If biologists have learned anything over the past decade, it is how similar all mammals are at the genetic level. 95% of the genes found in mice are also found in humans, and we even share a significant amount of genes and genetic circuitries with creatures as different as fruit flies or puffer fish. This might not come as much of a surprise to physiologists who have long used animals to learn about basic mechanisms in organ function that are shared across vertebrates or mammals, but the extent of overlap is still impressive to most. In many areas of biomedical research, rats or mice are the animal model of choice. And while most researchers are aware that mice are not just furry little humans that walk on all fours, some fundamental differences surprise even experts. Among 10 scientists who identify themselves as mouse geneticists, only one was aware that mice (and in fact all rodents) lack a very fundamental behavior: they do not vomit.
While that in itself raises all sorts of interesting questions (for example about the evolution of vomiting, and its advantages and disadvantages for the survival of a species), it poses a very specific problem when one tries to use rodents to study a drug with side effects that include nausea and emesis (the medical term for vomiting).
Annette Robichaud and colleagues at Merck Frosst Centre for Therapeutic Research in Montreal, Quebec, have faced this problem while developing drugs that inhibit a class of enzymes called class 4 phosphodiesterases, or PDE4s. PDE4 inhibitors have promise for the treatment of airway inflammatory diseases such as asthma, but their therapeutic potential has been limited by side effects of nausea and emesis. These side effects are thought to be caused by inhibition of PDE4s outside the airways. The PDE4 subfamily is composed of 4 subtypes that are present in overlapping but distinct tissues of the body, and the hope is that it might be possible to develop subtype-specific inhibitors that are effective in the airways but do not interfere with PDE4 activity in other tissues.
As a step towards that goal, the researchers at Merck Frosst set out to determine which PDE4 subtype is mediating the emetic response. The most direct way to do so is to take advantage of genetically engineered mice that lack particular subtypes. However, since mice do not exhibit an emetic response, Robichaud and colleagues had to measure a different response that is thought to correlate with emesis in creatures like us that do vomit. Fortunately, such a surrogate response exists: PDE inhibitors reverse the anesthetic effects of a different class of drugs called alpha2-adrenoceptor agonists, and this is thought to act via the same mechanism as the unwanted side effects.
As Robichaud and colleagues report in the September 30 issue of the Journal of Clinical Investigation, by studying the inhibitors ability to reverse anesthesia in mice that lacked two of the PDE4 subtypes, PDE4B and PDE4D, they could infer that inhibition of PDE4D is what mediates much of the emetic response.
The next step will be the development of selective PDE4 inhibitors that do not interfere with PDE4D function. Such drugs would be predicted not to affect alpha2-adrenoceptor agonist-mediated anesthesia in mice. More importantly, and to vindicate this complicated approach to pre-clinical drug development, they will hopefully maintain the beneficial anti-inflammatory effects in human airways without causing human patients to feel sick and vomit.
Materials provided by Journal Of Clinical Investigation. Note: Content may be edited for style and length.
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