Molecular mechanisms of neurotoxicity induced by polymyxins and

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Molecular mechanisms of neurotoxicity induced by polymyxins and chemo-prevention Chongshan Dai, Xilong Xiao, Jichang Li, Giuseppe D Ciccotosto, Roberto Cappai, Susheng Tang, Elena K. Schneider-Futschik, Daniel Hoyer, Tony Velkov, and Jianzhong Shen ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00300 • Publication Date (Web): 26 Oct 2018 Downloaded from http://pubs.acs.org on October 27, 2018

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ACS Chemical Neuroscience

Molecular mechanisms of neurotoxicity induced by polymyxins and chemoprevention

Chongshan Dai1, Xilong Xiao1, Jichang Li2, Giuseppe D. Ciccotosto3, Roberto Cappai3, Shusheng Tang1, Elena K. Schneider-Futschik3, Daniel Hoyer3,4,5, Tony Velkov2#, Jianzhong Shen1,# 1Department

of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, No.2 Yuanmingyuan West Road, Beijing 100193, P. R. China. 2Department

of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Northeast Agricultural University, Harbin, P. R. China; 3Department

of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, 3010, Australia. 4The

Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia. 5Department

of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.

*Joint corresponding authors: Tony Velkov, Telephone: +61 3 83449846. E-mail: [email protected] OR Jianzhong Shen, Telephone: +86 10 6273 3857; Fax: +86 10 6273 1032. E-mail: [email protected].

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Abstract Neurotoxicity is one major unwanted side-effects associated with polymyxins (i.e. colistin and polymyxin B) therapy. Clinically, colistin neurotoxicity is characterized by neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, facial and peripheral paresthesias. Pathologically, colistin-induced neurotoxicity is characterized by cell injury and death in neuronal cell. This review covers our current understanding of polymyxin-induced neurotoxicity, its underlying mechanisms, and the discovery of novel neuro-protective agents to limit this neurotoxicity. In recent years, an increasing body of literature supports the notion that polymyxin-induced nerve damage is largely related to oxidative stress and mitochondrial dysfunction. P53, PI3K/Akt and MAPK pathways are also involved in colistin-induced neuronal cell death. The activation of the redox homeostasis pathways such as Nrf2/HO-1 and autophagy have also been shown to play protective roles against polymyxin-induced neurotoxicity. These pathways have been demonstrated to be upregulated by neuro-protective agents including curcumin, rapamycin and minocycline. Further research is needed towards the development of novel polymyxin formulations in combination with neuro-protective agents to ameliorate this unwanted adverse effect during polymyxins therapy in patients.

Keywords: Polymyxins; Neurotoxicity; Mitochondria dysfunction; Apoptosis; Autophagy; Neuroprotective agents, Chemo-prevention.

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1. Introduction Antimicrobial resistance is currently a major public health concern; notably The World Health Organisation (WHO) has identified antibiotic resistance as one of the three greatest threats to human health.1 During the past two decade, there has been a dramatic decline in discovery and development of novel classes of antibacterial agents and, unfortunately, this has been concomitantly accompanied by an increase in the incidence of infections by multi-drug resistant (MDR) Gram-negative pathogens.2-7 The situation is especially worrying for MDR Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa, against which no new antibiotics will be available for many years to come.2 Infections caused by these MDR bacteria, often do not respond to conventional therapy and result in a longer duration of illness and higher risk of death. Coughing WHO has placed these three problematic pathogens at the top of its ‘2017 Antibiotic-resistant Priority Pathogens List’.1 This unfortunate situation has led to a resurgence in the clinical use of polymyxins (polymyxin B and E syn. colistin), as a last line treatments against MDR Gram-negative pathogens.8-9 Polymyxins are lipopeptide antibiotics that were first discovered in 1947.10 Unlike polymyxin B, which is available in the clinic as the sulphate salt, colistin is administered to patients as an inactive prodrug, colistin methanesulphonate (CMS). 11-12 Polymyxin B and colistin sulfate are for intravenous, oral and topical use, and colistimethate sodium (sodium colistin methanesulphonate, colistin sulfomethate sodium) for parenteral use (Figure 1); both can be delivered by inhalation.13 Since 1959, intravenous polymyxins have been used for the treatment of Gram-negative bacterial infections in clinic.8 The clinical use of polymyxins waned in the 1970s, following the early experience in the

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1960s which led to numerous cases of nephro- and neurotoxicity.8 A study that assessed the safety of intramuscular administration of CMS during 317 courses of therapy to 288 hospitalized patients revealed 83% of these patients experienced neurotoxicity during the first four days.14 Patients receiving intravenous CMS, have been reported to present with neurological symptoms including dizziness, visual disturbances, vertigo, confusion, hallucinations, seizures, ataxia, facial and peripheral paresthesias.1517

Symptoms of mild neurotoxicity (such as paresthesias) tend to be more frequent,

especially in elderly patients, but are often ignored because of the lack of objective assessment protocols.16, 18-20 A recent study showed that at higher polymyxin treatment doses, clinical outcomes are improved, albeit, therpy was associated with a greater incidence of adverse effects.21 Notably, high dose colistin exposure has been shown to induce apoptosis of cerebral cortex neurons, behavioral abnormalities and disrupted neurotransmitter levels in animal models.18,

22-24

These clinical manifestations indicate

that polymyxin-induced neurotoxicity can be divided into peripheral and central nervous system

(CNS)

associated

pathological

effects.

Abnormal

neuro-behavioral changes including sensory and motor dysfunction were detected when mice were intravenously injected with higher accumulated dosages of colistin (15 mg/kg per day) for 7 days.24 This review covers the current knowledge-base of the pathophysiology and molecular mechanisms of polymyxin-induced neurotoxicity, as well as novel neuroprotective agents.

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2. Clinical manifestations of polymyxin associated neurotoxicity In their excellent clinical review, Falagas and Kasiakou surveyed the literature from 1950 until May 2005 and concluded that there was a decrease in the reporting of adverse neurotoxic events associated with polymyxin therapy in patients between 19902005.19 On the other hand, neurotoxicity associated with colistin use was reported more frequently during 1960-70s.14,

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Bosso et. al., reported that neurotoxicity commonly

manifests as paresthesias and ataxia in 29% in patients that received intravenous dosages in excess of 5 mg/kg per day (range, 5.7–8.0 mg/kg per day).20 These temporal differences may be in part due to advancements in dosing practices with polymyxins.26 They also noted that the neurotoxic effects of polymyxins are usually mild and resolve promptly after discontinuation of the treatment. Wabby et. al., reported that a patient developed rapidly progressive weakness with dyspnea after 5 days of intravenous CMS (2.5 mg/kg every 12 h).16 Recently, a case study described a patient with a severe New Delhi metallo--lactamase-1 producing Escherichia coli infection who exhibited convulsions following intravenous CMS (37,500 IU/kg/8 h, equal to 1.25 mg colistin base/kg/8 h), followed by acute respiratory muscle weakness and apnoea.17 A report from John et. al., indicated that the administration of high doses of intravenous polymyxin B (3-6 mg/kg/day) are coincident with increased neurotoxicity events in patients.27 These clinical reports are in line with in vitro and animal studies that have shown

colistin-induced

neurotoxicity

to

be

dose-dependent.

Given

that

the

cerebrospinal fluid (CSF)-to-plasma ratio of intravenous colistin is 5% (increasing to >35% with meningeal inflammation), these adverse events are likely due to peripheral neurotoxicity.18, 23-24, 28

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In contrast to intravenous administration, the direct delivery of polymyxins into the central nervous system (CNS) via the intrathecal (ITH) or intraventricular (IVT) routes appears to be more effective and safer.29 The ITH/IVT polymyxin dosages suggested by the Infectious Diseases Society of America guidelines (2004) call for administration of at least 125,000 IU/per day; however, in the clinical setting, the dose is often chosen empirically and colistin IT doses of 40,000-500,000 IU/day have been reported.30-31 Clinical pharmacokinetic data for ITH/IVT colistin suggests that doses > 65,200 IU/day are necessary to achieve sustained concentrations above the MIC of 2 μg/mL (1 mg colistin is equal to 30, 000 IU) (for susceptible Gram-negative pathogens). 32

Moreover, variability between patients is often seen due to fluctuations of intracranial

pressures. In a recent overview, the clinical literature shows that across 62 cases of reported Gram-negative CNS infections treated with ITH colistin, the majority (83 %) were due to A. baumannii, followed by 14% due to P. aeruginosa and 3% K. pneumonia.31,

33-35

The mean duration of treatment was 17 days, and ranged 7-28

days.35 Neurotoxic manifestations including seizures, cauda equina syndrome, chemical meningitis/ventriculitis were reported in some patients, albeit no nephrotoxicity was observed.35 The co-administration of rifampicin, amikacin and tigecycline with ITH/IVT colistin has been shown to be effective for the treatment of MDR Gram-negative infections and should be considered if supported by synergy tests on CSF culture. Clearly, there is a need for scientifically-based dosage recommendations for ITH/IVT polymyxins to treat infections caused by MDR-Gram-negative pathogens in the CNS.31, 33-35

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3. Accumulation of polymyxins in the central nervous system Elucidating the mechanisms of polymyxin uptake into the CNS and neuronal cells is an important aspect of understanding their unwanted neurotoxic side-effects.36-38 It is well known that only small molecules with low molecular mass (

Molecular mechanisms of neurotoxicity induced by polymyxins and

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