Synergistic effects of chronic bryostatin-1 and alpha-tocopherol on spatial learning and memory in rats.
Evidence is emerging that protein kinase C (PKC) plays a crucial role in the neural processing of memory information and that PKC deficits underlie certain types of memory impairment, including Alzheimer's dementia. Chronic activation of PKC isozymes with bryostatin-1 induces synthesis of the proteins that are involved in memory consolidation and, therefore, may represent a pharmacological strategy for antidementic and memory therapies. PKC isozymes are, however, sensitive to oxidants, whose generation is also increased by PKC activation. Oxidants may be responsible for some adverse effects with PKC activators, potentially limiting their antidementic and memory-enhancing "benefit". We investigated the effects of intravenous bryostatin-1, a potent PKC activator, and of its co-administration with oral alpha-tocopherol, a potent antioxidant, on spatial learning and memory. Bryostatin-1 at a chronic and intravenous dose of 10 microg/m2 (2 doses/week for 3 weeks) alone did not significantly affect the spatial learning and memory, but showed a synergistic effect when co-administered with alpha-tocopherol (60 IU/kg, orally and daily for 3 weeks), a potent lipid-soluble antioxidant and also a possible inhibitor of PKC in peripheral tissues. Acute administration of the same doses, however, did not have obvious influence on the learning and memory. These results provide support for the strategy of achieving memory-enhancing benefits with PKC activators and restricting their oxidant-related adverse effects with alpha-tocopherol co-administration. These agents, therefore, may hold significant potential as new, combined antidementic and memory therapeutics in the future.
Sun
Miao-Kun
MK
Blânchette Rockefeller Neurosciences Institute, Rockville, MD 20850, USA. mksun@brni-jhu.org
Alkon
Daniel L
DL
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D054713:Bryostatins / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D007858:Learning / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology*
D000975:Antioxidants; D054713:Bryostatins; D020536:Enzyme Activators; D018697:Nootropic Agents; D017382:Reactive Oxygen Species; C046785:bryostatin 1; D011493:Protein Kinase C; D024502:alpha-Tocopherol