CJA
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Résumé de cet Article
Right arrow Full Text (PDF)
Right arrow Submit a scholarly reply
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Related articles in CJA
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Al-Jahdari, W. S.
Right arrow Articles by Goto, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Al-Jahdari, W. S.
Right arrow Articles by Goto, F.
Canadian Journal of Anesthesia 53:1078-1085 (2006)
© Canadian Anesthesiologists' Society, 2006
General Anesthesia

Propofol induces growth cone collapse and neurite retractions in chick explant culture

[Le propofol provoque un collapsus des cônes de croissance et des rétractions des neurites de poussin embryonnaire en culture]

Wael S. Al-Jahdari, MD*, Shigeru Saito, MD PhD*, Takashi Nakano, MD PhD{dagger} and Fumio Goto, MD PhD*

* From the Departments of Anesthesiology, and
{dagger} Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi-city, Gunma, Japan.

Address correspondence to: Dr. Shigeru Saito, Department of Anesthesiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi-city, Gunma, 371-8511, Japan. Phone: +81-27220-8454; Fax: +81-27220-8473; E-mail: shigerus{at}showa.gunma-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: Propofol neurotoxicity has been demonstrated in several cell culture systems. This study was undertaken to determine whether propofol has neurotoxic effects on peripheral, retinal, and autonomic neurons, and which neurons are particularly liable to injury by propofol.

Method: Dorsal root ganglia, retinal ganglion cell layers, and sympathetic ganglion chains were isolated from day eight chick embryos and cultured for 20 hr. Thereafter, propofol was added at various concentrations [5–300 µM (0.9–53 µg·mL–1)] to investigate its effects on these three types of neuronal tissue. Morphological changes were examined quantitatively by growth cone collapse assay. Propofol concentrations were measured using high performance liquid chromatography.

Results: Propofol induced growth cone collapse and neurite destruction. The three types of neurons tested exhibited significantly different dose–response relationships two hours after the application of propofol (P < 0.001) but not at 24 hr after application. The growth cone-collapsing effect was at least partially reversible in all three types of neurons after exposure to 100 µM propofol up to six hours, though reversibility was not observed after 24-hr exposure.

Conclusion: While the clinical safety profile of propofol has been well documented, at high concentrations propofol has potential neurotoxicity on growing neurons in vitro.


   Introduction
TOP
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
PROPOFOL (2,6-diisopropyl phenol) is an alkyl phenol derivative with wide clinical use as an anesthetic and sedative agent.1,2 Propofol has a phenolic hydroxyl group that donates electrons to free radicals and therefore, may complement endogenous antioxidants.3 This molecular structure might contribute to the neuroprotective effects of propofol which have been demonstrated during cerebral ischemia in humans4 and in an animal model.5 There is limited evidence from the pediatric population to suggest that propofol is safe when administered for neonates.6

In contrast to the safe neurological profile of propofol in the above settings, there have been several reports of neurological sequelae (convulsions) following prolonged sedation (three to five days) with propofol infused at rates between 6.0–18.1 mg·kg–1·hr–1 in children.7,8 Another potential concern is that metabolic acidosis may occur in association with renal, liver and heart failure 9–11 in both children and adults, when propofol infusion rates exceed 4 mg·kg–1·hr–1 and the duration of infusion is longer than 48 hr.

An in vitro study12 has shown that propofol causes irreversible damage to gamma-amino butyric acid (GABA)ergic neurons when given at a critical phase,13 where the aggregating brain cell culture in vitro undergoes a progressive structural and functional maturation. Spahr-Schopfer et al.14 showed that propofol has dose-dependent neurotoxic effects on dissociated cortical cell cultures. Zhu et al.15 demonstrated that propofol exacerbates neuronal injury mediated via N-methyl-D-aspartate types of glutamate receptors.

It is unclear if those studies which showed neurological sequelea in pediatric populations may relate to propofol when the drug is administered at relatively high concentrations for prolonged periods. Therefore, the present study was undertaken to investigate the effects of propofol on neurite extension from peripheral, retinal and autonomic neurons. Since the growth cone is a structure at the terminal of neurite that acts as driving force for guidance, and plays an important role in the growth of neurite, we examined the morphological changes of growth cones and neurites exposed to propofol. For quantitative assessment, we used a growth cone collapse assay that has been established to examine the effect of substances on growing neurons.16,17 To examine which neuronal subtype is most susceptible to propofol neurotoxicity, three different neuronal tissues [dorsal root ganglion (DRG), retinal ganglion cell layer (RET) and sympathetic ganglion chain (SYMP)] were isolated for explant cultures. Dorsal root ganglia are considered as peripheral sensory neurons, RET are considered as central neurons and SYMP as autonomic neurons. Avian embryos at embryonal day eight were used as tissue sources, as the sizes of growth cones are suitable for the collapse assay.18


   Methods
TOP
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the Institutional Animal Care Committee, chick neural tissues were isolated from day eight embryos. For preparation of peripheral neurons, DRG were dissected from lumbar paravertebral sites. For preparation of central neurons, temporal halves of retinas were prepared from bilateral eyes and cut into sections of approximately 0.5 mm2. Sympathetic ganglia were dissected from lumbar sympathetic chains. After trimming the cell clusters, the tissues were plated on laminin-coated cover slips and cultured in F-12 medium supplemented as described by Bottenstein et al.19 The medium contained 100 mg·mL–1 bovine pituitary extract, 2 mM glutamine, 100 U·mL–1 penicillin, 100 mg·mL–1 streptomycin, and 20 ng·mL–1 mouse 7S nerve growth factor. Cultures were maintained at 37°C, where oxygen was supplied through room air, and 5% CO2 was added.

Propofol was purchased from Sigma Chemical Co. (St. Louis, MO, USA). It was initially diluted in methanol, one of the most suitable solvents20 and then prepared in culture media. The final concentration of methanol after addition to culture media was less than 0.3%. We examined the effects of various concentrations of propofol. The propofol solution was prewarmed and gently added into the culture media after 20 hr of culture to achieve final concentrations of 5, 20, 50, 100, 200, 300, and 500 µM (0.9, 3.6, 9.0, 18.0, 36.0, 53.0, and 89 µg·mL–1, respectively). The volume of added propofol solution was 1/100 of the total volume of the culture medium.

Dose–response relationships for the cultured neurons were examined by a blinded observer to the treatment condition after two, four, six, 12 and 24 hr of exposure to propofol. Observation of living cells was completed within five minutes and confirmed on digitally stored microscopic images using CoolSNAP (Photometrics, Roper Scientific, Inc., Duluth, GA, USA). To examine the toxic effect of methanol, cell viability was examined by exposing the cells to the vehicle solution for the same time periods with propofol. The vehicle solution contained methanol diluted with free-propofol media for a final concentration < 0.3%. The cells cultured in the vehicle solution were compared with the cell cultured in methanol-free culture media.

In time-course studies, the tissues were kept in an incubator for 24 hr after the addition of propofol. In the experiment in which reversibility of neurons was examined after exposure to propofol, the tissues were kept in the incubator for two, six, and 24 hr after the addition of propofol, then, the media were gently replaced once with fresh, prewarmed medium that did not contain propofol. The tissues were directly viewed with a 40X phase objective using a phase-contrast microscope (IX70, Olympus Optical Co. Ltd., Tokyo, Japan) pre-exposure and after exposure to propofol without staining or fixation. Growth cones at the periphery of explants were scored for collapse assay if they were not in contact with or in close proximity to other growth cones or neurites. One hundred growth cones were viewed and scored per cover slip. Growth cones without filopodia and lamellipodia were counted as collapsed.16 The scoring method was as follows: an intact growth cone which had filopodia and extending lamellipodia was counted as zero, a growth cone having no filopodia and shrunken lamellipodia was counted as 0.5, and a growth cone without filopodia and lamellipodia was counted as one. The total growth cone collapse was estimated by the following equation:


Formula

Neurites were also morphologically examined, particularly for alongside bleb formation. The length of neurite was also measured. As a positive control, we examined cells exposed to 1 mM tetracaine, as we have previously shown that tetracaine has a significant neurotoxic effect.21 In culture media, propofol concentrations were monitored after propofol application every six hours using high performance liquid chromatography (HPLC), as reported previously.22 The 50% effective dose (ED50) values in the growth cone collapse assays were determined by fitting the data to the Boltzmann slope equation.

Cytotoxic assay
To examine the cytotoxic effect of propofol on neurons, we measured the lactate dehydrogenase (LDH) released from damaged cells to the media, using Wroblewski-La Due’s method,23 using a standard spectrophotometric assay kit as recommended by the manufacturer (Wako Pure Chemical Inc., Osaka, Japan). Propofol was used at 300 and 500 µM in this assay. Using this method, the amount of oxidized L-lactate was measured by the continuous increase in absorbance at 340 nm caused by the reduction of nicotinamide-adenine ninucleotide. Total LDH activity was analyzed by lysing the cells with a hypotonic buffer solution (10 mM Tris HCl, pH 7.6) and sonication.

Values are expressed as the mean ± SD of six independent measurements using independent cell cultures. The dose-response curves for growth cone collapse were analyzed by two-way ANOVA. The time-course of growth cone collapse and the washout effect were analyzed by one-way analysis of variance for repeated measurements. Mean values were compared by two-way ANOVA. Post hoc analysis was performed by the Scheffé test using Origin 7.0 software (Origin lab Co., Northampton, MA, USA). P values < 0.05 were considered significant.


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Morphologic observations
More than 90% of the neurites had growth cones with lamellipodia and filopodia at their leading edges before the application of propofol. Neither the sizes nor the shapes of the growth cones were identical amongst the three types of neurons. There was no difference between the cell cultured in methanol containing vehicle and those cultured in methanol-free media (data not shown). Following the application of high concentrations of propofol (≥100 µM) to the culture media, filopodia of growth cones retracted and lamellipodia were diminished in number and size (growth cone collapse; Figure 1Go). In some instances, especially at concentrations higher than 200 µM, blebs were formed at growth cones and alongside the neurites after 24 hr of exposure. After growth cone collapse, neurite shafts narrowed and some of the clusters of cell bodies detached from the bottom of the well, due to loss of adhesion to the culture plate. For each type of neuron, there were some neurons which were more resistant to propofol toxicity than others, and took more time to collapse and retract. These morphological changes occurred more gradually in DRG than in RET and SYMP, but were similar at the end of observation for the three types of neurons. When propofol concentration was > 50 µM, compared to vehicle, neurite lengths of DRG, RET, and SYMP after 24 hr exposure were decreased by 40 ± 17, 34 ± 10, and 26 ± 3%, respectively after 24 hr exposure. In contrast, they were not significantly different when propofol concentration was ≤50 µM. The morphological effect of propofol was comparable to that of 1 mM tetracaine.


Figure 1
View larger version (122K):
[in this window]
[in a new window]
  		FIGURE 1 Typical growth cone collapse and neurite retraction induced by 100 µM propofol (A-D) Dorsal root ganglion (DRG), (E-H) retinal ganglion cell layers (RET) and (I-L) sympathetic ganglion chains (SYMP). (A-B, E-F and I-J) Neurons cultured for 20 hr, immediately before exposure to propofol. (C-D, G-H and K-L) Collapsed growth cones and shrinking neurites of the three neuron types after exposure to propofol for two hours. Size bars in (A, E and I) also (C,G and K) = 10 µm; bars in (B, F and J) also (D, H and L) = 60 µm.

 
Dose-response study of propofol
At two hours after propofol application, there were significant differences in dose–response relationships for DRG, RET and SYMP (43 ± 3, 55 ± 5 and 62 ± 4 collapsed growth cone, respectively), (P < 0.001), but none at 24 hr after application (88 ± 5, 92 ± 5 and 89 ± 7 collapsed growth cone, respectively), (Figure 2Go) with 100 µM propofol. Compared to vehicle-exposed cells, significantly (P < 0.01) higher percentages of growth cone collapse were observed in DRG and RET when exposed to propofol at concentrations higher than 100 µM, at two hours after application. With 50 µM propofol, SYMP (27 ± 2) exhibited higher (P < 0.01) percentage of growth cone collapse compared to DRG and RET (13 ± 3 and 15 ± 2 collapsed growth cone, respectively). At 24 hr after propofol application, the minimum concentration of propofol required to induce significantly higher percentage growth cone collapse (compared to vehicle-exposed cells) was 50 µM for DRG, RET, and SYMP (P < 0.01). The ED50 values (mean ± SD) were 99.4 ± 4.2 µM for DRG, 81.6 ± 11.4 µM for RET, and 63.5 ± 4.6 µM for SYMP, while those at 24 hr were 43.5 ± 11.4 µM for DRG, 55.3 ± 3.4 µM for RET, and 57.8 ± 1.2 µM for SYMP, respectively.


Figure 2
View larger version (24K):
[in this window]
[in a new window]
  		FIGURE 2 Dose-response of propofol induced growth cone collapse The percentage of growth cone collapse was examined at two hours after propofol application and at 24 hr after the application. Two-way analysis of variance indicated that three dose-response cur ves were significantly different after two-hour exposure (P < 0.05) but not after 24 hr. *Significantly different from vehicle (P < 0.01). #Significantly different from vehicle (P < 0.05). §Significantly different among neuronal tissues (P < 0.05). Values are mean ± SD.

 
Time course of growth cone collapse
In DRG, RET, and SYMP cultures (Figure 3Go), percentage growth cone collapse of cells exposed to 100 µM propofol was higher than the corresponding value for vehicle-exposed cells at two hours after application (P ≤0.01). Significantly higher percentage collapse (P ≤0.05) was obtained with 50 µM propofol at 12 hr after application in RET, and at four hours after application in SYMP and DRG, compared to vehicle-exposed cells. At 24 hr, percentages of collapse were 30% in DRG, 36% in RET and 17% in SYMP, respectively. At lower concentrations, propofol induced growth cone collapse relatively slowly in all types of neurons examined. When the propofol concentration was 20 µM, the collapse was 19% in DRG, 36% in RET and 15% in SYMP, respectively. At the minimum examined concentration (5 µM), the propofol-induced-collapse in DRG, RET and SYMP was 12, 17 and 3%, respectively, after 24 hr of exposure.


Figure 3
View larger version (33K):
[in this window]
[in a new window]
  		FIGURE 3 Time course of growth cone collapse in DRG, RET, and SYMP One-way analysis of variance for repeated measurements indicated that the time course of Dorsal root ganglion (DRG), retinal ganglion cell layers (RET) and sympathetic ganglion chains (SYMP) growth cone collapse after exposure to propofol at less than 100 µM were significantly different from the time-course when propofol concentration was higher than 100 µM (P < 0.01). *#Significantly different from the value of vehicle exposed neurons at each time point (*P < 0.01, #P ≤0.05). Horizontal scale is not linear to the inter val time. Values are mean ± SD.

 
Reversibility of growth cone collapse
For all three types of neurons, percentage growth cone collapse after two, six, and 24 hr of exposure to 100 µM was significantly different from the values in vehicle exposed cells (P ≤0.01). However, when 100 µM propofol had been washed out from the culture media after two and six hours of exposure, percentage growth cone collapse gradually returned to the corresponding value for vehicle-exposed neurons in the case of DRG and SYMP (Figure 4Go). In the case of RET, after washout of propofol from the culture media, percentage growth cone collapse did not return to the value for vehicle-exposed neurons, regardless of the duration of exposure (Figure 4Go). In all types of neurons examined in this study, washout of propofol after exposure to 100 µM of propofol for 24 hr did not reverse neuronal damage. However, washout of propofol after exposure to 50 µM of propofol for 24 hr significantly reduced growth cone collapse percentage (Figure 5Go).


Figure 4
View larger version (25K):
[in this window]
[in a new window]
  		FIGURE 4 Growth cone collapse after washing out 100 µM propofol in dorsal root ganglion (DRG), retinal ganglion cell layers (RET), and sympathetic ganglion chains (SYMP) One-way analysis of variance for repeated measurements indicated that the growth cone collapse trends after two, six and 24 hr of exposure to propofol were significantly different in all neuronal types (P < 0.01). *Significantly different from the value of the corresponding vehicle exposed neurons (P < 0.01). §Significantly different from the growth cone collapse percentage immediately after exposure to propofol (pre-wash), (P < 0.01). The "pre-exposure" in the horizontal scale indicates the time point immediately before exposure to propofol; the "pre wash" indicates the time-point immediately before the washing out of propofol. Horizontal scale is not linear to the inter val time. Values are mean ± SD.

 

Figure 5
View larger version (23K):
[in this window]
[in a new window]
  		FIGURE 5 Growth cone collapse after washing out 50 µM propofol in dorsal root ganglion (DRG), retinal ganglion cell layers (RET), and sympathetic ganglion chains (SYMP) One-way analysis of variance for repeated measurements indicated that the growth cone collapse trends after 24 hr of exposure to propofol were not significantly different in all neuronal types (P < 0.05). *Significantly different from the value of the corresponding vehicle exposed neurons (P < 0.01). §Significantly different from the growth cone collapse percentage immediately after exposure to propofol (pre-wash) (P < 0.01). The "pre-exposure" in the horizontal scale indicates the time point immediately before exposure to propofol; the "pre wash" indicates the time-point immediately before the washing out of propofol. Horizontal scale is not linear to the inter val time. Values are mean ± SD.

 
Propofol concentrations in culture media
During the study period (24 hr), we measured time-dependent change of propofol concentration in culture media using HPLC after adding 20 µM of propofol. The results exhibited no significant changes (20.0 ± 0.2, 19.5 ± 0.5 and 18.4 ± 1.7 µM at zero, two and 24 hr, respectively) indicating that neither dilution nor metabolism of propofol had occurred.

Propofol cytotoxicity
Regardless of neuronal cell types, LDH leakage did not significantly increase after 24 hr exposure to 300 or 500 µM propofol (Figure 6Go).


Figure 6
View larger version (19K):
[in this window]
[in a new window]
  		FIGURE 6 Cytotoxic effect of propofol was measured by lactate dehydrogenase (LDH) leakage Neurons were exposed to 300 and 500 µM propofol. The LDH was measured at; pre-exposure, two hours and 24 hr after exposure to propofol. The corresponding value of vehicle exposed neurons was withdrawn from the value of propofol exposed cells. No significant increase was obser ved after the application of propofol in the three types of neurons. Values are mean ± SD.

 

   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In the present study, propofol exhibited dose-dependent neurotoxic effects on three types of neurons. Propofol at a concentration higher than 50 µM caused striking growth cone collapse and neurite destruction in growing neurons. When the concentration was 5 or 20 µM, propofol induced mild growth cone collapse, after 24 hr of exposure. Neurite lengths at these two concentrations were comparable to vehicle treated cells. Although our findings are not comparable to those of Vutskits et al.24 due to the difference in model and endpoint, both studies showed that propofol potentially has a neurotoxic effect. The dose-response curves at two hours of exposure could not be adequately fitted to the Boltzmann slope equation. The obtained ED50 values at two hours were different from those values shown in Figure 2Go. Statistical analysis of the curves in Figure 2Go for two hours of exposure indicated that these neurons differ in sensitivity to propofol. However, there was no significant difference among the three types of neurons in ED50 at 24 hr after application of propofol. Thus, differences in sensitivity were much less evident among types of neurons when exposure to propofol was extended.

The toxicity of propofol was reversible in DRG, RET, and SYMP when 50 µM propofol was applied for 24 hr. Reversible collapse was induced by 100 µM propofol with application for six hours in all three types of neurons, but when exposure time was extended to 24 hr, none of the three types of neurons recovered even after washout of propofol. These findings suggest that the toxicity of propofol depends on both concentration and duration of exposure. Several clinical reports7–10 also stated that exposure time and total dose directly correlated with toxicity of propofol. Although concentrations at 5 and 20 µM (0.9 and 3.6 µg·mL–1, respectively) used in this study were comparable to the serum propofol concentrations for some applciations,25 these concentrations were higher than the unbound concentration of propofol in serum or cerebrospinal fluid.26

It has been reported that propofol induces changes in the cytoskeletal organization of actin in cultured rat neurons and human glial cells.27 Jensen et al. 27 reported morphological damage to human glial cells exposed to propofol (1.7–280 µM). In their study, cells became round (with bleb formation) and then collapsed. In our study, when cells were exposed to high concentrations of propofol for extended durations some exhibited bleb formation, suggesting damage to cell membranes. This change might have been due to the increase in intracellular calcium levels observed shortly after the addition of propofol. Although we noticed toxic effects on growth cones and growing neurites in this study, the effects on cell bodies were considered to be minor in the neurons we examined, since LDH leakage (a sensitive method for detection of cytotoxicity) was not apparent when propofol concentration was ≤500 µM. Chen et al.28 showed that exposure of macrophages to high a concentration of propofol (300 µM) increases leakage of LDH and inhibits macrophage function. Although higher concentrations of propofol may destroy any type of cultured cell, it is possible that cells differ in vulnerability to propofol depending on cell type. Our findings suggest that such vulnerability also depends on the specific part of cells examined. In particular, growth cones and neurites were more vulnerable to propofol than neuronal cell bodies.

Propofol does not injure fully mature neurons. Several studies have revealed protective effects of propofol on neurons impaired by ischemia4,5,29 or drug toxicity.30 On the other hand, several studies have revealed neurotoxic effects of propofol on immature neurons.11,13,14,24 Here, we demonstrated toxic effects of propofol on extending neurites and growth cones. It is possible that the effects of propofol on neurons depend on their developmental stage and maturity. In addition, differences in protocols and the particular types of neurons examined might be responsible for discrepancies in findings concerning propofol toxicity.

A recent study by Vutskits et al.24 found that exposure of immature developing GABAergic neurons from rat to clinically relevant concentrations of propofol can induce long-term changes in dendritic arbor development. Previous studies31,32 reported that general destruction of growth cones in growing or regenerating nervous tissue by externally applied substances could disturb normal establishment of cytoarchitecture in the developing nervous system. Our findings regarding growth cone collapse might be related to disorganization of neuronal networks, which can result in long-term brain dysfunction.

There were certain limitations to this study, where the neurotoxicity of propofol was assessed by morphological observation alone (growth cone collapse and neurite length). Precise measurement of neurite area, neurite number, and neurite density could not be assessed in this study. We also caution that in vitro laboratory data cannot be directly applied to the clinical setting. It remains unclear if the effects of prolonged anesthesia or sedation with propofol at high concentrations could have potential neurotoxic effects in patients with regenerating or growing neurons (e.g., young pediatric patients).

We conclude that in high concentrations with sufficient duration of exposure, propofol may be associated with potential neurotoxicity on growing neurons in vitro. There is an accumulating body of in vitro evidence which provides a rational basis for further in vivo investigations of propofol neurotoxicity.


   Footnotes
 
Financial support: This work was supported by research grants from the Japanese government to Saito S. and Goto F. (Ministry of Science, Education and Sports).

This work was supported by research grants from the Japanese government to Saito S. and Goto F. (Ministry of Science, Education and Sports).

Competing interests: None declared.

Revision accepted July 13, 2006. Accepted for publication May 18, 2006.

This article is accompanied by an Editorial. Please see: Can J Anesth 2006; 53: 1069–73.


   References
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Sebel PS, Lowdon JD. Propofol: a new intravenous anesthetic. Anesthesiology 1989; 71: 260–77.[Medline]

2 Bryson HM, Fulton BR, Faulds D. Propofol. An update of its use in anaesthesia and conscious sedation. Drug 1995; 50: 513–59.[Medline]

3 Eriksson O, Pollesello P, Saris NE. Inhibition of lipid peroxidation in isolated rat liver mitochondria by the general anaesthetic propofol. Biochem Pharmacol 1992; 44: 391–3.[Medline]

4 Lavine SD, Masri LS, Levy ML, Giannotta SL. Temporary occlusion of the middle cerebral artery in intracranial aneurysm surgery: time limitation and advantage of brain protection. J Neurosurg 1997; 87: 817–24.[Medline]

5 Young Y, Menon DK, Tisavipat N, Matta BF, Jones JG. Propofol neuroprotection in a rat model of ischaemia reperfusion injury. Eur J Anaesthesiol 1997; 14: 320–6.[Medline]

6 Bacon RC, Razis PA. The effect of propofol sedation in pregnancy on neonatal condition. Anaesthesia 1994; 49: 1058–60.[Medline]

7 Lanigan C, Sury M, Bingham R, Howard R, Mackersie A. Neurological sequelae in children after prolonged propofol infusion. Anaesthesia 1992; 47: 810–1.[Medline]

8 Trotter C, Serpell MG. Neurological sequelae in children after prolonged propofol infusion. Anaesthesia 1992; 47: 340–2.[Medline]

9 Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003; 29: 1417–25.[Medline]

10 Casserly B, O’Mahony E, Timm EG, Haqqie S, Eisele G, Urizar R. Propofol infusion syndrome: an unusual cause of renal failure. Am J Kidney Dis 2004; 44: e98–101.[Medline]

11 Parke TJ, Stevens JE, Rice AS, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. BMJ 1992; 305: 613–6.[Medline]

12 Honegger P, Matthieu JM. Selective toxicity of the general anesthetic propofol for GABAergic neurons in rat brain cell cultures. J Neurosci Res 1996; 45: 631–6.[Medline]

13 Honegger P, Lenoir D, Favord P. Growth and differentiation of aggregating fetal brain cells in a serum-free defined medium. Nature 1979; 282: 305–8.[Medline]

14 Spahr-Schopfer I, Vutskits L, Toni N, Buchs PA, Parisi L, Muller D. Differential neurotoxic effects of propofol on dissociated cortical cells and organotypic hippocampal cultures. Anesthesiology 2000; 92: 1408–17.[Medline]

15 Zhu H, Cottrell JE, Kass IS. The effect of thiopental and propofol on NMDA- and AMPA-mediated glutamate excitotoxicity. Anesthesiology 1997; 87: 944–51.[Medline]

16 Raper JA, Kapfhammer JP. The enrichment of a neuronal growth cone collapsing activity from embryonic chick brain. Neuron 1990; 4: 21–9.[Medline]

17 Saito S. Cholinesterase inhibitors induce growth cone collapse and inhibit neurite extension in primary cultured chick neurons. Neurotoxicol Teratol 1998; 20: 411–9.[Medline]

18 Patterson PH. Process outgrowth and the specificity of connections. In: Hall ZW (Ed.). An Introduction to Molecular Neurobiology. Sunderland: Sinauer Associates; 1992: 388–427.

19 Bottenstein JE, Skaper SD, Varon SS, Sato GH. Selective survival of neurons from chick embryo sensory ganglionic dissociates utilizing serum-free supplemented medium. Exp Cell Res 1980; 125: 183–90.[Medline]

20 Busby WF Jr, Ackermann JM, Crespi CL. Effect of methanol, ethanol, dimethyl sulfoxide, and acetonitrile on in vitro activities of cDNA-expressed human cytochromes P-450. Drug Metab Dispos 1999; 27: 246–9.[Abstract/Free Full Text]

21 Saito S, Radwan I, Obata H, Takahashi K, Goto F. Direct neurotoxicity of tetracaine on growth cones and neurites of growing neurons in vitro. Anesthesiology 2001; 95: 726–33.[Medline]

22 Hiraoka H, Yamamoto K, Okano N, Morita T, Goto F, Horiuchi R. Changes in drug plasma concentrations of an extensively bound and highly extracted drug, propofol, in response to altered plasma binding. Clin Pharmacol Ther 2004; 75: 324–30.[Medline]

23 Levine I, Flief A, Sansur M, Wroblewski F. Clinical implications of lactic dehydrogenase activity in sputum. JAMA 1969; 207: 2436–7.[Medline]

24 Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Clinically relevant concentrations of propofol but not midazolam alter in vitro dendritic development of isolated gamma-aminobutyric acid-positive interneurons. Anesthesiology 2005; 102: 970–6.[Medline]

25 Feiner JR, Bickler PE, Estrada S, Donohoe PH, Fahlman CS, Schuyler JA. Mild hypothermia, but not propofol, is neuroprotective in organotypic hippocampal cultures. Anesth Analg 2005; 100: 215–25.[Abstract/Free Full Text]

26 Dawidowicz AL, Fijalkowska A, Nestorowicz A, Kalitynski R, Trojanowski T. Cerebrospinal fluid and blood propofol concentration during total intravenous anaesthesia for neurosurgery. Br J Anaesth 2003; 90: 84–6.[Abstract/Free Full Text]

27 Jensen AG, Lindroth M, Sjolander A, Eintrei C. Propofol induces changes in the cytosolic free calcium concentration and the cytoskeletal organization of cultured human glial cells and primary embryonic rat brain cells. Anesthesiology 1994; 81: 1220–9.[Medline]

28 Chen RM, Wu CH, Chang HC, et al. Propofol suppresses macrophage functions and modulates mitochondrial membrane potential and cellular adenosine triphosphate synthesis. Anesthesiology 2003; 98: 1178–85.[Medline]

29 Engelhard K, Werner C, Eberspacher E, et al. Influence of propofol on neuronal damage and apoptotic factors after incomplete cerebral ischemia and reperfusion in rats: a long-term observation. Anesthesiology 2004; 101: 912–7.[Medline]

30 Lin CR, Cheng JT, Lin FC, et al. Effect of thiopental, propofol, and etomidate on vincristine toxicity in PC12 cells. Cell Biol Toxicol 2002; 18: 63–70.[Medline]

31 Luo Y, Raible D, Raper JA. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 1993; 75: 217–27.[Medline]

32 Johnson AR. Contact inhibition in the failure of mammalian CNS axonal regeneration. Bioessays 1993; 15: 807–13.[Medline]


Related articles in CJA:

Is propofol neurotoxic to the developing brain?/Le propofol est-il neurotoxique pour le cerveau en développement?
Hossam El Beheiry and Brian Kavanagh
CJA 2006 53: 1069-1073. [Full Text]  



This article has been cited by other articles:


Home page
 Br J AnaesthHome page
D. Turina, V. M. Loitto, K. Bjornstrom, T. Sundqvist, and C. Eintrei
Propofol causes neurite retraction in neurones
Br. J. Anaesth., June 27, 2008; (2008) aen185v1.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
A. W. Loepke and S. G. Soriano
An Assessment of the Effects of General Anesthetics on Developing Brain Structure and Neurocognitive Function
Anesth. Analg., June 1, 2008; 106(6): 1681 - 1707.
[Abstract] [Full Text] [PDF]

Home page
 Canadian J. AnesthesiaHome page
H. E. Beheiry and B. Kavanagh
Is propofol neurotoxic to the developing brain?/Le propofol est-il neurotoxique pour le cerveau en developpement?
Can J Anesth, November 1, 2006; 53(11): 1069 - 1073.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Résumé de cet Article
Right arrow Full Text (PDF)
Right arrow Submit a scholarly reply
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Related articles in CJA
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Al-Jahdari, W. S.
Right arrow Articles by Goto, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Al-Jahdari, W. S.
Right arrow Articles by Goto, F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS