Conclusions

Cytokines are capable of acting as neuromodulators within the CNS. As such, they affect important brain activities such as sleep, appetite, and neuroendocrine regulation. An inadequate response to either internal or external challenge may induce inflammation, depression and sleep abnormalities by increasing the production of proinflammatory cytokines that are normally present in very low concentrations in the brain. An increased amount of inflammatory mediators affects the central and peripheral monoaminergic neurotransmitter systems, the activity of the HPA axis, and the innate immune response. Proinflammatory cytokines alter the cross talk and mutual interactions among the participants of these systems. As a consequence, a disturbance in one of these systems will also affect the other systems resulting in a long loop among them.

The inhibitory effect of TCAs both on the various monoamine uptake systems and on the production of proinflammatory cytokines also supports the idea that depression, sleep abnormalities, and some other disorders affecting the CNS, are closely linked to immunological alterations. This is not surprising as cytokines are involved not only in the immune response but also in a variety of other physiological and pathological processes, including the events in the peripheral nervous system and the CNS, that is, they are both immunoregulators and neuromodulators. There are currently no conclusive data to prove whether the inhibition of proinflammatory cytokines or the increase of biophase level of monoamines is sufficient for antidepressive effects, because of the problems of studying each in isolation. In addition, the heterogeneity of depressive and sleep disorders suggests that their study and therapy need a more complex approach. Therefore, we would like to call the attention to the importance of multiple targets in drug development rather than specificity. The observation however, that inflammation plays a crucial role both in psychiatric and sleep disturbances calls the attention to their common features, that should have therapeutic consequences and might also offer new targets in the development of antidepressants and sleep ameliorating drugs.

Acknowledgments. This work was supported by grants from the Hungarian Research Fund (OTKA) No. T-46896 (J. Sz.); No. TS-049868 (E.S.V.), and that of from the Scientific Committee of Ministry of Health No. 123/2003 (E.S.V.).

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