Ciprofloxacin-induced neurotoxicity: evaluation of possible underlying mechanisms

Abstract

Ciprofloxacin (CPX) is a fluoroquinolone antibiotic used for treating respiratory, urinary tract, gastrointestinal and abdominal infections. There are only a limited number of studies related to neurological adverse effects of this drug in therapeutic doses. Therefore, in the present study, we aimed to investigate the influence of CPX, when administered at pharmacological doses, on behavioral parameters of rats and the probable underlying mechanisms. CPX was administered in single oral daily doses of 20 and 50 mg/kg for 14 days in rats. CPX-induced depression and anxiety were evaluated by modified forced swimming test and elevated plus maze test, respectively. Also, spontaneous locomotor activity and motor coordination were assessed by activity cage and Rota-rod apparatus. Effects of CPX administration on brain serotonin, dopamine, γ-amino-butyric acid (GABA), glutamate, adrenaline and noradrenaline levels were determined by high performance liquid chromatography (HPLC) analysis. Contribution of oxidative stress to the changes induced by CPX administration was evaluated by measuring brain catalase, superoxide dismutase, glutathione (GSH) and malondialdehyde (MDA) levels. Our results indicated that depression-like and anxiety-like behaviors were observed only in the 50 mg/kg CPX-administered group with simultaneous decreases in the brain serotonin and GABA levels. In addition, in the brain homogenates of CPX-administered groups, increased MDA as well as decreased GSH and catalase activity with respect to their controls, indicated enhanced oxidative stress and weakened antioxidant defense system. In conclusion, repeated pharmacological doses of CPX were found to induce neurological toxicity. Also, altered brain neurotransmitter levels and increased oxidative stress observed in our study were thought to be the possible underlying mechanisms of ciprofloxacin-induced neurotoxicity.

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“…Concordant with this data, ciprofloxacin treated rats had reduced brain glutathione and catalase levels [34]. Ciprofloxacin in supraphysiologic doses increased brain oxidative stress in rats [35] thus would increase effect of photoexcited PpIX ROS generation if the rat data was replicated in humans at attainable clinical doses.…”

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“…An exception is fluoroquinolones, e.g., ciprofloxacin (61), which is currently used due to its strong activity against Gram-negative bacteria in spite of its toxicity (62) and the increasing number of bacteria that are resistant to it (63). Remarkably, the diastereomer had activity comparable to that of ciprofloxacin, which was found to cause ϳ64%, 77%, and 98% killing of intracellular bacteria when tested under our conditions on infected ⌬F508-CFBE at 1 M, 5 M, and 15 M, respectively (data not shown).…”

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“…In this study, as in the prior study of ciprofoxcanassociated neurotoxicity in rats, anxiety levels of animals were assessed using elevated plus maze testing. 8 Tis test depends on behavioral inhibition associated with certain features (open elevated arms or closed arms, for example) of the test apparatus. 10…”

“…7 Only one animal study has evaluated FQ-associated neuropsychiatric (NP) toxicity using therapeutic dosages of ciprofoxa-cin. 8 Tat study, conducted in 30 rats, evaluated controls and rates that received doses of 20 mg/ kg or 50 mg/kg administered orally for 14 days. Evidence of ciprofoxacin-associated depression, anxiety, and abnormal locomotor activity and motor coordination at the 50-mg/kg dose was reported.…”

“…Altered brain neurotransmitter levels and increased oxidative stress were identifed and thought to be the possible mechanisms of ciprofoxacin-associated neurotoxicity. 8…”