Induction of infarct tolerance by platelet-derived growth factor against reversible focal ischemia

Nerve growth factor, brain-derived neurotrophic factor, and other neurotrophic factors have been reported to have neuroprotective effects against global ischemia. To investigate whether the homodimer of platelet-derived growth factor B-chain (PDGF-BB) can protect neurons against focal temporary ischemia, PDGF-BB was administered to the rat brain for a prolonged period prior to, during, and after ischemia, since PDGF-BB protected rat neurons from global ischemia in our previous study. A total of 82 male Sprague-Dawley rats were used. Recombinant PDGF-BB, or saline was administered into the left neocortex via an implanted osmotic pump for 3 days (1.2 microg in total), 7 days (2 microgram or 4 microgram in total), or 14 days (4 microgram in total) pre-ischemia and 2 days post-ischemia. In an additional group, PDGF-BB (4 microgram in total) was administered for 14 days by osmotic pump and focal ischemia was induced after an additional 7-day interval following removal of the pump. Focal temporary ischemia was induced in the left MCA territory by bilateral CCA and MCA occlusion for 2 h. All rats were sacrificed 2 days after ischemia and the volume of cerebral infarct was analyzed using TTC staining. In a separate set of animals, regional cerebral blood flow (rCBF) was monitored by the hydrogen clearance method and laser Doppler flowmetry (LDF) of the neocortex after 14 days of intracerebral administration of PDGF-BB or saline. In the group receiving PDGF-BB (4 microgram in total) for 7 or 14 days pre-ischemia, there was a significant reduction of neocortical infarction compared to that in the control or saline-infused group. The size of cerebral infarct was smallest in the group that received PDGF-BB for 14 days, when ischemia was induced 7 days after removal of the pump. Regarding rCBF measurement, there were no significant differences in groups receiving PDGF-BB or saline infusion for 14 days. The potent neuroprotective effect of PDGF-BB on global ischemia was also demonstrated in the focal ischemia model. However, prolonged intracerebral infusion for 7 to 14 days was necessary to achieve a significant reduction of infarct volume. Neuroprotection was not due to increased collateral flow during ischemia.