Platelet-activating factor and progressive brain damage following focal brain injury.
The effects of a platelet-activating factor (PAF) antagonist on brain edema, cortical microcirculation, blood-brain barrier (BBB) disruption, and neuronal death following focal brain injury are reported. A neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was used to induce highly reproducible focal cortical lesions in anesthetized rats. Secondary brain damage in this model was characterized by progressive cortical hypoperfusion, edema, and BBB disruption in the vicinity of the hemispheroid lesion occurring acutely after injury. The histopathological evolution was followed for up to 4 days. Neuronal damage in the cortex and the hippocampus (CA-1) was assessed quantitatively, revealing secondary and progressive loss of neuronal tissue within the first 24 hours following injury. Pretreatment with the PAF antagonist BN 50739 ameliorated the severe hypoperfusion in 12 rats (increasing local cerebral blood flow from a mean +/- standard error of the mean of 40.5% +/- 8.3% to 80.2% +/- 7.8%, p less than 0.01) and reduced edema by 70% in 10 rats (p less than 0.05) acutely after injury. The PAF antagonist also reduced the progression of neuronal damage in the cortex and the CA-1 hippocampal neurons (decrease of neuronal death from 88.0% +/- 3.9% to 49.8% +/- 4.2% at 24 hours in the cortex and from 40.2 +/- 5.0% to 13.2% +/- 2.1% in the hippocampus in 30 rats; p less than 0.05). This study provides evidence to support progressive brain damage following focal brain injury, associated with secondary loss of neuronal cells. In this latter process, PAF antagonists may provide significant therapeutic protection in arresting secondary brain damage following cerebral ischemia and neurological trauma.
Frerichs
K U
KU
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Lindsberg
P J
PJ
Hallenbeck
J M
JM
Feuerstein
G Z
GZ
D000818:Animals; D001381:Azepines / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects; D001834:Body Water / Q000032:analysis; D001930:Brain Injuries / Q000503:physiopathology* / Q000517:prevention & control / Q000601:surgery; D002540:Cerebral Cortex / Q000098:blood supply; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D010539:Permeability / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012039:Regional Blood Flow; D014230:Triazoles / Q000627:therapeutic use
D001381:Azepines; D010972:Platelet Activating Factor; D014230:Triazoles; C064509:BN 50739