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Molecular mechanisms of neurotoxicity induced by polymyxins and chemo-prevention.

October 2018
ACS Chemical Neuroscience

October 2018

DOI:10.1021/acschemneuro.8b00300.

Authors:

University of Melbourne

Polymyxins (colistin and polymyxin B) are used increasingly for the treatment of life-threatening infections caused by multidrug resistant (MDR) Gram-negative pathogens, in particular Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. Neurotoxicity is one major unwanted side-effects associated with polymyxin therapy. 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 up-regulated 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.

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Review

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

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Molecular mechanisms of neurotoxicity induced by polymyxins and chemo-

prevention

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: Tony.Velkov@unimelb.edu.au OR

Jianzhong Shen, Telephone: +86 10 6273 3857; Fax: +86 10 6273 1032. E-mail:

sjz@cau.edu.cn.

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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 up-

regulated 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.15-

17 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 neuro-

protective 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 1990-

2005.19 On the other hand, neurotoxicity associated with colistin use was reported more

frequently during 1960-70s.14, 25 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 (<450 Da) and high lipid

solubility can efficiently permeate the healthy blood brain barrier (BBB) by a passive

trans-cellular process.39 The tight junctions of the inter-endothelial domains restrict the

passage of large hydrophilic molecules through the para-cellular route, and this is

expected to be the main reason underlying the low BBB penetration of polymyxins

(molecular mass 1,163 Da).40 This may also account for the higher incidence of

peripheral nervous system neurotoxicity as opposed to CNS-mediated neurotoxicity

associated with polymyxin therapy.16, 19 The brain uptake of colistin following a single

intravenous dose (5 mg/kg) or subcutaneous dose (40 mg/kg) to healthy mice was

shown to be negligible.40-43 However, it has been clinically demonstrated that

intravenous administration of CMS, an inactive prodrug of colistin, leads to detectable

levels of colistin in CSF of patients with CNS infections.32 This may be due to the

compromised BBB in patients with Gram-negative CNS infections resulting from

lipopolysaccharide release; the latter has been shown to damage the BBB.40-44

Coincidently, a study from our lab demonstrated that intravenous lipopolysaccharide

administration can increase the BBB transport of colistin in mice, which suggests that

the brain concentrations of colistin can be significantly enhanced during systemic

inflammation, as might be observed in patients with CNS infections.40-43 We also

showed that the continuous administration of intravenous colistin to mice can increase

the colistin concentration in brain tissue without injury of the BBB.22

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Our in vitro studies demonstrated that colistin uptake into mouse primary cortical

neuronal cells occurs in a concentration-dependent manner (un-published data). It has

been shown that there are three receptor pathways that included the endocytic receptor

megalin (MR), polypeptide transporter 2 (PEPT2), organic cation transporter 2 (OCTN2)

and p-glycoprotein (P-gp), which appear to co-governen the uptake of colistin into

kidney cells.36, 45-47 Colistin uptake has also been showed to occur in the lung epithelial

cells in a time and concentration-dependent manner.48 Notably, MR, PEPT2 and

OCTN2 are known to be expressed in neuronal cells.49-51 PEPT2 in particular, is present

in the apical membrane of choroid plexus epithelial cells (i.e. the CSF-facing), the site of

the blood-cerebrospinal fluid barrier (BCSFB), where it facilitates substrate efflux from

CSF to blood, thus reducing substrate distribution in CSF.52 A study from Jin et. al.

showed that P-gp inhibition significantly enhanced the uptake of colistin into brain tissue

of mice.42 Therefore, it is tenable to speculate that the disposition of polymyxins in the

CNS is somewhat dependent on the neuronal expression patterns of the

aforementioned transporters.

4. Polymyxin-induced neurotoxicity involves oxidative stress and mitochondrial

dysfunction

The CNS is very susceptible to oxidative damage due to its obligatory elevated

oxygen need and high content of polyunsaturated fatty acids.53 Mitochondria are vital for

maintaining basic cellular functions such as energy metabolism, ATP production and the

induction of cellular apoptosis should these essential functions go astray.54 We have

shown that mitochondria in the cerebrum of mice treated with colistin sulfate

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(intravenous injection at 15 mg/kg/day for 7 days) showed profound pathological

changes in their ultrastructure such as disruption of cristae and extensive swelling;

these were accompanied by biochemical perturbations including increased Ca2+-

induced mitochondrial permeability transition, decreased membrane potential and

reduced succinate dehydrogenase activity.24 Mitochondrial dysfunction was also

detected in primary neuronal cells of chicks treated with colistin at 4.15 and 8.3 μg/mL

for 24 h.55 Mitochondrial dysfunction is closely related to excessive reactive oxygen

species (ROS), which leads to damage to lipids, proteins, and DNA, and ultimately

results in cell death.56 In an in vitro mouse N2a neuronal cell model, colistin treatment

(200 μM for 24 h) significantly increased intracellular ROS levels and concomitantly

decreased glutathione (GSH) levels and the activity of the antioxidant enzymes

superoxide dismutase and catalase (CAT); the latter two operate in tandem to dissipate

ROS.28 Antioxidants such as N-acetyl cysteine and ascorbic acid have been shown to

protected neurons against colistin-induced oxidative stress via their scavenging ROS

activity.28 In addition, it is well known that SOD can catalyze the dismutation of the

superoxide anion into oxygen and hydrogen peroxide (H2O2); and subsequently, CAT

catalyzes the decomposition of H2O2 to water and oxygen. Thus, the concomitant

inhibition of SOD and CAT activities may partly contribute to the toxicity of colistin in

neuronal cells.28, 57-58 Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription

factor that regulates antioxidant genes by binding to their cognate antioxidant response

elements.59-60 Nrf2 activation promotes the expression of several phase II and

antioxidant enzymes such as heme oxygenase 1 (HO-1), SOD, and CAT.60 Not

surprisingly, we detected the activation of the Nrf2/HO-1 pathway during colistin-

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induced cell death in N2a cells and mouse cerebral cortices.24, 28, 61 Together, these

studies indicate a critical role of mitochondrial pathology and oxidative stress in

polymyxin-induced neurotoxicity.

5. Apoptotic pathways involved in polymyxin-induced neuronal cell death

Apoptosis plays a critical role in maintaining brain homeostasis in response to

drug-induced toxicity.62-64 Neuronal cell apoptosis is a notable pathological feature of

colistin-induced neurotoxicity and is dose-dependent.57-58, 61, 65-66 Our previous studies

demonstrated that colistin treatment at 50-200 μM for 24 h, can significantly induce

apoptosis in the neuronal cell lines N2a and PC12, or primary chick neurons28, 57-58, 65, 67-

70. The cytotoxicity of colistin appears to be dependent on the type and source of the

neuronal cell lines, which may relate to the expression levels of the aforementioned

receptors that mediate colistin up-take.28, 48, 65 For example, the HK-2 kidney cell line is

more susceptible to polymyxin-induced apoptosis than the A549 lung cell line, which

may be due to the differential expression of membrane transporters such as megalin,

which is prominently expressed on the apical membrane of human kidney cells, but not

in that of in lung epithelial cells.48 The uptake of polymyxins is thought to be mainly

mediated by PEPT2 in A549 cells48; whereas both PEPT2 and megalin are likely

involved in polymyxin uptake in HK-2 cells.36, 46, 48 The major pathways of colistin-

induced apoptosis that involve both the intrinsic mitochondrial and extrinsic death

receptor pathways, p53, MAPK, PI3K/Akt pathways in neuronal cells are discussed in

detail below (Figure 2).

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5.1 Extrinsic and intrinsic apoptotic pathways in polymyxin-induced neurotoxicity

During the process of colistin-induced neuronal cell apoptosis, both the death

receptor (extrinsic) and the mitochondrial (intrinsic) pathways are activated.71 The

mitochondrial pathway is regulated by the pro- and anti-apoptotic Bcl-2 family proteins,

that include Bax and Bcl-2.72 An increase in the Bax/Bcl-2 ratio and cytochrome C

(CytC) release is evident upon colistin treatment of N2a and PC12 neuronal cells, and

these events are concordant with mitochondrial outer membrane permeabilization.28, 48,

65 The release of CytC into the cytoplasm leads to the activation of caspases-3 and -9,

which in turn triggers apoptosis.73 Colistin treatment of PC12 cells also induced Fas and

Fas-L expression, followed by caspase-8 which is activated through the Fas-associated

death domain.70 Notably, caspase pan-inhibitors markedly inhibited colistin-induced

apoptosis in N2a cells, highlighting the key role of caspases across both the intrinsic

and extrinsic pathways.28 In addition, in a mouse model, colistin treatment (18 mg/kg for

7 or 14 days) markedly increased the expression of the 78-kDa glucose-regulated

protein (Grp78) in the cerebral cortices, a marker of the endoplasmic reticulum pathway

of apoptosis, which may also partly contribute to colistin-induced neurotoxicity.61

5.2 The role of the p53 pathway in polymyxin-induced neurotoxicity

There is demonstrable evidence that the p53 pathway participates in colistin-

induced apoptosis in cultured neuronal cells and in animal models.28, 48, 61, 65 Of note,

p53 is a major orchestrator of the cellular response to a broad array of stress types by

regulating apoptosis, cell cycle arrest, senescence, DNA repair and genetic stability.74

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Under normal physiological conditions, Mdm2-mediated ubiquitination and proteosomal

degradation control p53 levels. Whereas, under conditions of cellular stress, p53

undergoes reversible post-translational modifications such as acetylization,

ubiquitinoylation, phosphorylation, and sumoylation, which allow for its dissociation from

the suppressor.74 Colistin treatment of PC12 and N2a cells significantly increases p53

protein levels in the nuclear and cytoplasmic compartments as well as its mRNA levels.

In its primary role as a transcription factor, p53 primarily induces the expression of its

target genes, including DRAM, PUMA and Bax. DRAM is an effector of p53-mediated

apoptosis leads to autophagy. As a Bcl-2 homology 3 (BH3)-only family member, PUMA

has been implicated as a p53-upregulated modulator of apoptosis.28, 61, 65 It activates

Bax, which in turn initiates caspase-3 activation via the intrinsic mitochondrial apoptotic

pathway. Inhibition of p53 using an inhibitor PFT-α markedly decreased the expression

of Bax, cleaved-caspase-3 and attenuated colistin-induced cell apoptosis in PC12

neuronal cells.67 Together, it can be surmised that p53-PUMA-Bax pathway plays an

important role in colistin-induced neurotoxicity.

p53 also mediates cross-talk between the mitochondrial and death receptor

pathways by regulating caspase-8 gene expression and subsequent events concerned

with mitochondrial dysfunction.75-76 Recent studies showed that activation of p53 may

play a dual role in colistin-induced apoptosis in PC12 neuronal cells.65 The activation of

p53 inhibits the negative regulator of autophagy mTOR (mammalian target of

rapamycin) via AMP-activated protein kinase (AMPK) pathway activation, which in turn

induces autophagy, a protective response against colistin-induced neuronal cell

apoptosis.65, 67

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5.3 The role of the MAPK pathway in polymyxin-induced neurotoxicity

MAPKs are upstream modulators of apoptosis, and at least three subfamilies

have been identified: (i) extracellular signal-regulated kinases (Erks), (ii) c-Jun N-

terminal kinases (JNKs), and p38-MAPKs, which play key roles in a variety of cellular

and molecular process including apoptosis, autophagy, inflammation and immuno-

regulation.73 p38, JNK and Erk are usually considered as a biphasic signaling pathways

that can either act as pro-survival or pro-death, depending on the kinetics and duration

of activation.73 It has been shown that ERKs are important for cell survival, whereas

JNKs and p38-MAPKs are deemed stress responsive and involved in apoptosis.77

Polymyxin B activates JNK and Erk, but not p-p38, in human dermal fibroblasts.78 In a

mouse model, the activation of p-p38 and p-JNK was detected in colistin-induced

nephrotoxicity.79

Colistin treatment of PC12 neuronal cells significantly activated the expression of

p-JNK in a time-dependent manner, which cascaded into apoptosis via the

mitochondrial pathway.65 In colistin-treated N2a neuronal cells, opposing changes of p-

JNK (up-regulation) and p-Erk (down-regulation) were detected, indicating that co-

regulation of JNK and Erk contributed to colistin-induced apoptosis in this particular cell

line.61 Moreover, during colistin-induced oxidative stress, JNK activation can promote

mitochondrial ROS production by up-regulating the Bax/Bcl-2 ratio or p53 expression

(Figure 3).65

5.4 The role of the PI3K/Akt pathway in polymyxin-induced neurotoxicity

The serine/threonine protein kinase Akt/PKB, is one of the most multi-faceted

kinases in the human kinome.80 Akt/PKB plays important roles in response to growth

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factors and other extracellular stimuli to regulate several cellular functions including

nutrient metabolism, cell growth, apoptosis and survival. During its activation, Akt is

recruited to the plasma membrane, where it binds to the PI3K products, PI(3,4,5)P3 and

PI(3,4)P2, via its pleckstrin homology (PH) domain and exposes a pair of threonine-308

and serine-473 residues making them amenable to phosphorylation.81 The protein

expression levels of p-Akt are significantly decreased in response to colistin-induced

apoptosis in the RSC96 Schwann and N2a neuronal cell lines.61, 66 The pharmacological

inhibition of Akt using the inhibitor LY294002 markedly enhances colistin-induced

apoptosis, indicating that Akt plays a pro-survival role.61 In line with this finding, Akt

signaling plays an important pro-survival role in neurons exposed to oxidative stress

and against apoptosis induced by noxious xenobiotics, such as trimethyltin chloride,

acrylamide and methyl-4-phenylpyridine.82-84 Moreover, activated Akt confers cell

survival by phosphorylating its cytoplasmic targets, such as glycogen synthase kinase

(GSK)-3β, CREB, Bcl-2, Bax, and caspase-982-84. Not surprisingly, inhibition of Akt

exacerbates colistin-induced downregulation of Bcl-2 levels and mitochondrial

dysfunction in RSC96 and N2a cells.61, 66 CREB is a well-known neuronal cell pro-

survival factor. 85 Upon activation, p-CREB translocates to the nucleus and binds to

CBP; subsequently, the p-CREB-CBP complex binds to the CRE promoter to induce

synaptic remodeling and the expression of acetylcholine esterase, as well as various

neurotransmitter receptors and ion channels.86 Recently, Herkel and colleagues

reported that the activation of the Akt-CREB signaling pathway protects against stress-

induced cell death and attenuates NF-kB-mediated inflammatory response in

RAW264.7 cells.87 Our own data show that the inhibition of p-Akt by LY294002

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aggravates the loss of p-CREB in N2a cells, in cascade, to promote colistin-induced

apoptosis; this is in line with a recent report that shows activation of Akt and CREB to

play a pro-survival role against amyloid--induced neurotoxicity in rats.88Moreover, the

Akt pathway is activated by PI3K in response to growth factors such as NGF.89 NGF

was shown to stimulate auto-phosphorylation of TrkA, which activates PI3K/AKT

signaling.90 Notably, a previous study demonstrated that NGF is a key pro-survival

factor in neurons against oxidative stress and neurotoxicity induced by MPTP, MPP+, 6-

OHDA, and H2O2.91-93 Further, NGF supplementation effectively attenuates colistin-

induced neurotoxicity in a mouse model.94 Similarly, in a recent study we showed that

colistin treatment (200 μM for 24 h) significantly inhibited the expression of NGF and up-

stream receptor p75NTR as well as that of p-Akt and p-CREB protein, whereas, it

promoted the protein expression of p-TrkA.61 p75NTR can phosphorylate Akt via the

active phosphatidylinositol 3-kinase to promote cell survival.90

p-CREB interacts with the specific CREB-binding sequence in the promoter

region of NGF and induces NGF expression.95 Thus, any decrease in p-CREB protein

levels would exacerbate colistin-induced apoptosis via inhibition of NGF (Figure 4).61

Indeed, the balance and feedback regulation between NGF-p75NTR and Akt/CREB

pathways may play a critical role in colistin-induced neurotoxicity. Luo et. al., show that

Erk can parallel with Akt to co-positively regulated the nuclear trans-localization of p-

CREB.96 These findings suggest that the inhibition of p-Erk may partly participate in

colistin-induced loss of nuclear CREB. Our group’s data demonstrate that inhibition of

Akt down-regulates the expression of Nrf2 and HO-1.66 61 The PI3K/Akt pathway also

plays a key role in regulating Nrf2-ARE-dependent protection against oxidative stress

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caused by colistin. Taken together, these data suggest that the inhibition of the NGF-

p75NTR-Akt-CREB cascade promotes colistin-induced neuronal cell death.

6. The role of autophagy in polymyxin-induced neurotoxicity

Autophagy is an evolutionarily conserved catabolic degradation process by which

cellular proteins and organelles are engulfed by autophagosomes, digested in

lysosomes, and recycled in order to sustain cellular homeostasis in the face of various

stresses including nutrient deprivation, hypoxia, oxidative stress, and DNA damage. 97

Autophagy is known to be involved in the maintenance of neuronal homeostasis,

particularly in response to drug induced-oxidative stress (e.g. cisplatin, etoposide,

olanzapine and staurosporine) and mitochondrial dysfunction.63-64, 71, 98 In general, the

fate of the cell depends on the interplay between pro-apoptotic factors and autophagy,

wherein the latter blocks the induction of apoptosis or acts to delay apoptotic cell death,

and conversely pro-apoptotic caspase activation shuts off autophagy.54, 97 Our recent

study shows that colistin treatment (200 μM) of N2a cells down-regulates the expression

of mTOR and p70s6k, and up-regulates ULK1 expression, indicating that mTOR

inhibition-mediated autophagy is activated in this neuronal cell line following colistin

exposure. Notably, elevated autophagic degradation markers were observed using

transmission electron microscopic examination.61 Rapamycin treatment further inhibited

the expression of mTOR and p70s6k and up-regulated ULK1 expression, which protects

against apoptosis caused by colistin via increased autophagy.61, 68, 99 In contrast, co-

treatment with autophagy inhibitors, such as chloroquine (CQ), exacerbated colistin-

induced apoptosis.28 Furthermore, we have shown that the inhibition of apoptosis using

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the caspase inhibitor Z-VAD-FMK markedly attenuated colistin-induced autophagy in

N2a neuronal cells.28 The autophagy-lysosomal pathway plays an important protective

role in various neurodegenerative diseases.54, 100 We have shown that fluorescent

polymyxin probes do not co-localise with the lysosome specific dye LysoTracker Deep

Red, indicating a lack of co-localization of the probes within lysosomes, suggesting the

polymyxin itself may not be degraded via this pathway.101

p53 and JNK are two apoptotic-regulatory factors that are deregulated in

processes of drug, e.g β-amyloid, 3-chloro-1,2-propanediol, olaquindox,-induced nerve,

renal and liver toxicities.76, 99, 102 p53 and JNK can also directly affect autophagy by

regulating the expression of DRAM, a pro-autophagy and pro-apoptotic protein.75-76, 98

We have demonstrated that JNK activation in response to colistin treatment of PC12

neuronal cells results in phosphorylation of Bcl-2 which enhances autophagy by

disrupting the interaction between Bcl-2 and Beclin 1, an autophagy protein (Figure

3).65 Moreover, colistin treatment of PC12 cells can induce the nuclear localization of

p53, which cascades to enhance autophagy through transactivation of target genes

including DRAM (Figure 3).67 Inhibition of JNK by the specific inhibitor SP600125

markedly abolished the overexpression of p53 indiced by colistin treatment, indicating

that the JNK-p53 pathway may partly enhance colistin-induced autophagy.65 In addition,

the activation of p53 may also contribute to colistin-induced inhibition of mTOR, a direct

regulator of autophagy.67, 75 The collective literature indicate that autophagy plays a

protective role against polymyxin-induced apoptotic neuronal cell death; such that

autophagy purposes to recover cellular homeostasis via the degradation of damaged

organelles. Conversely, if polymyxin exposure has damaged the neuronal cell beyond a

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recoverable state, then the cell undergoes apoptotic cell death. Clearly, it is the inter-

play of the two pathways that determines the ultimate fate of the neuronal cell.

7. Chemo-prevention of polymyxin-induced neurotoxicity

Available population pharmacokinetic and pharmacodynamic data indicates that

the current recommended dosage regimens of polymyxins achieve suboptimal plasma

concentrations and that higher doses are needed to achieve effective bacterial killing

and to prevent the emergence of resistance.103 However, simply escalating the

polymyxin dose is not an option due to the limited window between antibacterial efficacy

and neurotoxicity. Therefore, the development of effective neuro-protective agents that

can be co-administered during polymyxin therapy is essential for effective and safe

antimicrobial chemotherapy with polymixins. Recent literature reports have provided

evidence that the co-administration of various agents such as curcumin, rapamycin and

minocycline exert a neuro-protective effect against colistin-induced neurotoxicity.57-58, 61

7.1 Curcumin

Curcumin a natural product polyphenol (diferuloylmethane), is the yellow pigment

component in the spice turmeric, extracted from the rhizome of Curcuma longa. Apart

from its tantalizing culinary applications in Indian cooking, curcumin has been reported

to possess a range of beneficial pharmacological properties such as anti-tumor, anti-

inflammatory and anti-oxidant activities.104-106 Accordingly, curcumin has been assessed

for it potential as a therapeutic agent against cancer, cardiovascular, neurological,

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autoimmune and metabolic diseases.107-109 Clearly, curcumin’s anti-inflammatory and

anti-oxidative properties hold a great deal clinical potential in a number of chronic and

neuro-protective diseases.107 To this end, our in vitro data showed that curcumin can

effectively attenuate colistin-induced neurotoxicity in N2a cells by inhibiting oxidative

stress, increasing the levels of the intracellular anti-ROS enzymes SOD, CAT and GSH

levels, and activating the Nrf2/HO-1 anti-oxidative stress pathway.58 Curcumin treatment

also down-regulates NF-kB and NF-kB-regulated genes involved in inflammation and

apoptosis in N2a cells.58 Although curcumin exhibits poor systemic availability when

administered via the oral route, various formulations for intravenous use, including

nanoparticles and liposomal encapsulation have shown promise as anti-neoplastic

agents.108-110 Available preclinical and phase I/II data suggest that curcumin is well

tolerated, and has a good safety profile.108 Encouragingly, a recent animal study

showed that rats that were orally administered curcumin (200 mg/kg/day) following

colistin treatment (IP administered 300,000 IU colistin/kg/day for 6 days), showed

markedly ameliorated histological damage and decreased markers of oxidative damage

and inflammation in their brain and kidney tissues compared to the colistin-only

treatment group.111 These data highlight the potential of curcumin as a

neuroprotective/nephroprotective agent that can be safely co-administered orally to

patients receiving polymyxin therapy.

7.2 Minocycline

Minocycline is a broad-spectrum tetracycline antibiotic reported to display

antioxidant and neuroprotective activities.112-116 Since minocycline and colistin produce

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a pharmacodynamically synergistic antibacterial effect117-118, their co-administration has

the potential to reduce colistin dosage and thus toxicity, whilst concomitantly exerting

improved bacterial killing, i.e ‘kill two birds with one stone’. Our data demonstrates that

minocycline could not only inhibit colistin-induced ROS generation, but also enhance

the antioxidant capacity of N2a cells by up-regulating the activities of SOD and CAT,

and thus attenuating colistin-induced mitochondrial dysfunction and apoptosis.57 The

potent antioxidant activity of minocycline is believed to be related to its ability to chelate

mitochondrial iron which catalyzes toxic hydroxyl radical formation.100 It can be

surmised from the above that intravenous minocycline-polymyxin combination therapy

overcomes many of the limitations of polymyxin monotherapy and holds great clinical

potential for treatment of CNS infections due to MDR Gram-negatives; notably, (i) The

favorable pharmacokinetic profile of intravenous minocycline119, (ii) antibacterial synergy

with polymyxins117-118, 120-121, 122 neuroprotective/nephroprotective properties122 and (iv)

stability against many tetracycline bacterial resistance enzymes.122

7.3 Salidroside

A recent study from our group shows that salidroside, a medicinal ingredient of

Rhodiola rosea, exerts a potent protective effect against colistin-induced cytotoxicity

and apoptosis in RSC96 Schwann cells.66 Previous studies have shown that salidroside

has neuroprotective effects against glutamate-induced apoptosis in rat primary

hippocampal neurons, as well as alleviating amyloid--induced cell death of human SH-

SY5Y neuroblastoma cells.123-124 Our study demonstrated that salidroside attenuates

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colistin-induced oxidative stress and modulates the PI3K/Akt/mitochondrial signaling

pathway.66

7.4 Rapamycin

mTORC1 is the mechanistic target for rapamycin and is part of a regulatory-

associated complex responsible for regulating cell growth in response to nutrients, such

as amino acids, oxygen, and cellular energy levels.125 mTORC1 and activated p70S6K

(a downstream target of mTOR) have been shown to be markedly elevated in the

cerebral cortex and hippocampus in animal models of Alzheimer’s disease and other

neurological diseases such as tuberous sclerosis.126 Rapamycin is a potent and specific

inhibitor of mammalian/mechanistic target of rapamycin (mTOR).127 A growing body of

evidence suggests that rapamycin possesses a neuroprotective role in many

neurodegenerative diseases.81, 88 Rapamycin pre-treatment inhibits the expression of p-

mTOR and p-p70s6k and up-regulates ULK1 expression, which induces autophagy to

help recover N2a neurons from colistin-induced cell death via inhibition of apoptosis.61

Our recent study shows that rapamycin administration at 2.5 mg/kg/day for 14 days can

effectively attenuate colistin-induced neurotoxicity in a mouse model.61 Rapamycin was

also shown to perturb the GSH levels and increased the transcription of anti-oxidant

genes mediated by cap-n-collar (the Drosophila orthologue of Nrf2), inhibiting colistin-

induced caspase-9 and -3 mediated apoptosis in N2a cells and mouse cerebral

cortex.61 In addition, we observed that colistin-induced ROS accumulation can activate

JNK and inhibit Erk1/2, also contributing to neuronal apoptosis.61 Xu et. al., showed that

rapamycin inhibited cadmium-induced phosphorylation of Erk1/2 and JNK and cleavage

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of caspase-3 in PC12 cells, SH-SY5Y cells and mouse primary neuronal cells.128-129

Indeed, rapamycin pretreatment can inhibit the expression of p-JNK, which may partly

contribute to inhibit colistin-induced oxidative stress and mitochondrial dysfunction.

Recently, Herkel and colleagues reported that the activation of the Akt-CREB signaling

pathway protects against stress-induced cell death and attenuates the NF-kB-mediated

inflammatory response in Raw264.7 cells.87 Our own data showed that rapamycin pre-

treatment recovered p-Akt and p-CREB to normal levels, in line with a recent report that

shows activation of Akt and CREB to partly contribute to the neuroprotective activity of

rapamycin against colistin-induced neurotoxicity in N2a cells.61, 88 Consistent with our

own data, previous studies have shown that rapamycin can increase Akt

phosphorylation through the inhibition of a negative feedback loop involving

mTORC1.130 Lehigh et. al., reported that target-derived NGF could mediate circuit

formation and synapse maintenance through TrkA endosome signaling within dendrites

to promote aggregation of post-synaptic protein complexes.131 Rapamycin pre-treatment

markedly up-regulated the expression of NGF and its downstream receptor protein p-

TrkA in N2a cells, which may partly contribute to the activation of Akt/CREB pathway

induced by rapamycin, to attenuate neuronal cell death.61 These finding highlights

rapamycin as a promising agent for prevention of colistin-induced oxidative stress and

neurotoxicity, similarly to minocycline, curcumin or salidroside.

8. Conclusions

There is increasing evidence supporting the potential development of novel combination

formulations of polymyxins with neuro-protective agents to reduce polymyxin-induced

neurotoxicity. It is notable that oxidative stress is one of the toxicological hallmarks of

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polymyxin-induced neurotoxicity. Mitochondria, as the major generator of ROS, appear

to play a prominent role in colistin-induced neuronal cell death by mediating apoptotic

pathways. Therefore, alleviating mitochondrial dysfunction is a potential target for the

prevention of polymyxin-induced neurotoxicity. Cellular autophagy also plays an

important role in the process of polymyxin-induced neurotoxicity. Data from animal

models and in vitro cell culture demonstrate that autophagy is markedly induced during

polymyxin treatment of neurons in a rescue attempt against apoptotic cell death.

Colistin-induced apoptosis and autophagy is also regulated by complex signal pathways,

such as PI3K/Akt, MAPK, NF-kB, p53, mTOR and Nrf2/HO-1, all of which represent

potential pharmacological targets. To this end drugs and supplements (i.e minocycline,

rapamycin, salidroside and curcumin) already approved for human use represent the

most tangible resource, as these ‘off the shelf’ agents are safe and effective for human

use. It appears that these compounds operate via diverse mechanisms to either inhibit

ROS production or stimulate cellular salvage and repair pathways to recover neuronal

homeostasis. On key criteria all of these compounds need to satisfy in order to be

clinically effective is the ability to accumulate in sufficient quantities in the CNS, which

where the advantages of ITH/IVT administration come into play. Clinical trials are clearly

warranted with these agents in patients receiving polymyxin therapy.

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Funding

This study was supported by Key Projects in Chinese National Science and Technology

Pillar Program during the 12th Five-year Plan Period (2015BAD11B03, to C.D., S.T.). T.

V. is supported by the Australian National Health and Medical Research Council

(NHMRC).

Transparency declarations

None to declare

Author Contributions

C.D, X.X, J.L, G.D.C, R.C, S.T, and E.K.S-F, wrote, edited and proof read the

manuscript. D.H, T.V, and J.S conceived the and proof read the manuscript.

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Figures and Captions

Figure 1: Chemical structures of polymyxin B, colistin and colistin

methanesulphonate (CMS). Thr: threonine; Leu: leucine; Phe: phenylalanine; Dab:,-

diaminobutyric acid.

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Figure 2. Schematic diagram depicting the major apoptosis pathways involved in

colistin-induced neurotoxicity. Colistin-induced apoptosis involves oxidative stress, the

activation of death receptor and mitochondrial pathways (aberration of the Bax/ Bcl2

ratio, loss of membrane potential and production of reactive oxygen species [ROS]) and

activation of caspase-3, -8, and -9. The activation of p53, c-Jun N-terminal kinases

(JNKs)/MAPK pathways and the inhibition of the PI3K/Akt pathway may contribute to

colistin-induced apoptosis. These pathways have been demonstrated to be targeted

regulated by neuro-protective agents including curcumin, rapamycin and minocycline.

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Figure 3. Proposed model for the crosstalk between p53 and JNK in the regulation of

colistin-induced apoptosis and autophagy in neuronal cells. P53 is a transcription factor

that primarily induces the expression pro-apoptotic and pro-autophagic genes including

DRAM, PUMA, AMPK and Bax. JNK activation can promote mitochondrial ROS

production by up-regulating the Bax/Bcl-2 ratio and p53 expression, which eventuates in

apoptosis. The activation of p53 and JNK can both promote autophagy, which protects

against colistin-induced apoptotic cell death.

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Figure 4. The role of the NGF and PI3K/Akt pathways in colistin-induced neurotoxicity.

In the neuronal cell, colistin could inhibit the expression of Akt, then down-regulated the

expression of transcription factor CREB (cAMP response element-binding protein),

which is a well-known neuronal cell pro-survival factor. CREB can translocate to the

nucleus and bind to cAMP response elements, expressed the target gene NGF. Colistin

potentially inhibits the NGF- p75NTR pathway, which creates a ‘perfect’ vicious cycle by

the inhibition of Akt pathway by colistin.

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45x17mm (300 x 300 DPI)

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ResearchGate has not been able to resolve any citations for this publication.

Taurine attenuates acrylamide-induced apoptosis via a PI3K/AKT-dependent manner

Article

Full-text available

Dec 2018
HUM EXP TOXICOL

As a potent neurotoxic agent, acrylamide (ACR) is formed in food processing at higher temperature. Taurine (TAU), a nonessential amino acid, is used to cure neurodegenerative disorders, followed by activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. In this article, we certified that antiapoptotic efficacy of TAU in vivo and vitro. ACR-treated rats received TAU by drinking water 2 weeks after ACR intoxication. The results showed that in treated rats, TAU alleviated ACR-induced neuronal apoptosis, which was associated with the activation of PI3K/AKT signaling pathway. TAU attenuated apoptosis caused by ACR through observing terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, measure of protein expression of Bcl-2, Bax, and caspase 3 activity. TAU-induced antiapoptotic effect is PI3K/AKT-dependent, which was proved in ACR-intoxicated ventral spinal cord 4.1 cells in the presence of AKT inhibitor, MK-2206. Therefore, our results demonstrated that TAU-attenuated ACR-induced apoptosis in vivo through a PI3K/AKT-dependent manner provided new sights in the molecular mechanism of TAU protection against ACR-induced neurotoxicity.

Vitexin protects dopaminergic neurons in MPTP-induced Parkinson’s disease through PI3K/Akt signaling pathway

Article

Full-text available

Mar 2018

Parkinson’s disease (PD) is a progressive neurodegenerative disease which is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Methods In this study, the neuroprotective effect of vitexin (Vit), a flavonoid compound isolated from Crataegus pinnatifida Bunge was examined in PD models both in vitro and in vivo. Results On SH-SY5Y cells, methyl-4-phenylpyridine (MPP⁺) treatment suppressed cell viability, induced apoptosis, and increased Bax/Bcl-2 ratio and caspase-3 activity. However, Vit improved these parameters induced by MPP⁺ treatment significantly. Further study disclosed that Vit enhanced the phosphorylation of PI3K and Akt which was downregulated by MPP⁺ in SH-SY5Y cells, the effect of which could be blocked by PI3K inhibitor LY294002 and activated by PI3K activator IGF-1. Moreover, results from the pole test and traction test suggested that Vit pretreatment prevented bradykinesia and alleviated the initial lesions caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in MPTP-treated mouse PD model. Vit also enhanced the activation of PI3K and Akt and suppressed the ratio of Bax/Bcl-2 and caspase-3 activity in MPTP-treated mice. Conclusion Taken together, this study demonstrated that Vit protected dopaminergic neurons against MPP⁺/MPTP-induced neurotoxicity through the activation of PI3K/Akt signaling pathway. Our findings may facilitate the clinical application of Vit in the therapy of PD.

A Dual Role of P53 in Regulating Colistin-Induced Autophagy in PC-12 Cells

Article

Full-text available

Oct 2017

This study aimed to investigate the mechanism of p53 in regulating colistin-induced autophagy in PC-12 cells. Importantly, cells were treated with 125 μg/ml colistin for 12 and 24 h after transfection with p53 siRNA or recombinant plasmid. The hallmarks of autophagy and apoptosis were examined by real-time PCR and western blot, fluorescence/immunofluorescence microscopy, and electron microscopy. The results showed that silencing of p53 leads to down-regulation of Atg5 and beclin1 for 12 h while up-regulation at 24 h and up-regulation of p62 noted. The ratio of LC3-II/I and autophagic vacuoles were significantly increased at 24 h, but autophagy flux was blocked. The cleavage of caspase3 and PARP (poly ADP-ribose polymerase) were enhanced, while PC-12-sip53 cells exposed to 3-MA showed down-regulation of apoptosis. By contrast, the expression of autophagy-related genes and protein reduced in p53 overexpressing cells following a time dependent manner. Meanwhile, there was an increase in the expression of activated caspase3 and PARP, condensed and fragmented nuclei were evident. Conclusively, the data supported that silencing of p53 promotes impaired autophagy, which acts as a pro-apoptotic induction factor in PC-12 cells treated with colistin for 24 h, and overexpression of p53 inhibits autophagy and accelerates apoptosis. Hence, it has been suggested that p53 could not act as a neuro-protective target in colistin-induced neurotoxicity.

Severe Infusion-Related Adverse Events and Renal Failure in Patients Receiving High-Dose Intravenous Polymyxin B

Article

Full-text available

Dec 2017
ANTIMICROB AGENTS CH

Very high doses of polymyxin B (PMB) have been addressed in in vitro experiments against carbapenem-resistant Gram-negative bacilli as a strategy to improve bacterial killing and suppress resistance emergence. However, the toxicities of very high doses in patients are unknown. This is a retrospective cohort study assessing patients receiving >3mg/kg/day or a total dose ≥250mg/day of PMB. The main outcomes were severe infusion-related adverse event according to Common Terminology Criteria for Adverse Criteria and renal failure category of RIFLE criteria for acute kidney injury (AKI) during treatment. A total of 222 were included for analysis of infusion-related events. The mean PMB dose was 3.61±0.97mg/kg/day (median total dose/day=268 mg). Severe infusion-related adverse events occurred in two patients determining an incidence of 0.9% (95% Confidence Interval, 0.2-3.2): one was classified as a life-threatening and one as severe adverse effect. Renal failure was analyzed in 115 patients: 25 (21.7%) patients presented renal failure (54 [47.0%] developed any degree of AKI, categorized as Risk [27.8%]; Injury [25.9%] and Failure [46.3%]). Vasoactive drug, concomitant nephrotoxic drugs and baseline creatinine clearance were independent risk factors for renal failure. Neither PMB daily dose scaled by body weight nor total daily dose were associated with renal failure. In-hospital mortality was 60% (134 patients): 26% (57 patients) occurred during treatment and none during infusion. Our data suggest that high dose schemes have acceptable safety profile and could be further tested in clinical trials assessing strategies to improve patients' outcomes and minimize the emergence of PMB resistance.

Colistin is Substrate of the Carnitine/Organic Cation Transporter 2 (OCTN2, SLC22A5)

Article

Full-text available

Oct 2017

Colistin is a polycation antibiotic used for the treatment of multidrug-resistance (MDR) gram-negative infections; nevertheless, its use is often limited by the high incidence of renal damage. The mechanism underlying colistin-induced nephrotoxicity is not known, but perhaps related to its accumulation in the renal cortex upon extensive reabsorption from the nascent urine. Because little is known about the membrane transport of colistin, the purpose of the present study was to characterize better the transport system involved in colistin renal handling by using HEK293 cells stably transfected with the main organic cation transporters expressed at the apical membrane of the proximal tubule. [(14)C]Colistin was transported by the carnitine/organic cation transporter 2 (OCTN2, SLC22A5) but not by the organic cation transporter 1 (OCT1) and N1 (OCTN1). Non-labeled colistin inhibited the OCTN2-mediated transport of [(3)H]L-carnitine in a non-competitive manner and that of [(14)C]tetraethylammonium bromide ([(14)C]TEA) in a competitive manner. Unlike that of [(3)H]L-carnitine, the [(14)C]colistin OCTN2-mediated uptake was Na(+)-independent. When endogenous OCTN2-mediated colistin transport was inhibited by co-incubation with L-carnitine, primary mouse proximal tubular cells were fully protected from colistin toxicity, suggesting that colistin toxicity occurred upon intracellular accumulation.

Nerve Growth Factor Confers Neuroprotection against Colistin-Induced Peripheral Neurotoxicity

Article

May 2020

Neurotoxicity is an unwanted side effect patient’s experience when receiving parenteral colistin therapy. The development of effective neuroprotective agents that can be co-administered during colistin therapy remains a priority area in antimicrobial chemotherapy. The present study aimed to investigate the protective effect of nerve growth factor (NGF) against colistin-induced peripheral neurotoxicity using a murine model. C57BL/6 mice were randomly divided into the following 6 groups: (i) untreated control, (ii) NGF alone 36 μg/kg/day (administered intraperitoneally), (iii) colistin alone (18 mg/kg/day administered intraperitoneally) and (iv-vi) colistin (18 mg/kg/day) plus NGF (9, 18 and 36 μg/kg/day). After treatment for 7 days, neurobehavioral and electrophysiology changes, histopathological assessments of sciatic nerve damage, and oxidative stress biomarkers were examined. The mRNA expression levels of Nrf2, HO-1, Akt, Bax, caspase-3 and -9 were assessed using quantitative RT-PCR. The results showed that across all the groups wherein NGF was co-administered with colistin, a marked attenuation of colistin-induced sciatic nerve damage and improved sensory and motor function were observed. In comparison to the colistin only treatment group, animals that received NGF displayed up-regulated Nrf2 and HO-1 mRNA expression levels and down-regulated Bax, caspase-3 and -9 mRNA expression levels. In summary, our study reveals that NGF co-administration protects against colistin-induced peripheral neurotoxicity via the activation of Akt and Nrf2/HO-1 pathways and inhibition of oxidative stress. This study highlights the potential clinical application of NGF as a neuroprotective agent for co-administration during colistin therapy.

Curcumin alleviates colistin-induced nephrotoxicity and neurotoxicity in rats via attenuation of oxidative stress, inflammation and apoptosis

Article

Aug 2018
CHEM-BIOL INTERACT

Colistin is an effective antibiotic against multidrug-resistant (MDR) gram-negative bacterial infections; however, nephrotoxic and neurotoxic effects are fundamental dose-limiting factors for this treatment. This study was conducted to assess the potential protective effects of curcumin, a phenolic constituent of turmeric, against colistin-induced nephrotoxicity and neurotoxicity, and the possible mechanisms underlying any effect. Twenty-four adult male albino rats were randomly classified into 4 equal groups; the control group (orally received saline solution), the curcumin-treated group (orally administered 200 mg curcumin/kg/day), the colistin-treated group (IP administered 300,000 IU colistin/kg/day) and the concurrent group (orally received 200 mg curcumin/kg/day concurrently with colistin injection); all rats were treated for 6 successive days. Colistin administration significantly increased serum creatinine, urea and uric acid levels as well as brain gamma butyric acid (GABA) concentrations. In renal and brain tissues, colistin significantly increased malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and caspase-3 expression levels. In addition, colistin significantly decreased catalase (CAT), glutathione (GSH), and B-cell lymphoma 2 (Bcl-2) expressions. Curcumin administration in colistin-treated rats partially restored each of these altered biochemical, antioxidant, inflammatory and apoptotic markers. Histopathological changes in renal and brain tissues were also alleviated by curcumin co-treatment. Our study reveals a critical role of oxidative damage, inflammation and apoptosis in colistin-induced nephrotoxicity and neurotoxicity and showed that they were markedly ameliorated by curcumin co-administration. Therefore, curcumin could represent a promising agent for prevention of colistin-induced nephrotoxicity and neurotoxicity.

Rapamycin Confers Neuroprotection against Colistin-Induced Oxidative Stress, Mitochondria Dysfunction, and Apoptosis through the Activation of Autophagy and mTOR/Akt/CREB Signaling Pathways

Article

Jan 2018

Our previous studies showed colistin-induced neurotoxicity involves apoptosis and oxidative damage. The present study demonstrates a neuroprotective effect of rapamycin against colistin-induced neurotoxicity in vitro and in vivo. In a mouse model, colistin treatment (18 mg/kg/d; 14 days) produced marked neuronal mitochondria damage in the cerebral cortex and increased activation of caspase-9 and -3. Rapamycin co-treatment (2.5 mg/kg/d) effectively reduced this neurotoxic effect. In an in vitro mouse neuroblastoma-2a (N2a) cell culture model, rapamycin pre-treatment (500 nM) significantly decreased colistin (200 μM) induced cell death from ~50% to 72%. Moreover, rapamycin showed a marked neuroprotective effect in the N2a cells by decreasing intracellular reactive oxygen species (ROS) production and by up-regulating the activities of the anti-ROS enzymes superoxide dismutase and catalase, and recovering GSH levels to normal. Moreover, rapamycin pre-treatment protected against colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis by up-regulating autophagy and activating the Akt/CREB, NGF and Nrf2 pathways, while inhibiting p53 signaling. Taken together, this is the first study to demonstrate that rapamycin protects against colistin-induced neurotoxicity by activating autophagy, inhibiting oxidative stress, mitochondria dysfunction and apoptosis. Our data highlight that regulating autophagy to rescue neurons from apoptosis may become a new targeted therapy to relieve the adverse neurotoxic effects associated with colistin therapy.

The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease

Book

Jan 2007
ADV EXP MED BIOL

Curcumin is derived from the root of the plant Curcuma longa (also called turmeric) and its medicinal uses have been described for over 5000 years. More than 1500 papers published within last half a century has revealed that curcumin has a potential in the treatment of wide variety of inflammatory diseases including cancer, diabetes, cardiovascular diseases, arthritis, Alzheimer, psoriasis etc, through modulation of numerous molecular targets. This is the first monograph to deal specifically with this subject.

Total synthesis of architecturally complex indole terpenoids: Strategic and tactical evolution

Article

Aug 2017

Indole terpenes have attracted the interests of synthetic chemists due to their complex architectures and potent biological activities. Examples of total syntheses of several indole terpenes were reviewed in this article to honor Professor KC Nicolaou.

Molecular mechanisms of neurotoxicity induced by polymyxins and chemo-prevention.

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