Received Date: 22-Jan-2014 Accepted Date: 14-May-2014 Article Type: Original Article
Effects of Colistin on the Sensory Nerve Conduction Velocity and F-wave in Mice Chongshan Dai1, Shusheng Tang1, Jichang Li2, Jiping Wang3 and Xilong Xiao1
1
College of Veterinary Medicine, China Agricultural University, Beijing, P. R. China.
2
College of Veterinary Medicine, Northeast Agricultural University, Xiangfang District, Harbin,
P. R. China. 3
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences,
Monash University, Parkville, Victoria, Australia.
(Received 22 January 2014; Accepted 14 May 2014)
Author for correspondence: Xilong Xiao, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, P. R. China (fax: +86 10 6273 1032., e-mail: [email protected]).
Abstract: The aim of this study was to examine the changes of sensory nerve conduction velocity (SNCV) and F-wave for colistin-induced peripheral neurotoxicity using a mouse model. Mice were administered with colistin 5, 7.5 and 15 mg/kg/d via a 3-min. intravenous infusion. The sensory nerve conduction velocity (SNCV) and F-wave were measured using the bipolar recording electrodes. The SNCV and F-wave latency changed in a dose- and time-dependent manner. The
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcpt.12272 This article is protected by copyright. All rights reserved.
significant increase of F-wave latency and significant decrease of SNCV appeared on day 3 (p < 0.05 and 0.01, respectively) in the 15 mg/kg/d group, and they were markedly changed on day 7 in the 7.5 mg/kg/d (p < 0.01 and 0.05, respectively) and 15 mg/kg/d groups (both p < 0.01). In addition, F-wave latency also significantly increased on day 7 in the 5 mg/kg/d group (p < 0.05) without any clinical signs. These results indicate that SNCV and F-wave latency were more sensitive in colistin-induced neurotoxicity in mice, which highlights the early monitoring tool of polymyxins neurotoxicity in the clinic.
Colistin (also know as polymyxin E) is a cationic polypeptide antibiotic and has been re-introduced into clinical practice over the last decade due to multidrug-resistant (MDR) Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae [1-4]. With the currently recommended dosage regimens, the rate of colistin-induced neurotoxicity in patients is lower than its nephrotoxicity [5]; however, it has been increasingly reported recently. Patients administered with intravenous colistin methanesulfonate (CMS), the inactive prodrug of colistin [6], may experience confusion, dizziness, facial and peripheral paraesthesia, visual disturbances, muscle weakness, hallucinations, vertigo, seizures and ataxia [5, 7]. Recently, a case study reported that a patient with severe New Delhi metallo-β-lactamase-1 Escherichia coli infection, received intravenous CMS (37,500 IU/kg/8h) and developed convulsion, followed by acute respiratory muscle weakness and apnoea [8]. In the clinic, mild neurotoxicity (e.g. facial and peripheral paraesthesia) can be easily ignored, especially in elderly patients [9, 10]. There is a dearth of information on the mechanism of colistin-induced neurotoxicity. In previous animal studies [4, 10, 11], colistin led to marked behavioural changes in mice or rats, including notable muscular weakness and ataxia. Furthermore, mitochondrial dysfunction was observed in mouse central nervous tissue and chicken neurons in vitro [4, 9]. In addition, axonal degeneration and demyelization in sciatic nerves were also reported when mice were intravenously administered with 15 mg/kg/d colistin for 7 days [11]. As electrodiagnostic evaluation is important for patients with peripheral neuropathy [12], it is important to examine
This article is protected by copyright. All rights reserved.
colistin-induced electrophysiological changes in vivo [13, 14]. Electrophysiological evaluation is considered as a classic diagnosis method for clinical neurotoxicity induced by anti-cancer drugs (e.g. cisplatin and paclitaxel [15, 16]). No general agreement has been reached regarding the method for assessing polymyxins neurotoxicity, especially peripheral neurotoxicity, even though scattered literature suggested it in the clinic [13, 17]. In neuro-electrophysiological studies, a strong electrical stimulus on the motor nerve can lead to both orthodromic and antidromic impulse conduction; the former reaches the muscle fibre, produces M-wave (i.e. the first compound action potentials (CAP). Antidromic impulse conduction reaches the motor neuron cell bodies of spinal cord; subsequently, orthodromic wave travels back towards the muscle, evokes the second CAP, namely the F-wave [18]. M-wave parameters are very useful for evaluating the lesions of peripheral nerves, such as motor nerve conduction velocity (MNCV) and compound action potential amplitude (CAPA) [19]. F-wave plays a critical role in the functional evaluation of both peripheral and central nerve systems [20] and it may be more sensitive than M-wave for monitoring axonal neuropathies [18, 21]. In addition, peripheral sensory dysfunction is the most common clinical sign for drug neurotoxicity [22], and it can be reflected by the sensory nerve conduction velocity (SNCV), a parameter primarily reflecting the function of feeling nerve C fibres [23]. In our previous study [11], abnormal MNCV and CAPA were observed when mice were injected with colistin 15 mg/kg/d for 7 days. In the present study, SNCV and F-wave were first examined as potential neurotoxicity indicators for colistin-induced neurotoxicity in mice and provided important information to understanding colistin-induced neurotoxicity.
Materials and Methods Chemicals. Colistin (sulfate, 20,195 U/mg) and pentobarbital sodium were purchased from Sigma-Aldrich (St Louis, MO, USA). Animal studies. All animal studies were approved by the Institutional Animal Care and Use Committee at the China Agricultural University. Adult female mice (Kunming, 18 - 20 g) were
This article is protected by copyright. All rights reserved.
obtained from Vital River Animal Technology Co., Ltd. (Beijing, China). Mice had free access to food and water during the experiments. The animal room was maintained at ~22°C and 50% relative humidity with a 12-hr light-dark cycle, and a one-week acclimation period was applied. Colistin (5, 7.5 or 15 mg/kg/d, which was approximately equal to that by 0.5 to 1.5 mg/kg/d in human beings when considering animal scaling and the pharmacokinetics of polymyxins) was administered as a short intravenous infusion for 1, 3 and 7 days in each group (n = 10 per time point in each group) [4]. For the 5 and 7.5 mg/kg/d groups, the dose was given 24 hourly, while for the 15 mg/kg/d group animals were administered in two 12-hourly doses to avoid acute toxicity. The plasma exposure produced by these three dosage regimens was clinically relevant when considering animal scaling and polymyxin pharmacokinetics in patients [24-26]. The control mice were dosed with an equal volume of sterile 0.9% normal saline. Electrophysiological examination. At 12 hr after the last dose on days 1, 3 or 7, 10 mice were selected for electrophysiological examination of each treatment (and control) group by using a BL-420E biological function determining system (TME Technology Co, Ltd, Chengdu, China). All electrophysiological examinations were conducted under general anaesthesia with sodium pentobarbital (i.p. 40 mg/kg; Sigma, St. Louis, MO, USA). To ensure accurate and reproducible measurements of the electrophysiological parameters, the neurophysiology test was conducted within 30 min. for each mouse. The rectal temperature was maintained at ~36°C with a heating lamp and pad. Briefly, the stimulating electrode was placed at the sciatic notch with supramaximal stimuli (5 V) using a 0.2-ms rectangular pulse from the BL-420E biological function determination system. CAP was measured from the fourth interosseous muscle of the hind foot and popliteal, respectively. The ground electrode was placed at the base of the tail. F-wave latency was measured from the stimulus artifact to the second CAP. For quantification of SNCV [27], the sciatic nerve at the left ankle joint level was stimulated and the sensory nerve action potential (SNAP) was measured at the proximal site of the sciatic nerve. The SNCV was calculated by dividing the distance from stimulation site to the recording site by the initial latency of SNAP.
This article is protected by copyright. All rights reserved.
Statistical Analysis. All data were presented as mean ± standard deviations (SD). Statistical analysis was performed with one-way analysis of variance, followed by the least significant differences (LSDs) post-hoc test using SPSS 17 (Chicago, USA). A p value
Effects of Colistin on the Sensory Nerve Conduction Velocity and F-wave in Mice Chongshan Dai1, Shusheng Tang1, Jichang Li2, Jiping Wang3 and Xilong Xiao1
1
College of Veterinary Medicine, China Agricultural University, Beijing, P. R. China.
2
College of Veterinary Medicine, Northeast Agricultural University, Xiangfang District, Harbin,
P. R. China. 3
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences,
Monash University, Parkville, Victoria, Australia.
(Received 22 January 2014; Accepted 14 May 2014)
Author for correspondence: Xilong Xiao, College of Veterinary Medicine, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, P. R. China (fax: +86 10 6273 1032., e-mail: [email protected]).
Abstract: The aim of this study was to examine the changes of sensory nerve conduction velocity (SNCV) and F-wave for colistin-induced peripheral neurotoxicity using a mouse model. Mice were administered with colistin 5, 7.5 and 15 mg/kg/d via a 3-min. intravenous infusion. The sensory nerve conduction velocity (SNCV) and F-wave were measured using the bipolar recording electrodes. The SNCV and F-wave latency changed in a dose- and time-dependent manner. The
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcpt.12272 This article is protected by copyright. All rights reserved.
significant increase of F-wave latency and significant decrease of SNCV appeared on day 3 (p < 0.05 and 0.01, respectively) in the 15 mg/kg/d group, and they were markedly changed on day 7 in the 7.5 mg/kg/d (p < 0.01 and 0.05, respectively) and 15 mg/kg/d groups (both p < 0.01). In addition, F-wave latency also significantly increased on day 7 in the 5 mg/kg/d group (p < 0.05) without any clinical signs. These results indicate that SNCV and F-wave latency were more sensitive in colistin-induced neurotoxicity in mice, which highlights the early monitoring tool of polymyxins neurotoxicity in the clinic.
Colistin (also know as polymyxin E) is a cationic polypeptide antibiotic and has been re-introduced into clinical practice over the last decade due to multidrug-resistant (MDR) Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae [1-4]. With the currently recommended dosage regimens, the rate of colistin-induced neurotoxicity in patients is lower than its nephrotoxicity [5]; however, it has been increasingly reported recently. Patients administered with intravenous colistin methanesulfonate (CMS), the inactive prodrug of colistin [6], may experience confusion, dizziness, facial and peripheral paraesthesia, visual disturbances, muscle weakness, hallucinations, vertigo, seizures and ataxia [5, 7]. Recently, a case study reported that a patient with severe New Delhi metallo-β-lactamase-1 Escherichia coli infection, received intravenous CMS (37,500 IU/kg/8h) and developed convulsion, followed by acute respiratory muscle weakness and apnoea [8]. In the clinic, mild neurotoxicity (e.g. facial and peripheral paraesthesia) can be easily ignored, especially in elderly patients [9, 10]. There is a dearth of information on the mechanism of colistin-induced neurotoxicity. In previous animal studies [4, 10, 11], colistin led to marked behavioural changes in mice or rats, including notable muscular weakness and ataxia. Furthermore, mitochondrial dysfunction was observed in mouse central nervous tissue and chicken neurons in vitro [4, 9]. In addition, axonal degeneration and demyelization in sciatic nerves were also reported when mice were intravenously administered with 15 mg/kg/d colistin for 7 days [11]. As electrodiagnostic evaluation is important for patients with peripheral neuropathy [12], it is important to examine
This article is protected by copyright. All rights reserved.
colistin-induced electrophysiological changes in vivo [13, 14]. Electrophysiological evaluation is considered as a classic diagnosis method for clinical neurotoxicity induced by anti-cancer drugs (e.g. cisplatin and paclitaxel [15, 16]). No general agreement has been reached regarding the method for assessing polymyxins neurotoxicity, especially peripheral neurotoxicity, even though scattered literature suggested it in the clinic [13, 17]. In neuro-electrophysiological studies, a strong electrical stimulus on the motor nerve can lead to both orthodromic and antidromic impulse conduction; the former reaches the muscle fibre, produces M-wave (i.e. the first compound action potentials (CAP). Antidromic impulse conduction reaches the motor neuron cell bodies of spinal cord; subsequently, orthodromic wave travels back towards the muscle, evokes the second CAP, namely the F-wave [18]. M-wave parameters are very useful for evaluating the lesions of peripheral nerves, such as motor nerve conduction velocity (MNCV) and compound action potential amplitude (CAPA) [19]. F-wave plays a critical role in the functional evaluation of both peripheral and central nerve systems [20] and it may be more sensitive than M-wave for monitoring axonal neuropathies [18, 21]. In addition, peripheral sensory dysfunction is the most common clinical sign for drug neurotoxicity [22], and it can be reflected by the sensory nerve conduction velocity (SNCV), a parameter primarily reflecting the function of feeling nerve C fibres [23]. In our previous study [11], abnormal MNCV and CAPA were observed when mice were injected with colistin 15 mg/kg/d for 7 days. In the present study, SNCV and F-wave were first examined as potential neurotoxicity indicators for colistin-induced neurotoxicity in mice and provided important information to understanding colistin-induced neurotoxicity.
Materials and Methods Chemicals. Colistin (sulfate, 20,195 U/mg) and pentobarbital sodium were purchased from Sigma-Aldrich (St Louis, MO, USA). Animal studies. All animal studies were approved by the Institutional Animal Care and Use Committee at the China Agricultural University. Adult female mice (Kunming, 18 - 20 g) were
This article is protected by copyright. All rights reserved.
obtained from Vital River Animal Technology Co., Ltd. (Beijing, China). Mice had free access to food and water during the experiments. The animal room was maintained at ~22°C and 50% relative humidity with a 12-hr light-dark cycle, and a one-week acclimation period was applied. Colistin (5, 7.5 or 15 mg/kg/d, which was approximately equal to that by 0.5 to 1.5 mg/kg/d in human beings when considering animal scaling and the pharmacokinetics of polymyxins) was administered as a short intravenous infusion for 1, 3 and 7 days in each group (n = 10 per time point in each group) [4]. For the 5 and 7.5 mg/kg/d groups, the dose was given 24 hourly, while for the 15 mg/kg/d group animals were administered in two 12-hourly doses to avoid acute toxicity. The plasma exposure produced by these three dosage regimens was clinically relevant when considering animal scaling and polymyxin pharmacokinetics in patients [24-26]. The control mice were dosed with an equal volume of sterile 0.9% normal saline. Electrophysiological examination. At 12 hr after the last dose on days 1, 3 or 7, 10 mice were selected for electrophysiological examination of each treatment (and control) group by using a BL-420E biological function determining system (TME Technology Co, Ltd, Chengdu, China). All electrophysiological examinations were conducted under general anaesthesia with sodium pentobarbital (i.p. 40 mg/kg; Sigma, St. Louis, MO, USA). To ensure accurate and reproducible measurements of the electrophysiological parameters, the neurophysiology test was conducted within 30 min. for each mouse. The rectal temperature was maintained at ~36°C with a heating lamp and pad. Briefly, the stimulating electrode was placed at the sciatic notch with supramaximal stimuli (5 V) using a 0.2-ms rectangular pulse from the BL-420E biological function determination system. CAP was measured from the fourth interosseous muscle of the hind foot and popliteal, respectively. The ground electrode was placed at the base of the tail. F-wave latency was measured from the stimulus artifact to the second CAP. For quantification of SNCV [27], the sciatic nerve at the left ankle joint level was stimulated and the sensory nerve action potential (SNAP) was measured at the proximal site of the sciatic nerve. The SNCV was calculated by dividing the distance from stimulation site to the recording site by the initial latency of SNAP.
This article is protected by copyright. All rights reserved.
Statistical Analysis. All data were presented as mean ± standard deviations (SD). Statistical analysis was performed with one-way analysis of variance, followed by the least significant differences (LSDs) post-hoc test using SPSS 17 (Chicago, USA). A p value
