No abstract

Several cytokines and their receptors are identified in brain; one of these is the proinflammatory cytokine interleukin-1beta that is synthesized and released from neurons and glia in response to stress or insult. Among the actions of interleukin-1beta is its ability to inhibit long-term potentiation in the hippocampus in vitro, an action that mimics one of the consequences of stress and age. It has been shown that the concentration of interleukin-1beta in brain tissue is increased in neurodegenerative conditions, and recent evidence from our laboratory has indicated an increase in the concentration of interleukin-1beta in the hippocampus of aged rats. These observations led us to consider that the underlying common cause of impaired long-term potentiation in aged and stressed rats might be increased endogenous interleukin-1beta concentration in hippocampus. The data presented here indicate that there was an inverse relationship between concentration of interleukin-1beta in the dentate gyrus and long-term potentiation in perforant path-->granule cell synapses in aged rats, stressed rats, and rats pretreated with interleukin-1beta. The evidence suggested that the cytokine induces formation of reactive oxygen species that triggers lipid peroxidation in vivo, as well as in vitro, and that these changes lead to depletion of membrane arachidonic acid that correlates with impaired long-term potentiation. We propose that three theories of aging, the glucocorticoid theory, the membrane theory, and the free radical theory, constitute three facets of age with one underlying trigger: an increase in the endogenous concentration of interleukin-1beta in hippocampus.

Long-term potentiation (LTP) in perforant path-granule cell synapses is decreased in aged rats, stressed rats, and rats injected intracerebroventricularly with the proinflammatory cytokine interleukin-1␤ (IL-1␤). One factor that is common to these experimental conditions is an increase in the concentration of IL-1␤ in the dentate gyrus, suggesting a causal relationship between the compromise in LTP and increased IL-1␤ concentration. In this study, we have investigated the downstream consequences of an increase in IL-1␤ concentration and report that the reduced LTP in rats injected intracerebroventricularly with IL-1␤ was accompanied by a decrease in KCl-stimulated glutamate release in synaptosomes prepared from dentate gyrus, although unstimulated glutamate release was increased. These changes were paralleled by increased activity of the stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase. Intracerebroventricular injection of IL-1␤ increased reactive oxygen species production in hippocampal tissue, whereas IL-1␤ and H 2 O 2 increased activities of both JNK and p38 in vitro. Dietary manipulation with antioxidant vitamins E and C blocked the increase in reactive oxygen species production, the stimulation of JNK and p38 activity, the attenuation of glutamate release, and the IL-1␤-induced inhibitory of LTP. We propose that IL-1␤ stimulates activity of stress-activated kinases, which in turn may inhibit glutamate release and result in compromised LTP and that these actions are a consequence of increased production of reactive oxygen species.Key words: LTP; dentate gyrus; IL-1␤; stress-activated kinases; glutamate release; reactive oxygen species Consistent with the high expression of IL-1 receptors in the hippocampus (Lechan et al., 1990;Ban et al., 1991;Parnet et al., 1994) are several observed effects of exogenous IL-1 in this brain area. For example, IL-1␤ exerts an inhibitory effect on (1) long-term potentiation (LTP) in CA1 (Bellinger et al., 1993), CA3 (Katsuki et al., 1990), and dentate gyrus (Cunningham et al., 1996; Murray and Lynch, 1998a,b), (2) release of acetylcholine (Rada et al., 1991) and glutamate (Murray et al., 1997) in hippocampal synaptosomes, (3) calcium influx in hippocampal synaptosomes (Murray et al., 1997), and (4) Ca 2ϩ channel currents in hippocampal neurons (PlataSalaman and ffrench-Mullen, 1994).The mechanism by which IL-1␤ inhibits LTP remains to be established. Because maintenance of LTP has been associated with increased glutamate release (Bliss and Collingridge, 1993;Canevari et al., 1994;McGahon and Lynch, 1996;McGahon et al., 1997), one factor that may contribute to inhibition of LTP is the inhibitory effect of IL-1␤ on glutamate release. However, it has been recently reported that the IL-1␤-induced attenuation of LTP in dentate gyrus in vitro is blocked by SB203580 (Coogan et al., 1997), an inhibitor of p38 that is one member of the family of mitogenactivated protein (MAP) kinases. The MAP kinase family has been identified as a major ...

Several neurodegenerative disorders are associated with evidence of inflammation, one feature of which is increased activation of microglia, the most likely cellular source of inflammatory cytokines like interleukin‐1β. It is now recognized that interaction of microglia with other cells contributes to maintenance of microglia in a quiescent state and the complementary distribution of the chemokine, fractalkine (CX3CL1) on neurons and its receptor (CX3CR1) on microglia, suggests that this interaction may play a role in modulating microglial activation. Here we demonstrate that both soluble and membrane‐bound fractalkine attenuate lipopolysaccharide‐induced microglial activation in vitro. We also show that fractalkine expression is reduced in the brain of aged rats and this is accompanied by an age‐related increase in microglial activation. Treatment of aged rats with fractalkine attenuates the age‐related increase in microglial activation and the evidence indicates that fractalkine‐induced activation of the phosphatidylinositol‐3 kinase pathway is required to maintain microglia in a quiescent state both in vivo and in vitro.

Using a one-step procedure we have prepared magnetic fluids comprising of polyelectrolyte stabilized magnetite nanoparticles. These nanocomposites are comprised of linear, chain-like assemblies of magnetic nanoparticles, which can be aligned in parallel arrays by an external magnetic field. We have shown the potential use of these materials as contrast agents by measuring their MR response in live rats. The new magnetic fluids have demonstrated good biocompatibility and potential for in vivo MRI diagnostics.