Morphogenetic protein-6 reduces ischemia-induced brain damage in rats

Background and Purpose-Bone morphogenetic protein-6 (BMP6) and its receptor s are expressed in adult and fetal brain. Receptors for BMP6 are upregulate d in adult brain after injury, leading to the suggestion that BMP6 is invol ved in the physiological response to neuronal injury. The purpose of this s tudy was to determine whether there was a neuroprotective effect of BMP6 in vivo and in vitro. Methods-Lactate dehydrogenase and microtubule-associated protein-2 (MAP-2) activities were used to determine the protective effect of BMP6 against H2O 2 in primary cortical cultures. The neuroprotective effects of BMP6 were al so studied in chloral hydrate-anesthetized rats. BMP6 or vehicle was inject ed into right cerebral cortex before transient right middle cerebral artery (MCA) ligation. Animals were killed for triphenyl-tetrazolium chloride sta ining, caspase-3 immunoreactivity and enzymatic assays, and TUNEL assay. A subgroup of animals were used for locornotor behavioral assays. Results-Application of H2O2 increased lactate dehydrogenase activity and de creased the density of MAP-2(+) neurons in culture. Both responses were att enuated by BMP6 pretreatment. Complementary in vivo studies showed that pre treatment with BMP6 increased motor performance and generated less cerebral infarction induced by MCA ligation/reperfusion in rats. Pretreatment with BMP6 did not alter cerebral blood flow or physiological parameters. There w as decreased ischemia-induced caspase-3 immunoreactivity, caspase-3 enzymat ic activity, and density of TUNEL-positive cells in ischemic cortex in BMP6 -treated animals. Conclusions-BMP6 reduces ischemia/reperfusion injury, perhaps by attenuatin g molecular events underlying apoptosis.