LP-37 Ciprofloxacin alters neuronal epigenetic patterns in vitro and in vivo at therapeutically relevant exposures

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Psychiatric and psychological adverse events (PPAEs) may emerge at late-stage drug development or post-marketing, substantially impacting patient safety. Ciprofloxacin (CPFX), a broad-spectrum fluoroquinolone used in infection treatment, has been associated with a high prevalence of PPAEs. Considering the relevance of epigenetic signaling in neuronal function, we assessed the impact of CPFX on neuronal epigenetic patterns both in vitro and in vivo . To this end, undifferentiated SH-SY5Y human neuroblastoma cells were treated with pharmacologically relevant concentrations of CPFX (0.1 and 10µM) or vehicle (0.01% HCl) for 24 and 96h. Global DNA methylation (%5-mC) and Histone H3 acetylation levels were quantified with commercial fluorometric kits. We observed that 0.1 and 10µM CPFX increased global histone acetylation (1.3-1.5-fold, p<0.01) at 96h (but not at 24h), compared to vehicle, without affecting global %5-mC. To investigate CPFX-induced epigenetic changes on the whole brain, %5-mC and Histone 3 lysine 9 acetylation (H3K9ac) levels were measured by immunofluorescence in the nucleus accumbens (NAcc), prefrontal cortex (PFC) and hippocampal formation (HF) of brain tissue sections from adult male Sprague-Dawley rats daily administered 20 or 100mg/kg CPFX (dose regimens set after neuropharmacokinetic assays) or vehicle (methylcellulose) by gavage, for 4 weeks. The target intensity per total number of cells per area was analysed with an inhouse ImageJ software-based semi-automatic method. We observed that 20 and 100mg/Kg CPFX reduced by 10% (p<0.05 vs. vehicle) the %5-mC in the Nacc and PFC, respectively, suggesting transcriptional activation. Also, 20 and 100mg/Kg CPFX reduced H3K9ac levels in the Nacc and PFC by 7 and 8% (p<0.05 vs. vehicle), respectively. Notably, decreased H3K9ac levels have been linked to depression-like behaviors. Our findings show that CPFX alters neuronal epigenetic patterns in vitro and the whole rat brain, in areas related to cognitive functions (PFC) and to emotional response and reward (NAcc), hinting at a link between CPFX and PPAEs. The distinct in vitro and in vivo epigenetic patterns may be explained by the different model complexity (e.g. various neuronal cell phenotypes and other cell types in vivo ), and the likely regiospecificity of the epigenetic changes in the brain. Assessing the epigenetic impact of CPFX in other neuronal phenotypes and glial cells thus becomes important to ascertain whether CPFX-induced epigenetic changes underlie the onset of PPAEs. Funding: Innovative Medicines Initiative 2-JU, via H2020 framework and EFPIA (grant agreement No 821528); Portuguese Foundation for Science and Technology (FCT) via projects UIDP/04378/2020 and UIDB/04378/2020 (UCIBIO), and LA/P/0140/2020 (i4HB). FCT also supports SIM, CPT and JPS via PhD grants 2020.09080.BD, 2022.13857.BD and research contract (under Scientific Employment Stimulus) 2021.01789. CEECIND/CP1662/CT0014, respectively.

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