Depression is complex illness characterized by disruptions in the functioning of physiological, neuroendocrine and behavioural processes. Of these, sleep disturbance and circadian rhythm abnormalities constitute the most prevalent signs of depression. Prokineticin 2 (PROK2) is a new chemokine that binding to Prokineticin receptor 1 (PKR1) and 2 (PKR2), exerts numerous biological effects involved in pain, inflammatory processes, neurogenesis, behavior and circadian rhythms. Circadian rhythms are prominent in a variety of behavioral and physiological processes, including sleep/wake cycles, and disrupted circadian rhythms are strictly associated with major depression. PROK2/PKRs are highly expressed in the suprachiasmatic nucleus (SCN), the master pacemaker that drives circadian rhythms in mammals, and PKRs are expressed in all of the primary SCN target areas, most of which are involved in depression. Studies indicate that PROK2 signaling plays a critical role in the stress-related traits in mice and establish a possible molecular link between circadian rhythms and depression illness. Indeed, in wild type mice, central infusion of PROK2 let to increased anxiety and depression-like behaviors; in contrast, mice deficient in PROK2 or in PKR1 gene (preliminary data from our lab) display reduced anxiety and depression-like behaviors. In the present project we want to investigate the involvement of the prokineticin system in two animal models of depression. Considering that our research group have at its disposal an antagonist of the PKRs (PC1) we want to evaluate if blocking the PROK system, somehow targeting or affecting the circadian systems, could represent a new pharmacological strategy for the treatment of depression disorders. Another aspect that we want to investigate is to evaluate if targeting the PROK system, could lead to a more rapid onset of antidepressant effect that, still now, represents a very important limit of the available pharmacological treatments.
The interest of this project is due to the fact that, for the first time, we aim to investigate the potential antidepressant and/or anxyolitic effect resulting from the pharmacological blockade of the prokineticin system. The new chemokine PROK2 and its receptors, PKR1 and PKR2, represents a new system involved in a wide range of physiological and pathological functions and evidences indicate a functional role of PROK2 in anxiety and depression-like behaviors, representing PROK2 a molecular link between circadian rhythms and mood regulation (1). Disrupted circadian rhythms are strictly associated with many mood disorders. It is known that, most severe depression symptoms typically occur in the morning hours, that depression is more prevalent in geographic areas that receive little sunlight for extended periods of time and that seasonal affective disorder occurs only in the winter months when there are shorter days (2). Moreover, reduced sleep efficiency, increases in sleep latency, and early morning awakenings have all been documented in patients with major depression disorder. The mammalian suprachiasmatic nucleus (SCN) is the master pacemaker that drives diverse circadian rhythms: behavioral studies, in rats with bilateral SCN lesions, suggest that disruption of the SCN has a protective effect on depression-like behavior (3). Phenotypes of SCN-lesioned rats share many similarities with PROK2 -/- mice (1) consistent with the fact that PROK2 is an output molecule for the SCN clock to communicate with primary SCN targets (4). PROK2 plays a critical role in the regulation of stress-related traits (1) and PKR2 is expressed in all of the primary SCN target areas such as lateral septum, paraventricular and dorsomedial hypothalamic nucleus and amygdala (5), which are involved in the mood regulations. Although the introduction of selective serotonin reuptake inhibitors (SSRI) have had a crucial impact in the treatment of depression, they also have problematic implications: they often exacerbate the symptoms of insomnia and show therapeutic delayed onset. This latency prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy. In the present project we want to investigate the involvement of the prokineticin system in animal models of depression. Considering that our research group have at its disposal an antagonist of the PKRs (PC1) (6-9) we want to evaluate if blocking the PROK system, somehow targeting or affecting the circadian systems, could represent a new pharmacological strategy for the treatment of depression disorders. Another aspect that we want investigate is to evaluate if targeting the PROK system, is possible to obtain a more rapid onset of antidepressant effect that is, still now, a very important limit of the available pharmacological treatments. If our hypothesis will be confirmed, this study, besides an advancement of basic knowledge for the treatment of depression, could represent a starting point for further translational and pre-clinical research.
1) Li J.D. et al.(2009). Neuropsychopharmacology 34: 367-373.
2) TurekF.W. (2007). Int. Clin. Psychopharmacol. 22: S1-S8.
3) Tataroglu O et al. (2004). Brain Res. 1001: 118-124.
4) Li J.D. et al (2006). J Neurosci. 26: 11615-11623.
5) Cheng MY et al. (2006). J Comp. Neurol. 498: 796-809.
6) Giannini, E, Lattanzi R. et al. (2009). Proc. Natl. Acad. Sci. USA 106: 14646-14651.
7) Severini C., Lattanzi R. et al.(2015). Scient. Rep. 5: 15301.
8) Maftei, D. et al. (2014). Br. J. Pharmacol. 171: 4850-4865.
9) Balboni G. et al. (2008). J. Med. Chem. 51: 7635-7639.