Fever can provoke "febrile" seizures (FS). Because complex FS may promote development of temporal lobe epilepsy, understanding their mechanisms is clinically important. Using an immature rodent model and transgenic technology, we examined the role of interleukin-1beta, (IL-1beta), a pyrogenic, proinflammatory cytokine, in FS. IL-1beta receptor-deficient mice were resistant to experimental FS. This resistance appeared independent of genetic background and was attributed to lack of IL-1beta signaling, because exogenous cytokine reduced seizure threshold in wild-type but not receptor-deficient mice independent of strain. In addition, high IL-1beta doses induced seizures only in IL-1beta receptor-expressing mice. These data indicate that IL-1beta signaling contributes critically to fever-induced hyperexcitability underlying FS, constituting a potential target for their prevention.

Selective serotonin reuptake inhibitors, such as fluoxetine (FLX), are the most commonly used drugs in the treatment of major depression. However, there is a limited understanding of their molecular mechanism of action. Although the acute effect of selective serotonin reuptake inhibitors in elevating synaptic serotonin concentrations is well known, the clinical amelioration of depressive symptoms requires 14 -21 days of treatment, suggesting that numerous other rearrangements of function in the CNS must take place. In the present study, we demonstrated that 14 days of FLX treatment up-regulated galanin mRNA levels by 100% and GalR2-binding sites by 50%, in the rat dorsal raphe nucleus, where galanin coexists with serotonin. Furthermore, a galanin receptor antagonist, M40, attenuated the antidepressant-like effect of FLX in the forced swim test, a rodent preclinical screen commonly used to evaluate antidepressant-like efficacy. Direct activation of galanin receptors by a galanin receptor agonist, galnon, was found to produce an antidepressant-like effect in the same task. Two other antidepressant treatments also affected the galaninergic system in the monoaminergic nuclei: Electroconvulsive shock elevated galanin mRNA levels in dorsal raphe nucleus, whereas sleep deprivation increased galanin mRNA levels in the locus coeruleus, further underlining the connection between activation of the galaninergic system and antidepressant action of various clinically proven treatments. O ur understanding of the molecular mechanism of action of fluoxetine (FLX), beyond its effect of elevating synaptic serotonin [5-hydroxytryptamine (5-HT)] concentration, is limited. The delay in the onset of clinical antidepressant effect suggests that transcriptional and translational events, leading to functional changes in signaling within the major serotoninergic nucleus dorsal raphe nucleus (DRN) and in its projection areas, may be required for these therapeutic effects (1-3). One potential player in mediating the long-term effects of FLX, besides 5-HT, is the neuropeptide galanin. Galanin, through its three G-protein-coupled receptors, GalR1, GalR2, and GalR3 (4), regulates homeostatic and motivated behaviors including pain perception, sleep, food intake, sexual activity, learning, and memory (5). Galaninergic transmission modulates the activity of monoaminergic neurons in the ventral tegmental area, DRN, and locus coeruleus (LC) (6-10). Galanin receptor subtypes GalR1 (7) and GalR2 are expressed in DRN neurons (11) that can be activated by galanin dendritically released from the dorsal raphe 5-HT neurons (9, 12) or from surrounding galanin immunoreactive terminals (7). In the noradrenergic nucleus LC, an area that is closely connected both structurally and functionally to DRN (13,14), GalR1 expression is induced by morphine withdrawal (15), and the galanin receptor agonist, galnon, was shown to attenuate several withdrawal signs (16). It is worth noting that drug withdrawal often precipitates symptoms of depression, and depression is a ...

BB-loop ͉ protein-protein interaction ͉ IL-1␤ signaling ͉ fever

SummaryGender is a profound determinant of aging and lifespan, but little is known about gender differences in free radical homeostasis. Free radicals are proposed as key elements in the multifactorial process of aging and it is predicted that the longer-lived gender should have lower levels of oxidative stress. While the majority of studies on aging have included a single gender, recent studies in rats compared genders and found that females, the longer-lived sex, had lower oxidative stress and mitochondrial dysfunction than males. We explored the association between oxidative stress and gender-specific aging in C57BL6 mice, in which females are the shorter-lived gender. Reactive oxygen species (ROS) were measured in young and old mice by confocal imaging of dihydroethidium (DHE) oxidation in the brain, and by electron paramagnetic resonance (EPR) spectrometry of isolated brain mitochondria. Both genders exhibited significant agedependent increases in ROS. However, females had a greater increase with age than males in DHE oxidation but not mitochondrial EPR. Superoxide dismutase 1 (Sod1) and glutathione peroxidase 1 (GPx1) protein levels were lower in old females. To determine whether enhancing antioxidant defenses would eliminate gender differences in lifespan, mice were treated chronically with a superoxide dismutase mimetic. Treatment blocked the age-dependent increase in ROS, with a greater effect in females on DHE oxidation, but not mitochondrial EPR. Treatment also increased lifespan to a greater degree in females. Our results indicate that differences in ROS homeostasis contribute to gender divergence in survival, but also suggest that mitochondrial superoxide production may not be primarily responsible for gender differences in lifespan.

Interleukin (IL)-cytokine ͉ interleukin ͉ protein-protein interaction ͉ inflammation I nterleukin (IL)-1␤ is a proinflammatory cytokine (1, 2) known to mediate a variety of host responses to infection and inflammation. These effects include components of the acute phase response such as induction of the elevation of body temperature (fever), anorexia, and somnolence through effects on non-rapideye-movement sleep (3-5). The concentration of this cytokine and its receptor are highly modulated during CNS injury, neurodegeneration, and inflammation (6). Chronic action of IL-1␤ in the brain leads to induction of additional inflammatory mediators, such as IL-6 and TNF␣, and to the induction of biosynthetic enzymes for inflammatory mediators including cyclooxygenase-2 (COX2) and inducible NO synthase (7). Upon binding of IL-1␤, the type-I IL-1 receptor (IL-1RI) forms a signaling heterodimer with the IL-1 receptor accessory protein (IL-1RAcP) (8). Both IL-1RI and IL-1RAcP belong to the family of Toll-like receptor proteins (9, 10), which transduce signaling through interactions with other Toll͞IL-1 receptor (TIR) domain-containing proteins. Upon IL-1␤ binding, the cytosolic TIR-domain adaptor protein myeloid differentiation primary response protein 88 (MyD88) associates with both the IL-1RI and IL-1RAcP, triggering the recruitment of a series of signaling proteins (11,12), leading to the activation of mitogenactivated protein kinases (13) and, ultimately, to the activation of the transcription factor NF-B (14, 15).We have shown previously with the use of a synthetic lowmolecular-weight MyD88 mimetic, hydrocinnamoyl-L-valyl pyrrolidine (AS-1), that disruption of the interaction of MyD88 with the IL-1RI͞IL-1RAcP complex prevents the development of the fever response induced by IL-1␤ in mice (16). These data support the hypothesis that the transcription-dependent effects (induction of COX2 and prostaglandin E 2 ) induced by IL-1␤ actions in the anterior hypothalamus (AH) require MyD88, similar to IL-1␤-mediated effects in macrophages (17,18).We prepared a novel series of bifunctional TIR domain mimetics that were used on primary cultures of preoptic area (POA)͞AH neurons (obtained from wild-type and MyD88 Ϫ/Ϫ mice) for the analysis of the rapid effects of IL-1␤ exposure on two main signaling kinases responsible for the regulation of ion channels in neurons, the protein tyrosine kinase Src and the serine͞threonine kinase Akt͞PKB. We show that Src activation depends on the recruitment of the adaptor protein MyD88 to the IL-1RI͞IL-1RAcP receptor complex in POA͞AH neurons. The activation of Akt͞PKB depended on PI3-kinase activation, through binding of its p85 subunit to IL-1RI, but independent of MyD88 association. The clear separation of the two pathways activated by IL-1␤ in POA͞AH neurons observed in the presence of the MyD88 mimetics suggests that these compounds may have relevant antiinflammatory actions and promote neuronal survival in the nervous system.