be engaged? And how are anxiolysis and analgesia connected? “Moreover, from a translational perspective, we need to identify specific therapeutic targets as well as clinical candidates for preclinical toxicology and, eventually, human testing. Optimistically, this may happen within 2 years”, he concludes. Kathryn Senior
THE LANCET Neurology Vol 2 February 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Rights were not granted to include this image in electronic media. Please refer to the printed journal. Clostridium botulinum
ation and allow the protease to enter the cytosol as an active enzyme without expending any of the cell’s energy. That, he told The Lancet Neurology, creates the possibility of discovering molecules directed against the channel. “If you block that channel, you will be able to abrogate the action of the toxin, not by touching the enzyme, but by precluding it from entering the
Dr Gary Gaugler/Science Photo Library
Although the cosmetic uses of Clostridium botulinum neurotoxin enjoy tremendous popularity, the toxin’s negative effects—as an agent of food poisoning and, potentially, of bioterrorism—remain untamed. In a step that could help to identify antitoxin agents, scientists at the University of California at San Diego have discovered how the toxin moves from endosomes into the cytosol (Nat Struct Biol 2002; 10: 13–18). The toxin, which blocks neurotransmitter release at presynaptic motor-neuron terminals, is made of two parts: a light chain metalloprotease that exerts its toxic action and a heavy chain channel that allows the protease to cross the endosomal membrane after the toxin is taken up into neurons. Attempts to block the protease have been successful in vitro but have been less successful in vivo, according to the lead author Mauricio Montal. But the channel, thought an “interesting feature but probably an epiphenomenon”, had been largely ignored, according to Montal.
cytosol from the acidic endosome”, says Montal. Although such blocking agents are still at the conceptual stage, his team has a grant to screen known molecules for blocking properties—a sort of prophylactic strategy against the toxin’s activity that could one day be applied to other metalloprotease toxins, such as tetanus and anthrax. Bernhard Rupp (Lawrence Livermore National Laboratory, Livermore, CA, USA) said the study “provides additional understanding of the complex, multistep mechanism of clostridial neurotoxicity and host cell invasion”. Rupp, who has studied the structure of the toxin, told The Lancet Neurology that an approach to drug discovery, in which screening targets each step in a pathway rather than just the toxic step, is becoming more common. For botulinum toxin “this is of particular interest, as targeted delivery of a inhibitor to the actual place of action of the light chain inside the neuron poses a major difficulty in effective drug development”. Ivan Oransky
Calm down, it’s not cannabis. . . Tetrahydrocannabinol, the psychoactive constituent of cannabis, acts via CB1 cannabinoid receptors and has various effects, including a lowering of anxiety. Researchers have now developed drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. “Inhibitors of anandamide hydrolysis such as those identified in our study may provide an innovative mechanism to treat anxiety and depression, one that may offer advantages in terms of efficacy and/or side-effect profile over existing therapies”, comments senior author Daniele Piomelli (University of California, Irvine, CA, USA). Piomelli and colleagues developed compounds that are potent, selective, and systemically active inhibitors of fatty acid amide hydrolase (FAAH), which degrades the endogenous cannabinoid ananamide. In rats, the inhibitors showed benzodiazepine-like properties in standard behavioural
70
tests of anxiety. The behavioural effects were accompanied by increased brain concentrations of anandamide and were prevented by blocking the CB1 receptor with antagonists (Nat Med 2003: 9: 76–81). Maurice Elphick (School of Biological Sciences, Queen Mary, University of London, UK) thinks that inhibitors of FAAH could be used in the future for treatment of human disorders such as chronic anxiety and pain. “However”, he says, “the selectivity of this approach may be dependent on endogenous production of endocannabinoids in relevant brain regions.” At the moment, he stresses that whether endocannabinoid synthesis is increased in human beings as a consequence of anxiety or pain is unknown. “Relevant to this study is the recent paper by Sipe and coworkers (Proc Natl Acad Sci USA 2002 99: 8394–99 ) reporting that humans with a mutated version of FAAH have
an increased likelihood of street drug use and problem drug/alcohol use. This provides further important evidence that in humans, FAAH plays an important role in normal human brain function”, he adds. “There is much basic research still to be done and, of course, our hypothesis needs to be validated in phase II clinical studies”, warns Piomelli. Important open questions include: What regions of the brain are involved in the anxiolytic actions of the FAAH inhibitors? What additional neurotransmitter systems might be engaged? And how are anxiolysis and analgesia connected? “Moreover, from a translational perspective, we need to identify specific therapeutic targets as well as clinical candidates for preclinical toxicology and, eventually, human testing. Optimistically, this may happen within 2 years”, he concludes. Kathryn Senior
THE LANCET Neurology Vol 2 February 2003
http://neurology.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.