18.8.1 Effect of Multitarget Drugs (e.g., Monoamine Transporter Blockers)
More recently, a number of studies focused on the pro and anti-inflammatory cytokine balance in major depressive disorders. A dysregulation within the cytokine balance could induce depressive symptoms due to lower levels of anti-inflammatory cytokines and higher levels of proinflammatory cytokines. Anti-inflammatory cytokines or cytokine receptors are known to evoke an antiinflammatory state both on their own (IL-10, TGFP) receptors and also by the blockade of the binding of proinflammatory stimuli to their cell surface receptors (IL-1ra, soluble TNF receptors II). Growing evidence supports the idea of an anti-inflammatory action of antidepressants, which could explain their efficiency on depressive symptoms. In some clinical studies, it has been reported that antidepressants may attenuate the effects of proinflammatory cytokines by increasing the production of anti-inflammatory cytokines such as IL-10 and IL-1ra. Most antidepressant treatments could significantly reduce the IFNy/IL-10 ratio and have negative immunoregulatory effects (Maes et al. 1999b).
Currently, the most important and widely used antidepressants are the inhibitors of monoamine-transporters, among them the tricyclic antidepressants (TCAs) and their improved counterparts. The correlation between antidepressant treatment and immunological changes demonstrated that treatment with TCAs had complex time-dependent immunoregulatory effects. Short-term administration of TCAs was shown to stimulate cell-mediated immunity and to increase IL-1 bioactivity, while prolonged treatment significantly increased the secretion of IL-10 (Maes et al. 1999b). In contrast, other groups concluded that the effect of chronic treatment with antidepressants was probably not mediated by the effect of TCAs on peripheral cytokine production, because even a 5-week-long treatment with TCAs did not alter the LPS-induced expression of TNF-a, while IL-1P release is unknown (Yirmiya et al. 2001).
In our earlier studies, it was shown that cytokine production was under tonic, sympathetic control (Vizi 1998; Elenkov et al. 2000). In an animal depression model achieved by reserpine treatment, a significantly higher TNF-a response was observed (Szelenyi et al. 2000a). Recently it was demonstrated that both an acute treatment of mice with the antidepressant desipramine (an inhibitor of norepinephrine transporter (NET)), and genetic modifications of mice that lead to NET deficiency (NET-KO) resulted in a significant decrease in the LPS-evoked TNF-a response (Szelenyi and Selmeczy 2002; Selmeczy, Szelenyi, and Vizi 2003).
The extent and/or the duration of monoamine neurotransmitter action are one of the key points in the development of therapies for depression. The extracellular monoamine concentration is basically determined by the balance of its release and uptake. The release of NE, e.g., is controlled by the negative feedback mechanism of presynaptic a2-ARs (Vizi 1979; Kiss et al. 1995), as it was discussed above. For the rapid removal of norepinephrine released from sympathetic neurons, its reuptake via NET is responsible. Antidepressants have been reported to inhibit the activity of monoamine transporters that result in an increased biophase level of monoamines. A
similar effect could be achieved by genetic removal of the transporter gene as it was realized in NET-KO (Xu et al. 2000), DAT-KO (Moron, Brockington, Wise, Rocha, and Hope 2002), and 5HTT-KO mice (Alexandre et al. 2006). These animals behave like mice chronically treated with antidepressants, exhibiting high extracellular monoamine levels. Long-term inhibition of the NET by antidepressants has been reported to change the density and function of pre and postsynaptic a2-ARs, which may contribute to the antidepressant effects of NET inhibitors such as desipramine. In the NET-KO animals, it was demonstrated that the density of a2-AR is up-regulated in the brainstem, hippocampus, and striatum (Gilsbach et al. 2006). In these mice the a2-AR autoreceptors are not desenzitized and the inhibitory tone on NE release is stronger as the consequence of elevated extracellular NE concentration (Vizi et al. 2004).
Since the extracellular levels of monoamines is highly dependent on the activity of their transporters, it was assumed that, in acute treatment of mice, not only with desipramine but also other monoamine transporter inhibitors exhibiting antidepressant characteristics (dopamine transporter and serotonin transporter inhibitors), had modulatory effects on the inflammatory immune response. Whereas an approximately 3-week long chronic treatment is necessary to start the therapeutic antidepressant effect of these drugs, it was studied whether the immunomodulatory effect was also present after chronic treatments.
It was revealed recently (Szelenyi, Selmeczy, and Vizi 2004) that the immunomodulatory effect was more significant on the LPS-induced cytokine production in the acute than that of chronic treatments; showing that the high extracellular monoamine level, i.e., the presence of the monoamine transporter inhibitor was necessary during LPS induction. All the three monoamine transporter inhibitors were effective to different extents in our experiments (Fig. 18.3), which supported the hypothesis that the immunomodulatory effect of these drugs was correlated with the actual increased in extracellular monoamine levels evoked by them. However, this was not in direct correlation with their mood effects. Concerning the crucial role that cAMP plays in cytokine production, it may be supposed that TCAs produce their immunomodulatory effects through this signaling mechanism. The antidepressant effects of phosphodiesterase inhibitors (like rolipram) (Fig. 18.2) (Zhu, Mix, and Winblad 2001) and the overexpression of the cAMP response element binding protein (CREB) in the hippocampus after chronic antidepressant administration (Chen, Shirayama, Shin, Neve, and Duman 2001), might support this assumption. An increasing amount of evidence is available, however, that chronic treatment with TCAs has pleiotropic effects in addition to blocking the monoamine uptake systems, which contribute to exert their antidepressive action in the CNS.
Clinical observations indicate that TCAs may attenuate the adverse effects of glucocorticoids, and consequently the release of proinflammatory cytokines is decreased (Chen et al. 2001). As well as the interactive relationship between NE release regulating a2-adrenoceptor sensitivity and the TNF-a levels in the CNS (Nickola, Ignatowski, Reynolds, and Spengler 2001) TCAs may exert their effect also through interaction with other monoamine uptake systems, for example, the dopaminergic and serotonergic systems, that were shown to be promiscuous (Moron et al. 2002; Selmeczy et al. 2003; Vizi et al. 2004).
chronic antidepressant administration
fluoxetine+LPS ~r kl iL*
acute antidepressant administration
desipramine+LPS GBR12909+LPS fluoxetine+LPS
Figure 18.3. Comparison of the effects of acute and chronic antidepressant treatment on the cytokine balance. In acute experiments, Balb/c mice were injected intraperitoneally (i.p.) with the drugs (10 mg/kg), 60 min before the administration of lipopolysaccharide (LPS) (10 mg/kg i.p.). In the chronic protocol the same procedure was daily repeated for 3 weeks but LPS-induction was performed only on the last day. Control animals received the same diluent as vehicle and the same volume of saline. Blood sample was taken 90 min after the LPS administration, and the plasma TNF-a or IL-10 content was determined by ELISA technique.
The suppressive effect of increased serotonin release on the LPS-induced proinflammatory cytokine secretion cannot be attributed to the serotonin-releasing properties of selective serotonin reuptake inhibitors (SSRIs) (Connor, Dennedy, Harkin, and Kelly 2001). Sleep continuity is improved by the rise in the synaptic levels of serotonin. Among tricyclic antidepressants trimipramine and amitriptyline are the best to improve sleep disorders. Stimulation of serotonin-2 (5-HT2) receptors is thought to underlie insomnia and changes in sleep architecture are seen with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) (Thase 1999; Aszalos 2006).
The plasma concentration of proinflammatory cytokines might also be in correlation with the treatment responsiveness. Increased plasma concentrations of IL-6 and acute-phase proteins have been found in patients with a history of nonresponse to antidepressants when compared with treatment-responsive patients (Maes, Bosmans, De Jongh, Kenis, Vandoolaeghe, and Neels 1997). Similarly, patients with evidence of increased inflammatory activity before treatment were reported to be less responsive to antidepressants or sleep deprivation (a potent short-term mood elevator) (Lanquillon, Krieg, Bening-Abu-Shach, and Vedder 2000; Benedetti, Lucca, Brambilla, Colombo, and Smeraldi 2002). However, if the efficiency of antidepressants is primarily realized by their anti-inflammatory effects, anti-inflammatory drugs should also be effective in the treatment of major depressive disorders. Our results suggest that other signaling routes may also participate in the immunomodulatory role of antidepressant drugs, in other words, they have multiple targets that might explain the lack of correlation between their effectiveness and specificity in blocking a certain monoamine transporter, as well as, the limited antidepressant efficacy of anti-inflammatory drugs (Szelenyi et al. 2004).
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