title: Intravenous human interleukin-1alpha impairs memory processing in mice: dependence on blood-brain barrier transport into posterior division of the septum.
abstract: Peripherally administered cytokines profoundly affect the central nervous system (CNS). One mechanism by which they could affect the CNS is by crossing the blood-brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1alpha (hIL-1alpha; mIL-1alpha) are transported across the murine BBB with a high rate of transport into the posterior division of the septum (PDS), but it is unknown whether BBB transport is relevant to their actions. Here, we injected species-specific blocking antibodies into the PDS to determine whether transport across the BBB is required for blood-borne hIL-1alpha to affect memory. Retention was impaired in a dose-dependent manner when hIL-1alpha was injected either by tail vein (i.v.) or into the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1alpha was reversed by injecting a blocking antibody (Ab) specific for hIL-1alpha into the PDS. This shows that much of the memory impairment induced by hIL-1alpha depends on its ability to cross the BBB. Ab specific for mIL-1alpha was also effective in reversing memory impairment, showing that hIL-1alpha releases mIL-1alpha from endogenous stores. Whether the mIL-1alpha was released from peripheral stores, which would require it to cross the BBB, or from brain stores is unknown. In conclusion, these results show that exogenous, blood-borne hIL-1alpha affects memory by releasing mIL-1alpha from endogenous stores and by crossing the BBB to act at sites within the PDS.
authors.affiliation: Veterans Affair Meical Center, St Louis, Missouri 63106, USA. bankswa@slu.edu
authors.forename: W A
authors.initials: WA
authors.lastname: Banks
authors.forename: S A
authors.initials: SA
authors.lastname: Farr
authors.forename: M E
authors.initials: ME
authors.lastname: La Scola
authors.forename: J E
authors.initials: JE
authors.lastname: Morley
mesh_terms: D000465:Algorithms; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D020665:Septum of Brain / Q000378:metabolism* / Q000502:physiology*
chemical_list: D016207:Cytokines; D007375:Interleukin-1