Astrazeneca, Stroke, Cerovive, Renovis, and TRPM7.
1) Like much free radical pathogenesis, that in stroke is likely messenger mediated. In so-called "Redox-signaling" an electronically-activated molecule works primarily as a biological messenger ( redoxsignaling.com ). TRPM7 is an absolutely classic example of redox-signaling.
2) TRPM7 also sits on the cell surface. There is a significant extracellular component to free radical pathogenesis.
I have long known this from our studies with superoxide dismutase and catalase, which do not enter cells-- too big, for one thing. Yet, in our hands, these proteins are antiinflammatory, stimulate hair growth, minimize the toxicity of 6-hydroxydopamine to neuronal cells in culture ( a good model for redox-mediated neuronal destruction ), ameliorate hyperbaric oxygen-induced seizures, etc..
PBN disulfonicacid ( AstraZeneca's antistroke drug "Cerovive", aka PBN disulfate ) appears to be another example, as are the equivalent sulfate and disulfate spin traps I list in my '502 patent, along with PBN itself. As with large proteins such as SOD, such charged lipid-insoluble molecules do not penetrate cells very well and have a "low volume of distribution". The latter makes them go farther as well as minimizing potental intracellular toxicity.
This is why the TRPM7 redox-mediated ion channel is of such great interest. It is in the right spot on the cell surface and does the right thing. My wild guess is that if TRPM7 is not what mediates much radical-mediated tissue damage, it is something similar. Na, it can't be that easy.
3) As is common when patents are involved, there is citation amnesia on this point ( you know who you are <G> ). However, my friend and colleague Harry B Demopoulus and his coworkers were the first to present good evidence for a role for free radicals in stroke . See nitrone.com for a list of papers.
OT, but amusing: in addition to his many scientific contributions, Dr. Demopoulos ( "Dr D" ) had speaking parts in the odd Clint Eastwood movie and played a significant positive role in the Doris Duke estate business. My mind positively reels....
Peter H Proctor, PhD,MD
Finally: "Cerovive" is the registered trademark of the AstraZeneca corporation. |
