Bone morphogenetic protein-6 reduces ischemia-induced brain damage in rats.
OBJECTIVE
Bone morphogenetic protein-6 (BMP6) and its receptors are expressed in adult and fetal brain. Receptors for BMP6 are upregulated in adult brain after injury, leading to the suggestion that BMP6 is involved in the physiological response to neuronal injury. The purpose of this study 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 H(2)O(2) in primary cortical cultures. The neuroprotective effects of BMP6 were also studied in chloral hydrate-anesthetized rats. BMP6 or vehicle was injected into right cerebral cortex before transient right middle cerebral artery (MCA) ligation. Animals were killed for triphenyl-tetrazolium chloride staining, caspase-3 immunoreactivity and enzymatic assays, and TUNEL assay. A subgroup of animals were used for locomotor behavioral assays.


RESULTS
Application of H(2)O(2) increased lactate dehydrogenase activity and decreased the density of MAP-2(+) neurons in culture. Both responses were attenuated by BMP6 pretreatment. Complementary in vivo studies showed that pretreatment 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 was decreased ischemia-induced caspase-3 immunoreactivity, caspase-3 enzymatic activity, and density of TUNEL-positive cells in ischemic cortex in BMP6-treated animals.


CONCLUSIONS
BMP6 reduces ischemia/reperfusion injury, perhaps by attenuating molecular events underlying apoptosis.
Wang
Y
Y
National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD, USA. ywang@intra.nida.nih.gov
Chang
C F
CF
Morales
M
M
Chou
J
J
Chen
H L
HL
Chiang
Y H
YH
Lin
S Z
SZ
Cadet
J L
JL
Deng
X
X
Wang
J Y
JY
Chen
S Y
SY
Kaplan
P L
PL
Hoffer
B J
BJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001783:Blood Flow Velocity / Q000187:drug effects; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002544:Cerebral Infarction / Q000209:etiology / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
C525818:Bmp6 protein, rat; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D018696:Neuroprotective Agents; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases