Evaluation of modulators of cAMP-response in terms of their impact on cell cycle and mitochondrial activity ofLeishmania donovani

Abstract

2 With the identification of novel cAMP binding effecter molecules in Trypanosoma, 3 role of cAMP in kinetopalstida parasites gained an intriguing break through. Despite 4 earlier demonstrations of role of cAMP in survival of Leishmania during macrophage 5 infection, there is essential need to specifically clarify involvement of cAMP in 6 various cellular processes in the parasite. In this context, we sought to gain a 7 comprehensive understanding of the effect of cAMPanalogs and cAMP-8 phosphodiesterase (PDE) inhibitors on proliferation of log phase parasites. 9 Administration of both hydrolysable (8-pCPT-cAMP) and non-hydrolysable analogs 10 (Sp-8-pCPT-cAMPS) of cAMP resulted in significant decrease of Leishmania 11 proliferation. Amongst the various PDE inhibitors, etazolate was found to be potently 12 anti-proliferative. BrdU cell proliferation and K/N/F-enumeration microscopic study 13 revealed that both cAMP analogues and selective PDE inhibitors resulted in 14 significant cell cycle arrest at G 1 phase with reduced S-phase population. 15 Furthermore, careful examination of the flagellar motility patterns revealed 16 significantly reduced coordinated forward flagellar movement of the promastigotes 17 with a concomitant decrease in cellular ATP levels. Alongside, 8-pCPT-cAMP and 18

Assessment of the genotoxicity and cytotoxicity of etazolate in cultured human lymphocytes

“…In the current study, etazolate at the concentrations examined did not impact the proliferative capacity of cultured human lymphocytes. In a study on Leishmania donovani promastigotes, etazolate was shown to have an antiproliferative effect at a dose of 24 µM (Saha et al, 2020). In addition, in an animal study on mice epidermal mitosis, etazolate has been shown to inhibit mitosis at concentrations between 10 and 100 µM (Birnbaum et al, 1976).…”

MiR-139-5p has an antidepressant-like effect by targeting phosphodiesterase 4D to activate the cAMP/PKA/CREB signaling pathway

“…Recently, the efficacy of PDE4D inhibitors has been investigated. Among the first generation of well-known and clinically tested PDE4 inhibitors, the prototype rolipram was the first selective PDE4 inhibitor with potent anti-inflammatory actions to be studied (21). However, severe unacceptable adverse events, including nausea and vomiting, blocked the clinical application of rolipram (22).…”

“…Available at https://dx.doi. org/10.21037/atm- 21 Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the noncommercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-ncnd/4.0/.…”

Evaluation of Modulators of cAMP-Response in Terms of Their Impact on Cell Cycle and Mitochondrial Activity of Leishmania donovani

“…We would like to acknowledge the DST-INSPIRE Faculty Programme, DST-PURSE Programme, University of Kalyani, DST-FIST, Department of Zoology, University of Kalyani, PRG, University of Kalyani, NASI Senior Scientist Fellowship. This manuscript has been released as a preprint at [Biorxiv-the preprint server for biology] (Saha et al, 2020).…”