Pentoxifylline and insulin-like growth factor-I (IGF-I) abrogate kainic acid-induced cognitive impairment in mice.
Hippocampal insults involving neuroimmune mechanisms can impair learning and memory in a variety of tasks. The present study was designed to assess the effect of pentoxifylline, an inhibitor of tumor necrosis factor alpha (TNFalpha), and insulin-like growth factor-I (IGF-I) on kainate (KA)-induced impairment in spatial memory. Male mice received a subcutaneous injection of a dose of KA (15 mg/kg) that had no cytotoxic effect on hippocampal neurons as confirmed by Fluorojade B staining. This dose resulted in an impairment of spatial memory in a two-trial recognition task 11 days later. Intraperitoneal administration of pentoxifylline (200 mg/kg) abrogated this effect. Repeated intracerebroventricular injection of IGF-I (2 microg/mouse on day 1 followed by 1 microg/mouse on days 2-5) abrogated KA-induced deficits in spatial memory whereas acute IGF-I (2 microg/mouse on day 1 only) had mixed effects. These findings indicate that endogenous TNFalpha is probably involved in the detrimental effects of kainate on cognition and that exogenous IGF-I can oppose these effects, probably by antagonizing TNFalpha-induced neurotoxicity.
Bluthé
Rose-Marie
RM
Integrative Neurobiology, CNRS - INRA - University Victor Segalen, Bordeaux, France. rosemarie.bluthe@wanadoo.fr
Frenois
François
F
Kelley
Keith W
KW
Dantzer
Robert
R
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004193:Discrimination Learning / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005452:Fluoresceins; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000627:therapeutic use*; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D009930:Organic Chemicals / Q000378:metabolism; D010431:Pentoxifylline / Q000627:therapeutic use*
D005452:Fluoresceins; D016166:Free Radical Scavengers; D018970:Insulin-Like Growth Factor Binding Protein 1; D009930:Organic Chemicals; C435731:fluoro jade; D010431:Pentoxifylline; D007608:Kainic Acid