Postischemic PKC activation rescues retrograde and anterograde long-term memory.
Therapeutics for cerebral ischemia/hypoxia, which often results in ischemic stroke in humans, are a global unmet medical need. Here, we report that bryostatin-1, a highly potent protein kinase C (PKC) activator, interrupts pathophysiological molecular cascades and apoptosis triggered by cerebral ischemia/hypoxia, enhances neurotrophic activity, and induces synaptogenesis in rats. This postischemic therapeutic approach is further shown to preserve learning and memory capacity even 4 months later as well as long-term memory induced before the ischemic event. Our results of electromicroscopic and immunohistochemical analyses of neuronal and synaptic ultra-structure are consistent with a PKC-mediated synaptic remodeling and repair process that confers long-lasting preservation of spatial learning and memory before and after the cerebral ischemic/hypoxic event, suggesting a previously undescribed therapeutic modality for cerebral ischemia/hypoxia and ischemic stroke.
Sun
Miao-Kun
MK
Blanchette Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26505, USA. mksun@brni-jhu.org
Hongpaisan
Jarin
J
Alkon
Daniel L
DL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D054713:Bryostatins / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008854:Microscopy, Electron; D009043:Motor Activity / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013572:Synaptic Vesicles / Q000187:drug effects / Q000648:ultrastructure; D013997:Time Factors
D054713:Bryostatins; D020536:Enzyme Activators; D011493:Protein Kinase C