PKC activator therapeutic for mild traumatic brain injury in mice.
Traumatic brain injury (TBI) is a frequent consequence of vehicle, sport and war related injuries. More than 90% of TBI patients suffer mild injury (mTBI). However, the pathologies underlying the disease are poorly understood and treatment modalities are limited. We report here that in mice, the potent PKC activator bryostatin1 protects against mTBI induced learning and memory deficits and reduction in pre-synaptic synaptophysin and post-synaptic spinophylin immunostaining. An effective treatment has to start within the first 8h after injury, and includes 5 × i.p. injections over a period of 14 days. The treatment is dose dependent. Exploring the effects of the repeated bryostatin1 treatment on the processing of the amyloid precursor protein, we found that the treatment induced an increase in the putative α-secretase ADAM10 and a reduction in β-secretase activities. Both these effects could contribute towards a reduction in β-amyloid production. These results suggest that bryostatin1 protects against mTBI cognitive and synaptic sequela by rescuing synapses, which is possibly mediated by an increase in ADAM10 and a decrease in BACE1 activity. Since bryostatin1 has already been extensively used in clinical trials as an anti-cancer drug, its potential as a remedy for the short- and long-term TBI sequelae is quite promising.
Zohar
Ofer
O
Blanchette Rockefeller Neurosciences Institute, West Virginia University, 9601 Medical Center Drive, Rockville, MD 20850, USA. zohar@brni-jhu.org
Lavy
Rotem
R
Zi
Xiaomei
X
Nelson
Thomas J
TJ
Hongpaisan
Jarin
J
Pick
Chaim G
CG
Alkon
D L
DL
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001930:Brain Injuries / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D054713:Bryostatins / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011493:Protein Kinase C / Q000378:metabolism*
D000970:Antineoplastic Agents; D054713:Bryostatins; D018696:Neuroprotective Agents; C046785:bryostatin 1; D011493:Protein Kinase C