BDNF protects neurons following injury by modulation of caspase activity.
BACKGROUND
Neurotrophins can protect against apoptotic death following neuronal injury. In a previous article, we showed that activation of the trk receptor is required, but the subsequent mechanisms of action remain unclear. Because the caspase family of cysteine proteases plays a central role in the apoptotic process, we examined the effect of the neurotrophins on caspase activation.


METHODS
Primary neuronal cultures from the embryonic rat cortex were injured with radiation, oxygen deprivation, or oxygen-glucose deprivation. Neurons were treated with brain-derived growth factor (BDNF) or caspase inhibitors. The level of injury was assayed by measuring lactate dehydrogenase release. Western blots were used to note the presence and activation of the caspases 1, 2, 3, 8, and 9--with and without treatment with BDNF.


RESULTS
Proenzymes for caspases 1, 2, and 3--but not for caspases 8 or 9 were expressed. With radiation or oxygen deprivation, but not oxygen-glucose deprivation, caspase 3 was activated. Treatment with BDNF was protective against radiation and oxygen deprivation only. Treatment with BDNF also blocked the activation of caspase 3. A similar effect was achieved by directly blocking caspase 1 or 3 activation using an inhibitor.


CONCLUSIONS
In this study, we showed that BDNF treatment inhibits caspase 3 activation following neuronal injury. This is a central event: when injury did not lead to caspase 3 activation, BDNF treatment was not protective. These results suggest one mechanism by which the neurotrophins protect neurons following injury.
Kim
Dong H
DH
Department of Neurosurgery,The Brigham and Women's Hospital, Boston, MA 02115, USA.
Zhao
Xiurong
X
D000818:Animals; D001930:Brain Injuries / Q000517:prevention & control*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D061945:Caspase Inhibitors; D002540:Cerebral Cortex / Q000196:embryology / Q000293:injuries*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D019208:Brain-Derived Neurotrophic Factor; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors