EFFECT OF FINASTERIDE TREATMENT IN MALE RAT: DEPRESSIVE-LIKE BEHAVIOR AND RELATED PARAMETERS

Neuroactive steroids are important physiological modulators of the nervous system as well as protective agents in different psychiatric and neurodegenerative diseases. This group of molecules includes hormonal steroids released by peripheral steroidogenic tissues and neurosteroids directly synthetized in nervous system. One key process regulating the synthesis of these molecules is the enzyme 5α-reductase (5α-R). This enzyme converts progesterone (PROG) and testosterone (T) to their 5α-reduced metabolites, dihydroprogesterone (DHP) and dihydrotestosterone (DHT), respectively. These metabolites are then further converted into other neuroactive steroids, such as tetrahydroprogesterone (THP) and isopregnanolone (ISOPREG) in the case of DHP and 5α- androstane-3α, 17β-diol (3α-diol) and 5α-androstane-3β, 17β-diol (3β-diol) in the case of DHT. In agreement, with the protective role exerted by neuroactive steroids their levels are affected in neurodegenerative as well as psychiatric disorders. In particular, persistent alteration of plasma neuroactive steroid levels associated with major depression has been recently reported in men after the suspension of the treatment for androgenetic alopecia with finasteride, an inhibitor of the enzyme 5α-R. Thus, these patients are affected by the so-called post-finasteride syndrome (PFS). Interestingly, suspension of finasteride treatment did not only lead, as expected, to an alteration of 5α-reduced metabolites of PROG and T but also to a global alteration of neuroactive steroid levels. Moreover, recent observations performed in male rats, show that this persistent alteration in neuroactive steroid levels did not only occur in plasma and CSF but also in the brain. On this basis, in the present PhD project, we have ascertained whether subchronic finasteride treatment (i.e. 20 days) and one month of its withdrawal may induce depressive-like behavior in this animal model. In addition, the effect of finasteride on other depressive-related parameters such as neurogenesis, gliosis, neuroinflammation/inflammation and gut microbiota have been analysed. At the end of finasteride treatment, we observed: 1) increased proliferation in the subgranular zone of the dentate gyrus; 2) increased number of microglia with reactive phenotype in the hilus and 3) increased mRNA levels of TNF-α. One month after finasteride withdrawal, we reported: 1) decreased proliferation in the subgranular zone; 2) decreased granule cell density in the granule cell layer; 3) increased astrogliosis in the hilus and 4) a possible (i.e., only detected by Student's t-test) increased of mRNA levels of IL-1β in the hippocampus. Moreover, these latter changes coincide with the onset of depressive-like behavior, suggesting that long-term effects of finasteride treatment on neurogenesis and neuroinflammation may participate in the lasting effects of the drug on depressive-like behavior, which are detected even one month after discontinuation of the drug. In addition, peripheral inflammation assessment revealed, after drug treatment, a significant decrease in plasma levels of IL-1β in finasteride-treated vs control animals. On the other hand, in agreement with literature and with the depressive-like behavior, a significant increase in plasma levels of IL-1β in finasteride-treated vs control animals at withdrawal period was observed. These observations seem to support a role of peripheral inflammation in addition to what we reported on neuroinflammation. Finally, alteration of gut microbiota (i.e., an increase in Bacteroidetes phylum and in Prevotellaceae family at the end of the treatment and a decrease in Ruminococcaceae family, Oscillospira and Lachnospira genus at the end of the withdrawal period) was detected. It should be noted that important changes in the levels of neuroactive steroids such as PROG and DHP are detected in the hippocampus by one month after finasteride withdrawal. Since neuroactive steroids regulate neurogenesis, gliosis and neuroinflammation, and since PFS patients also show changes in neuroactive steroid levels, the effect of finasteride on depression, neuroactive steroid levels, neurogenesis and neuroinflammation/inflammation may be interrelated events. In addition, the changes here observed at the end of treatment and at withdrawal on gut microbiota may depict further possible signals involved in the so call gut microbiota-brain axis. In conclusion, finasteride treatment in male rats has long term effects on depressive-like behavior, hippocampal neurogenesis, neuroinflammation/inflammation and gut microbiota composition.