Combination chemotherapy extends the therapeutic window to 60 minutes after stroke.
We sought to extend the therapeutic window for acute stroke therapy using the combination of a glutamate antagonist and a GABA agonist, which in prior studies was effective if given 5 min after stroke. We used a quantal bioassay to measure neuroprotective potency after injection of several thousand microspheres into the cerebral circulation of rats. The GABA-A agonist muscimol, but not MK-801, was effective if given 30, 45, or 60 min after embolization (potency ratio compared with saline of 3.0, 2.3, 1.8, respectively). If muscimol was combined with MK-801 at lower doses of each drug, the combination was neuroprotective (potency ratio of 4.2). Agonists of GABA-A, but not GABA-B, receptors blocked the toxic vacuolization seen in the cingulate and retrosplenial cortex after MK-801 treatment. Combination chemotherapy appears to extend the time window for acute stroke therapy in rats to 1 h and to result in fewer side effects.
Lyden
P
P
Department of Neurosciences, UCSD School of Medicine, Veterans Administration Medical Center, California, USA.
Lonzo
L
L
Nunez
S
S
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000473:pathology; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists / Q000627:therapeutic use*; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D008297:Male; D008863:Microspheres; D009118:Muscimol / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014617:Vacuoles / Q000648:ultrastructure
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D018696:Neuroprotective Agents; D009118:Muscimol; D016291:Dizocilpine Maleate