ginkgolide-k and Infarction--Middle-Cerebral-Artery

Ginkgolide K (GK) is a new compound extracted from the leaves of Ginkgo biloba, which has been recognized to exert anti-oxidative stress and neuroprotective effect on ischemic stroke. While whether it plays an enhanced effect on angiogenesis during ischemic stroke remains unknown. The aim of this study was to investigate the effect of ginkgolide K on promoting angiogenesis as well as the protective mechanism after cerebral ischemia-reperfusion. Using the transient middle cerebral artery occlusion (tMCAO) mouse model, we found that GK (3.5, 7.0, 14.0 mg/kg, i.p., bid., 2 weeks) attenuated neurological impairments, and promoted angiogenesis of injured ipsilateral cortex and striatum after 14 days of cerebral ischemia-reperfusion in mice. Further, GK (3.5 mg/kg in vivo, 10 μM in vitro) significantly up-regulated the expressions of HIF-1α and VEGF in tMCAO mouse brains and in b End3 cells after OGD/R, and GK-induced upregulation of HIF-1α and VEGF in b End3 cells could be abolished by JAK2/STAT3 inhibitor AG490. Our results demonstrate that GK promotes angiogenesis after ischemia stroke through increasing the expression of HIF-1α/VEGF via JAK2/STAT3 pathway, which provide an insight into the novel clinical application of GK and its analogs in ischemic stroke therapy in future.

Topics: Animals; Brain; Disease Models, Animal; Ginkgo biloba; Ginkgolides; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Infarction, Middle Cerebral Artery; Janus Kinase 2; Lactones; Male; Mice; Mice, Inbred C57BL; Middle Cerebral Artery; Neovascularization, Physiologic; Reperfusion Injury; Signal Transduction; STAT3 Transcription Factor; Tyrphostins; Vascular Endothelial Growth Factor A

Ginkgolide K, a natural platelet-activating factor receptor antagonist, was isolated from the leaves of Ginkgo biloba. However, little is known about its neuroprotective effect in ischemia-reperfusion (I/R)-induced cerebral injury. Hence, the present study was carried out to investigate the effect of ginkgolide K on neuroprotection and the potential mechanisms in the rat I/R model induced by middle cerebral artery occlusion (MCAO). The rats were pretreated with ginkgolide K 2, 4 and 8 mg/kg (i.v.) once a day for 5 days before MCAO. Neurological deficit score (NDS), brain water content, 2,3,5-triphenyltetrazolium chloride (TTC) staining and pathology of brain tissue, as well as indexes of oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS)] were measured at 24 h after ischemia. The results indicated that pretreatment with ginkgolide K significantly diminished the volume of infarction and brain water content, and improved NDS. Moreover, ginkgolide K markedly reversed the level of MDA, NO, NOS and SOD to their normal state in serum or cerebral ischemic section. In addition, hematoxylin and eosin staining showed the neuronal injury was significantly improved after being pretreated with ginkgolide K. These findings demonstrate that ginkgolide K exhibits neuroprotective properties through its antioxidative action in MCAO rats.

Topics: Animals; Antioxidants; Brain; Brain Edema; Brain Ischemia; Disease Models, Animal; Ginkgolides; Infarction, Middle Cerebral Artery; Lactones; Male; Malondialdehyde; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Rats, Sprague-Dawley; Stroke; Superoxide Dismutase