Severe weight loss and debilitative wasting of lean body mass frequently complicate the treatment of patients suffering from malignancy or chronic infection. Termed cachexia, this syndrome of anorexia, anemia, and weakness further increases cancer mortality; some data indicate that as many as 30% of cancer patients die from cachexia, rather than tumor burden (1-3). The severity of cachexia may be unrelated to tumor size or parasite load, and profound wasting has been observed in patients with tumor burdens of only 0.01-5.0% body mass (4). If not reversed, cachexia-associated derangements of homeostasis lead to immunological deficiencies, organ failure, and multiple metabolic abnormalities . While it is clear that a variety of mechanisms participate in the pathogenesis of cachexia, and that cachexia adversely affects prognosis, the etiology of this syndrome is not known.For a number of years we have been searching for endogenous, humoral mediators of cachexia, beginning with the characterization of metabolic changes in trypanosome-infected rabbits that develop profound cachexia and lose up to 50% of lean body mass within weeks. In later stages of disease a paradoxical increase in circulating triglycerides occurs, attributable to systemic suppression of lipoprotein lipase (LPL)t (5). A bacterial LPS-inducible serum factor which suppresses LPL in mice, and several other key lipogenic enzymes in the adipocyte cell line 3T3-L1, was isolated and named cachectin (6, 7). Cachectin evokes a state of cellular cachexia by suppressing the expression of several mRNAs encoding essential lipogenic enzymes (8, 9). Myocytes also show changes in cellular metabolism after exposure to cachectin in vitro, including a prompt decrease in resting transmembrane potential difference and depletion of intracellular glycogen stores with increased lactate efflux, and a later increase in hexose transporters (10,11). It has been suggested that cachectin may play a

The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses.

The commitment of cells to replicate and divide correlates with the activation of cyclin-dependent kinases and the inactivation of Rb, the product of the retinoblastoma tumor suppressor gene. Rb is a target of the cyclin-dependent kinases and, when phosphorylated, is inactivated. Biochemical studies exploring the nature of the relationship between cyclin-dependent kinase inhibitors and Rb have supported the hypothesis that these proteins are on a linear pathway regulating commitment. We have been able to study this relationship by genetic means by examining the phenotype of Rb؉͞؊p27؊͞؊ mice. Tumors arise from the intermediate lobe cells of the pituitary gland in p27؊͞؊ mice, as well as in Rb؉͞؊ mice after loss of the remaining wild-type allele of Rb. Using these mouse models, we examined the genetic interaction between Rb and p27. We found that the development of pituitary tumors in Rb؉͞؊ mice correlated with a reduction in p27 mRNA and protein expression. To determine whether the loss of p27 was an indirect consequence of tumor formation or a contributing factor to the development of this tumor, we analyzed the phenotype of Rb؉͞ ؊p27؊͞؊ mice. We found that these mice developed pituitary adenocarcinoma with loss of the remaining wild-type allele of Rb and a high-grade thyroid C cell carcinoma that was more aggressive than the disease in either Rb؉͞؊ or p27؊͞؊ mice. Importantly, we detected both pituitary and thyroid tumors earlier in the Rb؉͞؊p27؊͞؊ mice. We therefore propose that Rb and p27 cooperate to suppress tumor development by integrating different regulatory signals.A number of proteins prevent entry of cells into S phase. One group, Rb and the related proteins p107 and p130, act by redirecting or sequestering transcription factors regulating genes required for S phase (1, 2). Another group, members of the Ink4 (p15, p16, p18, and p19) and Cip͞Kip families (p21, p27, and p57), act by inhibiting the cyclin-dependent kinases (cdks), CDK4͞6 and CDK2 (3). Furthermore, these kinases are responsible for the coordinate phosphorylation and inactivation of the growth-suppressive functions of Rb (4-6). In tumor-derived cell lines lacking Rb, CDK4 function is dispensable for entry into S phase (7). However, CDK2 kinase activity is essential for proliferation, irrespective of Rb status, suggesting that, in addition to its role in inactivation of Rb, CDK2 has another function required for S phase (8).These cell-culture-based studies suggest that CDK4 and Rb lie in a common regulatory pathway, whereas CDK2 regulates Rb inactivation and an as-yet unidentified pathway. Biochemical studies on the association of p27 with cyclin D2͞CDK4 and cyclin E͞CDK2 complexes have shown that, at physiological amounts, p27 seems to inhibit CDK2 preferentially over CDK4 (9, 10). Based on these studies, we speculated that the simultaneous disruption of p27 and Rb might mimic the constitutive activation of the CDK2 pathway and remove the requirement for the CDK4 pathway. A caveat, however, is that the relationship between these pr...

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A simple and reliable animal model to quantify interleukin-1 (IL-1) production at a site of inflammation has been developed and characterised. This model involves the subcutaneous implantation of sterile Teflon chambers (30 mm x 10 mm diameter) into the backs of mice. After 14 days, a straw coloured transudate fluid was present in the lumen of the implanted chamber which was withdrawn for the determination of baseline measurements of various inflammatory parameters. A localised chronic inflammatory response was then induced in the chambers by injection of 1% zymosan or Bordetella pertussis vaccine (BPV) (in presensitised animals). The local inflammatory reaction in the chamber, over a 30 day time course, was characterised by leucocyte infiltration, and marked increases in protein, prostaglandin E2, IL-1 and IL-6 concentrations in the chamber fluid. A rapid increase in plasma concentrations of the acute-phase reactant serum amyloid P (SAP) also occurred. This model allows repeated samples to be obtained from the same animal for the assessment of inflammatory parameters and may be useful for investigating the mechanisms controlling the production of IL-1 during the inflammatory response in vivo.

Most preclinical studies investigating the effects and the mechanism of action of antidepressants have been performed in naive rodents. This is inappropriate because antidepressants act on specific symptoms of the pathological condition, such as distress and anxiety. We have developed a mouse model of anxiety/depression based on addition of corticosterone to drinking water. This model is highly reproducible and easy to set up compared with unpredictable chronic mild stress. The serotonin 1A (5-HT 1A ) autoreceptor is known to play a role in mood disorders and their treatments. An increase in somatodendritic 5-HT 1A autoreceptor density in the dorsal raphe (DR) attenuates the therapeutic activity of selective serotonin-reuptake inhibitors (SSRIs), whereas their functional desensitization promotes activation of brain serotonergic transmission, thereby representing an adaptive change relevant to their therapeutic effect. Here we assessed the effects of sustained administration of the SSRI fluoxetine on 5-HT 1A autoreceptor sensitivity in mice administered with corticosterone. Fluoxetine attenuated hypothermia induced by the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin, decreased DR 5-HT neuronal activity, and decreased 5-HT release in both vehicle-and corticosterone-pretreated mice. However, such desensitization was more pronounced in corticosterone-pretreated mice. This change had an overall effect on serotonergic tone because we found a greater firing rate of 5-HT neurons associated with an enhancement of 5-HT outflow in the DR of corticosterone-pretreated mice in response to fluoxetine compared with the corresponding group of vehicle-pretreated mice. These results provide cellular explanations for the antidepressant effects produced by SSRIs in subjects with pathological conditions but not in naive animals or healthy volunteers.

Although studies support the hypothesis that the inactivation of 5-HT(2A) and/or 5-HT(2C) receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT(2B) receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern.