Title

 

Authors

C. Montanari¹, S. Alboni¹, C. Benatti¹, F. Tascedda¹, N. Brunello<sup>1

1</sup>University of Modena, Department of Biomedical Sciences, Modena, Italy.

 

Abstract

Nowadays the current treatment for depression, the most common psychiatric disorder in the Western World, remains still inadequate. This major problem arises from the fact that the pathophysiology of depression has not been elucidated yet and that any antidepressant treatment is based on empirical data, not on the mechanisms of action. In the past few decades it is becoming more and more evident that depression is associated with a profound unbalance between the nervous, the endocrine- and the immune- systems. This suggests the possibility that molecules that regulate the homeostasis of these systems may contribute to the onset and/or the maintenance of depression. For instance, some inflammatory biomarkers, as cytokines, are important neuro-endocrine-immuno modulators and have been proposed to play a role in depression. Cytokines and their receptors can be synthesized in the brain by both glia and neurons and can act in the central nervous system modulating neural excitability and functioning, controlling the hypothalamic-pituitary-adrenal (HPA) axis activity and regulating as well the local inflammatory response. The plasma levels of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12) and tumor necrosis factor-α (TNFα) result increased in depressed patients [1]. In addition, the pro-inflammatory cytokine interleukin-18 (IL-18), originally isolated as interferon-gamma (IFNγ) inducing factor, seemed to be involved in psychiatric disorders such as depression and in the stress response that is strongly related to the depressive disease [2]. To gain insight into the possible immune targets of these antidepressants, we evaluated the expression of several inflammatory mediators in the hypothalamus of naive Sprague Dawley rats chronically (28 days) treated with fluoxetine (5mg/kg, i.p.) or imipramine (15mg/kg, i.p.), two of the most widely prescribed antidepressants, a serotonin selective reuptake inhibitor and a tricyclic compound, respectively. We focused our attention on the hypothalamus since it plays a key role in the pathogenesis of depression and in determining the depressive symptomatology. In fact this brain region participates in the control of the HPA axis activity and in the stress response as well as it coordinates physiological functions such as sleep and food intake that have been found altered in an high percentage of depressed patients. Notably, hypothalamus is a key structure for brain cytokine expression and function.
By means of quantitative Real Time PCR experiments we were able to demonstrated that chronic fluoxetine treatment determined a significant reduction of IL-6 and IFNγ expression levels with respect to the group treated with saline, without affecting the levels of IL-1, TNFα and IL-18 system transcripts. Interestingly, chronic imipramine administration significantly decreased not only the IL-6 and IFNγ mRNA levels, but also the IL-12, IL-18 receptor and IL-6 receptor expression when compared to the group treated with saline.
Our data suggest that a decrease in the expression of inflammatory biomarkers, such as inflammatory cytokines and their receptors, may represent a common mechanism of action of both the chronic treatments with fluoxetine and imipramine in the hypothalamus.
 
[1] Schiepers, O.J., Wichers, M.C., Maes, M., 2005 Cytokines and major depression. Progress in neuro-psychopharmacology & biological psychiatry 29(2), 201-217.
[2] Merendino, R.A., Di Rosa, A.E., Di Pasquale, G., Minciullo, P.L., Mangraviti, C., Costantino, A., Ruello A., Gangemi, S., 2002 Interleukin-18 and CD30 serum levels in patients with moderate-severe depression. Mediators of Inflammation 11(4), 265-267.