Previous and Future PSSD research

Previous PSSD studies involving Dr. Roberto Melcangi

Giatti S., Cioffi L., Diviccaro S., Chrostek G., Piazza R., Melcangi R. C. Transcriptomic Profile of the Male Rat Hypothalamus and Nucleus Accumbens After Paroxetine Treatment and Withdrawal: Possible Causes of Sexual Dysfunction. Mol. Neurobiol, 2024, 12035, https://doi.org/10.1007/s12035-024-04592-9

Giatti S., Diviccaro S., Cioffi L., Melcangi R.C. Post-Finasteride Syndrome and Post-SSRI Sexual Dysfunction: Two clinical conditions apparently distant, but very close. Frontiers in Neuroendocrinology, 2023, 101114, ISSN 0091-3022, https://doi.org/10.1016/j.yfrne.2023.101114.

Diviccaro S., Giatti S., Cioffi L., Falvo E., Piazza R., Caruso D., Melcangi R.C. Paroxetine effects in adult male rat colon: Focus on steroidogenesis and microbiota. Psychoneuroendocrinology 143: 105828, 2022  https://doi.org/10.1016/j.psyneuen.2022.105828

Giatti S., Di Domizio A., Diviccaro S., Cioffi L., Marmorini I., Falvo E., Caruso D., Contini A., Melcangi R.C. Identification of a novel off-target of paroxetine: Possible role in sexual dysfunction induced by this SSRI antidepressant drug. J. Mol. Structure 1268:133690, 2022 https://doi.org/10.1016/j.molstruc.2022.133690 

Giatti S., Diviccaro S., Cioffi L., Falvo E., Caruso D., Melcangi R.C. Effects of paroxetine treatment and its withdrawal on neurosteroidogenesis. Psychoneuroendocrinology 132:105364, 2021. https://doi.org/10.1016/j.psyneuen.2021.105364

Giatti, S., Diviccaro, S., Panzica, G. et al. Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin?. Endocrine 61, 180–193 (2018). https://doi.org/10.1007/s12020-018-1593-5

Previous PSSD studies involving Dr. Antonei Csoka

Riya R. Kanherkar, Bruk Getachew, Joseph Ben-Sheetrit, Sudhir Varma, Thomas Heinbockel, Yousef Tizabi, Antonei B. Csoka, "The Effect of Citalopram on Genome-Wide DNA Methylation of Human Cells", International Journal of Genomics, vol. 2018, Article ID 8929057, 12 pages, 2018. https://doi.org/10.1155/2018/8929057

Antonei B. Csoka, Moshe Szyf, Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology, Medical Hypotheses, Volume 73, Issue 5, 2009, Pages 770-780, ISSN 0306-9877, https://doi.org/10.1016/j.mehy.2008.10.039. (https://www.sciencedirect.com/science/article/pii/S0306987709002916)

Future research plans of Dr. Roberto Melcangi

Identification of possible genes altered in the hypothalamus (i.e., the brain region more important for neuroendocrine control). To do that, we are using mRNA sequencing analysis (i.e., an innovative analysis that uses next-generation sequencing to reveal the presence and quantity of differentially expressed mRNA in a biological sample) in male rats treated with paroxetine. The effect of this SSRI will be explored after subchronic treatment and during withdrawal. We are conducting the same analysis in animals treated with finasteride, so it will be interesting to verify whether common genes are affected in PSSD and PFS.

Morphology of peripheral nerves, myelination process, and intraepidermal nerve fiber density (Small Fiber Neuropathy). Indeed, PSSD patients report genital numbness or paresthesia, suggesting peripheral neuropathy. In this context, it is important to highlight that we have demonstrated that PFS patients show peripheral neuropathy (Melcangi R.C. et al., J Steroid Biochem Mol Biol 2017).

Many clinical endpoints and reliable biomarkers are missing when considering PSSD. Hence, we aim to investigate the potential role of MicroRNAs in the PSSD experimental model as a biomarker for PSSD. MicroRNAs are a class of small, non-coding RNAs that regulate gene expression. These molecules possess the necessary characteristics to be considered ideal biomarkers, including accessibility, high specificity, and sensitivity. MicroRNAs are already utilized as biomarkers in various cancer types, cardiovascular diseases, sepsis, and nervous system disorders. Therefore, evaluating their role in the PSSD experimental model will provide a proof of concept for expanding their exploration in clinical settings.

In our ongoing exploration to understand the potential common pathways between Post-Finasteride Syndrome (PFS) and PSSD, we made an important discovery. Our recent data (Giatti S. et al., J. Mol. Struct., 2022) confirms that paroxetine, similar to finasteride, has the ability to inhibit phenylethanolamine N-methyltransferase (PNMT), the key enzyme involved in the production of the stress hormone epinephrine. This finding builds upon our previous observations (Giatti S. et al., J. Med. Chem. 2021) in a post-finasteride experimental model, which demonstrated finasteride's interaction with off-target proteins.

The significance of this discovery lies in the suggestion that the research conducted on PFS may offer valuable insights into PSSD and vice versa. We believe this is a crucial development as it indicates a potential overlap in pathways between these two conditions. In light of these findings, we are now investigating whether paroxetine's interaction with PNMT is unique to this particular medication or if other SSRIs possess similar capabilities.

We aim to investigate the potential brain pathways leading to sexual dysfunction. In rodent experimental models, we will assess male sexual motivation and performance through behavioral tests. The information obtained from these tests will also indicate the key brain areas involved, allowing us to focus our subsequent molecular analysis on these tissues.

The gut-brain axis is widely recognized for its significance, as the gut communicates with the brain through the vagus nerves and gut microbiota. However, it is still unclear whether microbial molecular mediators, negatively affected by paroxetine treatment, play a role. Therefore, we will evaluate bacteria-derived metabolites such as short-chain fatty acids, serotonin, dopamine, and other neurotransmitters to explore their involvement in the effects of paroxetine on the brain.

Our observations have been obtained so far only in males; however, PSSD also occurs in females. Considering that neurosteroidogenesis and gut microbiota population, which are affected by paroxetine treatment in males, have been demonstrated to be influenced in a sex-dimorphic manner by various neuropathologies, it is possible that these two parameters may also be affected differently by paroxetine treatment in females. Therefore, we intend to explore the effect of paroxetine on neurosteroidogenesis and gut microbiota in females. Additionally, in this experimental model, it would be interesting and useful to investigate the potential involvement of the female vaginal microbiome in the context of sexual impairment and estrus cycle alterations.