Development of cognitive enhancers based on inhibition of insulin-regulated aminopeptidase.
The peptides angiotensin IV and LVV-hemorphin 7 were found to enhance memory in a number of memory tasks and reverse the performance deficits in animals with experimentally induced memory loss. These peptides bound specifically to the enzyme insulin-regulated aminopeptidase (IRAP), which is proposed to be the site in the brain that mediates the memory effects of these peptides. However, the mechanism of action is still unknown but may involve inhibition of the aminopeptidase activity of IRAP, since both angiotensin IV and LVV-hemorphin 7 are competitive inhibitors of the enzyme. IRAP also has another functional domain that is thought to regulate the trafficking of the insulin-responsive glucose transporter GLUT4, thereby influencing glucose uptake into cells. Although the exact mechanism by which the peptides enhance memory is yet to be elucidated, IRAP still represents a promising target for the development of a new class of cognitive enhancing agents.
Chai
Siew Yeen
SY
Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. sychai@florey.edu.au
Yeatman
Holly R
HR
Parker
Michael W
MW
Ascher
David B
DB
Thompson
Philip E
PE
Mulvey
Hayley T
HT
Albiston
Anthony L
AL
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D018697:Nootropic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D006454:Hemoglobins; D018697:Nootropic Agents; D010446:Peptide Fragments; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C074309:LVV-hemorphin-7; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase