Alkermes Inc. has found in animal models that its calpaininhibitor is capable of limiting the brain damage associatedwith stroke -- even when the compound is given up to threehours after the stroke has occurred.
Raymond Bartus, senior vice president of neurobiology atAlkermes (NASDAQ:ALKS), and his colleagues will present thedata from the rat studies Saturday at the 11th Annual Meetingof the Neurotrauma Society in Washington, D.C.
Calpains are calcium-dependent intracellular proteases thatexist in an inactive state in healthy neuronal cells. But after anischemic event such as a stroke or heart attack, theintracellular calcium levels rise to the point that they activatethe calpain proteases.
The enzymes then attack and degrade cytoskeletal proteins andare known to activate or degrade several importantintracellular signal transducers (such as protein kinases andphosphatases).
However, there is a delay between the ischemic event and thedestruction of neurons, providing a potential point oftherapeutic intervention.
In the studies that will be reported Saturday, Bartus and hiscolleagues looked at the ability of one particular compound,AK275, to reduce the size of the infarct resulting fromexperimentally induced middle cerebral-artery occlusion. Theyinfused the compound, which is a dipeptide keto amide,directly onto the rats' cerebral cortexes.
The purpose of this approach was to eliminate the variablesunavoidably associated with an intravenous injection (such aspharmacokinetics and hemodynamics) and to focus on whetherthe compound did indeed prevent or reduce the amount ofdamage done to the brain tissue by an induced ischemia.
"Clearly, the goal is to interrupt the neuropathological cascade"that leads to cell death, Bartus told BioWorld.
The animal studies demonstrated that AK275 did just that.Whether infused onto the cortex four hours prior to theischemic event or as late as three hours afterward, AK275reduced the size of the infarct significantly -- in many cases bymore than 50 percent, and sometimes by as much as 75percent.
"These data demonstrate that inhibition of calpain alone issufficient to provide dramatic protection against ischemia in ananimal model," Bartus said.
The calpain inhibitors, which were originally discovered byresearchers associated with Cortex Pharmaceuticals Inc.(NASDAQ:CORX), have been developed through a collaborationbetween Cortex and Alkermes of Cambridge, Mass. Thecompanies have applied a combination of high-volumescreening of chemical libraries, directed synthesis, formulationof structure/activity relationships and the enzymologicalcharacterization to come up with active compounds.
According to the amended terms of the collaboration, reachedin October 1992, Alkermes has the rights to develop and usethe calpain inhibitors for both chronic and peripheralneurodegenerative disorders, while Cortex of Irvine, Calif.,retains the commercial rights for all non-neurologicalapplications.
These assignations are slightly blurry at the moment, however.
Cortex recently announced that preclinical research conductedby its own collaborators demonstrated that the calpaininhibitors can reduce vasospasm in coronary, carotid andcerebral arteries. Alkermes and Cortex now disagree as towhether the condition of cerebral vasospasm should be classedas a central nervous system problem or a vascular one.
Alkermes' stock closed at $8.75 a share, down 25 cents, onThursday; Cortex's shares were down 6 cents to $1.88 a share.
-- Jennifer Van Brunt Senior Editor
(c) 1997 American Health Consultants. All rights reserved.