Improving effect of Ginkgolide B on mitochondrial respiration of ischemic neuron after cerebral thrombosis in tree shrews

Abstract

It has been known that platelet activating factor receptors (PAFR) may mediate many acute pathological responses and that PAFR antagonist Ginkgolide B (GB) possesses multiple effects, but the actions of GB on PAFR affinity and mitochondrial respiration in the ischemic neuron were unclear until now. This study explored the possible effects of GB on PAFR and the mitochondrial respiration of the neuron in the ischemic microenvironment. Thrombotic cerebral ischemia in tree shrews was induced by a photochemical reaction; changes in the regional cerebral blood flow (rCBF, using (99m)Tc tracer technique), the brain water content (specific gravimetric method), PAFR (3H-labelled PAF assay), the respiratory control rate (RCR), the phosphorus-oxygen (P/O) ratio of mitochondrial respiration (Clark oxygen electrode), mitochondrial permeability transition (MPT) pore, and the mitochondrial ultrastructure in the ischemic neurons were also observed. Data were compared between the two groups (the ischemia group vs the sham group, and the ischemia group vs the GB group). There were high affinity and low affinity sites for PAFR on the tree threws' brain cell membranes. The varying-affinity PAFR binding sites, the respiration state III, the state IV, RCR, the P/O ratio of the mitochondria, and the rCBF all decreased markedly (respectively, P < 0.01 and P < 0.05), but the water content increased (P < 0.01) in the ischemia group after the application of cerebral thrombosis. In tree shrews treated with GB (5 mg/kg i.v.) 6 hours after photochemical reaction, their PAFR binding sites and respiratory state increased markedly. The rCBF gradually increased and the brain edema ameliorated (P < 0.01) at 24h after cerebral ischemia. There were significant differences between the ischemia group and sham group (P < 0.01). In GB treated isolated neurons' mitochondria, with or without cerebral ischemia, the energy metabolism of the mitochondria had not been changed. The activation of the PAFR may play an important role in the inhibition of the mitochondrial respiration and the induction of neuronal damage after cerebral thrombosis; however, GB possesses neuroprotective effects by improving mitochondrial metabolism.