Chronic intracerebroventricular delivery of the secretory phospholipase A2 inhibitor, 12-epi-scalaradial, does not improve outcome after focal cerebral ischemia-reperfusion in rats

Phospholipase A(2)s (PLA(2)s) seem to be involved in the pathophysiology of ischemic brain injury, but their specific role is far from being completely understood. The present study was carried out to ascertain how and to what extent secretory PLA(2)s (sPLA(2)s) activity influences outcome after cerebral ischemia-reperfusion, and to correlate this with the inflammatory response. To do this we used the potent and selective sPLA(2) inhibitor, 12-epi-scalaradial. Male Wistar rats were separated into three groups: a control group receiving intracerebroventricular vehicle, and two groups receiving intracerebroventricular 0.005 or 0.5 mu g/h 12-epi-scalaradial. Every animal was subjected to middle cerebral artery (MCA) occlusion (90 min, intraluminal thread technique) under continuous monitorization of cerebrocortical perfusion (CP, laser-Doppler flowmetry), followed by reperfusion (3 days). Neurological status, infarct volume, and myeloperoxidase (MPO) activity were the main end points. Three days after the 90-min ischemia period, neurological examination did not reveal significant differences between the three groups of rats. Control rats showed a mean infarct volume of 145.9 +/- 24.7 mm(3) (21 +/- 4.1% of the ipsilateral hemisphere volume), while mean infarct volume in rats treated with 0.005 or 0.5 mu g/h 12-epi-scalaradial increased to 164.8 +/- 86.8 mm(3) (22.0 +/- 10.9%) and 211.5 +/- 12.2 mm(3) (28 +/- 3%, P < 0.05), respectively. Treatment with the highest dose of 12-epi-scalaradial (0.5 mu g/h) increased MPO activity in the ipsilateral hemisphere by about 140% (from 0.59 +/- 0.59 to 1.42 +/- 1.03 units of activity/g of tissue in comparison with the control ischemic hemisphere, P < 0.05). Overall, our results point to a positive rather than a negative influence of sPLA(2) activity during ischemia. This, along with its inability to decrease the inflammatory response, does not allow to propose the use of 12-epi-scalardial as a potential drug for stroke therapy.