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Anesth Analg 2005;101:1163-1169
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ane.0000167268.61051.41

NEUROSURGICAL ANESTHESIA

Section Editor:
David S. Warner

Pre- or Postinsult Administration of Lidocaine or Thiopental Attenuates Cell Death in Rat Hippocampal Slice Cultures Caused by Oxygen-Glucose Deprivation

Hong Cao, MD*{ddagger}§, Ira S. Kass, PhD*{dagger}{ddagger}, James E. Cottrell, MD*, and Peter J. Bergold, PhD{dagger}

Departments of *Anesthesiology and {dagger}Physiology & Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York; {ddagger}Department of Anesthesiology, Xuzhou Medical College, Jiangsu Province; and §Anesthesiology Department, Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang Province, People’s Republic of China

Address correspondence and reprint requests to Ira S. Kass, PhD, Department of Anesthesiology, Box 6, State University of New York Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. Address e-mail to ira.kass{at}downstate.edu.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Lidocaine and thiopental improve recovery when administrated during hypoxia and ischemia; however, the effect of pre- or postinsult treatment alone is unknown. We applied either lidocaine or thiopental to hippocampal slice cultures from 20-day-old rats either before or after 10 min of oxygen-glucose deprivation (OGD). Propidium iodide (PI) fluorescence was used as an indicator of neuronal death for 7 days after OGD. OGD-induced neuronal death, in both the Cornus Ammonis 1 (CA1) and the dentate gyrus regions, peaked the first day after ischemia. Preinsult administration of either lidocaine (10, 100 µM) or thiopental (250, 600 µM) significantly reduced the damage measured on the first and second days after OGD; these drugs also significantly decreased the summed daily post-OGD PI fluorescence in both regions. Postinsult administration of lidocaine (10, 100 µM) or thiopental (250, 600 µM) significantly decreased the PI fluorescence on the first day after OGD; postinsult administration of these drugs also attenuated the summed daily post-OGD PI. These data indicate that the administration of lidocaine or thiopental either before or directly after OGD reduced neuronal damage in this in vitro model of cerebral ischemia. Postischemic administration is frequently the first opportunity for treatment.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Cerebral ischemia is a major cause of death and disability; much effort has been expended to discover drugs that reduce neuronal damage caused by this insult. Treatment with either lidocaine or thiopental improves recovery if it is administered during an ischemic or hypoxic insult (1–6). It is difficult to administer protective drugs during ischemia. Frequently, treatment can only be initiated either before or after the ischemic insult. Thus, we tested the effect of lidocaine or thiopental when present either only shortly before or shortly after oxygen-glucose deprivation (OGD), an in vitro model of ischemia.

Large concentrations of lidocaine act as a local anesthetic that blocks nerve conduction; smaller concentrations (10 µM) are used as an antiarrhythmic drug and this concentration does not alter neuronal excitability (1,3,7). Both lidocaine concentrations improved recovery from hypoxia in acute rat hippocampal slices (1,3). Thiopental is a barbiturate anesthetic that, when given at large concentrations, protects against hypoxic and ischemic neuronal damage. Thiopental is often used in the intensive care unit for serious neurological injury cases. However, large doses of barbiturates that protect neuronal tissue induce coma and thereby preclude the neurological examination of patients.

Acute rat hippocampal slices have yielded important information concerning the mechanisms by which anesthetics alter hypoxic and ischemic neuronal injury. However, the short survival time of acute slices in vitro prevents the study of delayed injury. Slice cultures maintain normal physiology and histology for weeks in vitro; this allows the examination of neuronal loss for many days after OGD (8–11). Frequently, the earliest a drug can be used clinically is after the onset of a stroke. We therefore examined the effect of postinsult administration of lidocaine and thiopental on delayed neuronal damage after OGD.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The experimental protocol was approved by the Institutional Animal Care and Use Committee of SUNY Downstate. Sprague-Dawley rats aged 20 days were anesthetized with halothane, decapitated, and their brains removed. The slice culture techniques were modified from Stoppini et al. (12); see Xiang et al. (9) for details. The hemispheres were immersed in prechilled (4°C) modified Gey’s balanced salt solution (mGBSS) for 20–30 min and bubbled vigorously with a 95% O2/5% CO2 gas mixture. mGBSS is (in mM): CaCl2, 1.5; KCl, 4.9; KH2PO4, 0.2; MgCl2, 11.0; MgSO4, 0.3; NaCl, 138.0; NaHPO4, 0.8; NaHEPES, 25; glucose, 28.0; and pH, 7.2. An individual hippocampus was isolated and 400-µm-thick transverse slices were prepared using a McIllwain tissue chopper (Brinkman Instruments, Westbury, NY). The slices were placed in ice-cold mGBSS and observed using a dissection microscope. Only slices with uninterrupted bright transparent neuronal layers were plated onto Millicell CM filters. The cultures were maintained in elevated potassium (5.1 mM K) slice culture medium at 32°C in a 5% CO2 + air atmosphere for 2 days (25% horse serum, 50% Basal Essential Media-Eagles, 25% Earle’s balanced salt solution [EBSS], 25.0 mM NaHEPES, 1.0 mM glutamine, 28.0 mM glucose, pH 7.2). The slice cultures were then switched to physiological potassium slice culture medium (25% horse serum, 50% Basal Essential Media-Eagles, and EBSS modified so that the potassium concentration was 2.66 mM). After 7 days in this medium, the horse serum was reduced to 5% and the media was exchanged every 3 days.

PI is a cell-impermeable, fluorescent dye that provides a sensitive and quantitative assay of cell death (10). When a cell dies, PI enters, binds to the DNA, and the cell becomes fluorescent. Before imaging, slice cultures were incubated in PI (5 µg/mL) containing slice culture medium for 30 min at 37°C. PI epifluorescence images were obtained with a CCD camera on a Zeiss Axiovert 100 microscope using rhodamine optics. Fluorescence images were normalized using InSpeck fluorescent beads and analyzed using NIH image version 1.58 software. The video readouts of the mean pixel value in manually delineated areas were saved and designated as PI epifluorescence units, which indicates the amount of cell death. Slice cultures retain hippocampal structure; the Cornus Ammonis 1 (CA1) pyramidal and dentate granule (DG) cell layers were readily apparent (Fig. 1A). After fluorescent imaging, the cultures were washed with slice culture medium and returned to the incubator. The PI assay has been used successfully to quantify cell death in slice cultures (10,13,14). Neurons that stain positive for PI on one day do not retain dye and stain positive on subsequent days when the PI is washed out of the slice after the assay (10). As with the present study, neuronal loss was assayed in slice cultures for 7 days. In the study by Xiang et al. (10), some cultures received a daily PI assay, other cultures received the PI assay only on days 1, 3, and 7. The amount of PI staining on days 1, 3, and 7 was the same with both staining procedures suggesting that the changes in the daily PI staining were caused by the staining of newly dying cells rather than the long-term retention of PI in dead cells.



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  		Figure 1. Preexposure to lidocaine or thiopental before oxygen-glucose deprivation (OGD) reduces propidium iodide (PI) fluorescence in hippocampal slice cultures. Ten minutes before the onset of OGD, slice cultures were either untreated or treated with lidocaine (10 µM) or thiopental (250 µM). Slice cultures were submerged in Earle’s balanced salt solution containing no glucose and bubbled with 95% N2 5% CO2 for 10 min OGD. PI fluorescence was assayed in slice cultures 1 h before OGD (day 0) and at daily intervals for 7 days after OGD (days 1–7). The mock-OGD slice cultures were not subjected to OGD. A, For each treatment, multiple video micrographs of PI fluorescence are shown for a representative slice culture. B, Summary of the reduction of PI fluorescence in the Cornus Ammonis 1 (CA1) region by pre-OGD exposure to either lidocaine or thiopental. Both 10 µM lidocaine (10 µM L) and 250 µM thiopental (250 µM T) significantly reduced the PI index compared with the untreated OGD group (OGD) on the first and second day after OGD (analysis of variance, P < 0.0001; Newman-Keuls test, *P < 0.05). Separate statistical tests were done for each day.

 

After 14 days in vitro, spontaneous neuronal loss was assayed using the PI assay. Slice cultures were then transferred to slice culture medium containing 5.6 mM glucose and incubated at 37°C, in an air + 5% CO2 atmosphere for 3 days before OGD or mock-OGD. Cultures were subjected to OGD by submerging them for 10 min in a 100-mL beaker containing 50 mL of EBSS containing no glucose and bubbled with 95% N2, 5% CO2 (untreated OGD group). The mock-OGD group was submerged for 10 min in EBSS containing 5.6 mM glucose and bubbled with 20% O2, 75% N2, and 5% CO2. All treatments were performed at 37°C and all groups were returned to slice culture medium at 37°C after the OGD. For the next 7 days, the PI assay was performed each day to measure neuronal death.

For the preinsult administration of lidocaine, either 10 µM or 100 µM lidocaine was added in the medium 10 min before OGD (Pre10L or Pre100L). The slice was then transferred to 50 mL of EBSS without drug and subjected to OGD as described above. Although no lidocaine was present in the EBSS during OGD, it is likely that lidocaine remained in the neurons during OGD and it is possible that this lidocaine acted during OGD to protect. For the postinsult administration of lidocaine, 10 or 100 µM lidocaine was added to slice culture media for 10 min immediately after OGD (Post10L or Post100L) and then washed out. For the pre- and postinsult administration of thiopental, 250 and 600 µM thiopental was used instead of lidocaine; all other procedures were the same (Pre250T, Pre600T, Post250T, or Post600T). The PI assay was performed on all groups daily for 7 days after the OGD.

The data were presented as mean ± sem and analyzed using a one-way analysis of variance. The number of slices in each group (n) is given in the Results section. The Newman-Keuls multiple comparison test was used to detect differences between the PI indexes each day in the same slice region between the groups (10) We calculated the sum of the daily PI values for 7 days after OGD for each group and compared this summed value between groups in the same slice region using the Newman-Keuls test. A P value of <0.05 was considered statistically significant for all tests.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All comparisons between groups in this section are made from the same slice region. There are no comparisons between the DG and the CA1 region. Before OGD, the PI index was minimal in all groups. The CA1 and DG regions of the untreated group before OGD had a low PI index (CA1, 8 ± 2; DG, 7 ± 2; n = 22), that did not differ significantly from the mock-OGD group (CA1, 9 ± 1; DG, 10 ± 1; n = 20). The PI index peaked the first day after OGD in both the CA1 (57 ± 7) and DG (37 ± 4) regions; these values were significantly more than those of the mock-OGD group on the first day (CA1, 13 ± 2; DG, 11 ± 2) (Fig. 1). The sum of the PI measurements ({Sigma}PI) in the OGD group was 292 ± 27 for the CA1 region and 206 ± 13 for the dentate region, which was significantly increased compared with the mock-OGD group (CA1, 98 ± 13; DG, 85 ± 8) (Fig. 2). These data indicate that OGD induces delayed neuronal loss in both the CA1 and DG regions.



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  		Figure 2. Preexposure to lidocaine or thiopental before oxygen-glucose deprivation (OGD) reduces the 7-day sum of the post-OGD propidium iodide (PI) fluorescence in hippocampal slice cultures. The experiments are as described in Figure 1, except that the daily post-OGD PI fluorescence values were added together for 7 days after OGD. Either lidocaine 10 µM (L 10) or 100 µM (L 100) or thiopental 250 µM (T250) or 600 µM (T600) was present 10 min before, but not during 10 min of OGD. The mock-OGD group (Mock) was not subjected to OGD. The bars represent the mean ± the standard error of the mean (n >> 12 for each group, except for the T600 group in which n = 9). The Cornus Ammonis 1 (CA1) region (A, open bars) and the dentate region (B, filled bars) were analyzed separately with an analysis of variance (P < 0.0001) followed by the Newman-Keuls test; all groups were significantly different from the untreated OGD group (OGD) (*P < 0.01).

 

Preinsult administration of 10 or 100 µM lidocaine or 250 or 600 µM thiopental significantly reduced the PI indexes in CA1 and DG regions for the first 2 days after OGD (Fig. 1). The first day after OGD, the PI indexes were lower in the Pre10L (CA1, 27 ± 6; DG, 17 ± 5, n = 17) and Pre100L (CA1, 14 ± 4; DG, 8 ± 2; n = 15) groups than in the untreated OGD group (CA1, 57 ± 7; DG, 37 ± 4; n = 22). The {Sigma}PI for 7 days after OGD was significantly decreased in both the Pre10L group (CA1, 211 ± 19; DG, 119 ± 10) and the Pre100L group (CA1, 149 ± 18; DG, 90 ± 10) as compared with the untreated OGD group (CA1, 292 ± 27; DG, 206 ± 13) (Fig. 2). When thiopental (250 and 600 µM) was applied before OGD, the first day post-OGD PI indexes in the Pre250T group (CA1, 10 ± 2; DG, 8 ± 2; n = 12) and the Pre600T group (CA1, 25 ± 9; DG, 16 ± 7; n = 9) were significantly less for each region than those in the untreated OGD group (57 ± 7, 37 ± 4; n = 22) (Fig. 1). The {Sigma}PI was significantly decreased in both the Pre250T group (CA1, 120 ± 22; DG, 92 ± 11) and the Pre600T group (CA1, 158 ± 23; DG, 144 ± 15) as compared with the untreated OGD group (CA1, 292 ± 27; DG, 206 ± 13) (Fig. 2). Preinsult administration of either lidocaine or thiopental attenuates neuronal loss after OGD.

When either lidocaine or thiopental was given for 10 min, starting directly after the end of OGD, the PI indexes in the CA1 and DG regions were significantly attenuated the first day after OGD (Fig. 3). When lidocaine was administered after OGD, the first day PI indexes in both the Post10L (CA1 18 ± 3; DG, 17 ± 2; n = 12) and the Post100L (CA1, 15 ± 3; DG, 9 ± 2; n = 14) groups were significantly less than in the untreated OGD group (CA1, 57 ± 7; DG, 37 ± 4; n = 22). The {Sigma}PI for 7 days after OGD was also significantly decreased in both the Post10L (CA1, 178 ± 15; DG, 154 ± 11) and the Post100L (CA1, 157 ± 17; DG, 130 ± 13) groups compared with the untreated OGD group (CA1, 292 ± 27; DG, 206 ± 13) (Fig. 4). When thiopental was administered after OGD, the first day PI indexes in the Post250T (CA1, 14 ± 2; DG, 11 ± 1; n = 14) and the Post600T (CA1, 28 ± 3; DG, 20 ± 3; n = 13) groups were less than those in the untreated OGD group (CA1, 57 ± 7; DG, 37 ± 4; n = 22) (Fig. 3). The {Sigma}PI was significantly decreased in both the Post250T (CA1, 178 ± 10; DG, 133 ± 8) and the Post600T (CA1, 202 ± 13; DG, 147 ± 14) groups compared with the untreated OGD group (CA1, 292 ± 27; DG, 206 ± 13) (Fig. 4). These data suggest that administration of either lidocaine or thiopental immediately after OGD reduces neuronal loss.



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  		Figure 3. Postexposure to lidocaine or thiopental directly after oxygen-glucose deprivation (OGD) reduces propidium iodide (PI) fluorescence in hippocampal slice cultures. PI fluorescence was assayed in slice cultures 1 h before OGD (day 0). Slice cultures were submerged in Earle’s balanced salt solution containing no glucose and bubbled with 95% N2 5% CO2 for 10 min (OGD). Immediately after OGD, slice cultures were either untreated or treated with lidocaine (10 µM) or thiopental (250 µM). After a 10-min treatment, the drugs were washed out and PI fluorescence was assayed at daily intervals (days 1–7). The mock-OGD slice cultures were not subjected to OGD. A, For each treatment, multiple video micrographs of PI fluorescence are shown for a representative slice culture. B, Summary of the reduction of PI fluorescence in the Cornus Ammonis 1 (CA1) region by treatment with lidocaine or thiopental after OGD. Both 10 µM lidocaine (10 µM L) and 250 µM thiopental (250 µM T) significantly reduced the PI index the first day after OGD as compared with the untreated OGD group (OGD) (analysis of variance, P < 0.0001; Newman-Keuls test, *P < 0.05). Separate statistical tests were done for each day.

 


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  		Figure 4. Postexposure to lidocaine or thiopental directly after oxygen-glucose deprivation (OGD) reduces the 7-day sum of the post-OGD propidium iodide (PI) fluorescence in hippocampal slice cultures. The experiments are as described in Figure 3 except that the daily post-OGD PI fluorescence values were added together for 7 days after OGD. Either lidocaine 10 µM (L 10) or 100 µM (L 100) or thiopental 250 µM (T250) or 600 µM (T600) was present for 10 min immediately after OGD, but not during 10 min of OGD. The mock-OGD group (Mock) was not subjected to OGD. Bars represent the mean ± the standard error of the mean (n >> 12 for each group). The Cornus Ammonis 1 (CA1) region (A, open bars) and the dentate region (B, filled bars) were analyzed separately with an analysis of variance (P < 0.0001) followed by the Newman-Keuls test; all groups were significantly different from the untreated OGD group (OGD) (*P < 0.01).

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Previous results from our laboratory have demonstrated that both thiopental and lidocaine can reduce CA1 pyramidal cell damage in acute hippocampal slices by delaying the neuronal depolarization during hypoxia and enhancing the recovery of the resting membrane potential after hypoxia (1,3,15). In the current study, we examined the effect of lidocaine and thiopental on delayed neuronal damage for 7 days after OGD using hippocampal slice cultures from 20- to 30-day-old rats. The concentrations of thiopental and lidocaine used in the current study are based on our previous studies using acute hippocampal slices, 10 µM lidocaine corresponds to the maximal serum concentration used for antiarrhythmicity, and 250 and 600 µM thiopental approximate a barbiturate coma dose (1,3,15). A 10-minute episode of OGD was sufficient to induce neuronal loss suggesting that slice culture neurons displayed sensitivity to OGD similar to acute hippocampal slice neurons in vitro and hippocampal neurons in vivo. Hippocampal slice cultures have been successfully used to examine the effect of isoflurane on delayed neuronal damage (16). It is important to examine delayed damage when examining anesthetic protection because recent studies have shown an immediate improvement that was not sustained after ischemia in vivo with isoflurane; indeed, those authors showed an enhancement of cell death on day 4 after ischemia in the isoflurane group (17–19).

When either lidocaine or thiopental was present for only 10 minutes before, but not during, OGD, there was significantly less damage for the first 2 days after OGD compared with the untreated OGD slices. The cumulative damage, as measured by the sum of the daily PI fluorescence for the 7 days after OGD, was also significantly less for both drugs compared with the untreated OGD group (Fig. 2). This indicates that overall neuronal damage subsequent to OGD is reduced when these drugs are present before OGD. Although lidocaine and thiopental are not present in the extracellular solution during OGD, these lipid soluble drugs may still be present in the neurons and on the membranes because of incomplete washout. These results support our previous studies in acute slices, in which we found enhanced short-term recovery after hypoxia with thiopental and lidocaine and indicate that the protection we previously found acutely is sustained (1,3,15).

Because the onset of stroke and ischemia is frequently not predictable, we examined whether applying drugs after OGD can also reduce delayed neuronal damage. We found that when either lidocaine or thiopental was present for 10 min immediately after, but not before or during, OGD, the neuronal damage was significantly less on the first day after OGD. The cumulative damage, as measured by the sum of the PI fluorescence for the 7 days after OGD, was also significantly reduced (Fig. 4). Thus, adding either lidocaine or thiopental immediately after OGD can reduce delayed neuronal damage in this model.

High lidocaine concentrations have been demonstrated in vivo and in vitro to improve recovery from ischemia and hypoxia; however, few studies have examined lidocaine at its lower antiarrhythmic concentration. We found that small-dose lidocaine reduced neuronal damage when given before OGD. When applied before middle cerebral artery occlusion, small-dose lidocaine reduced infarct size and neuronal damage (20). In the penumbra, cytochrome c release and caspase 3 activation were attenuated 4 hours after ischemia and fewer apoptotic cells were observed 24 hours after ischemia (21). In the current studies, small-dose lidocaine was also protective when applied after OGD. Although administration starting at the end of in vivo ischemia has not been studied, lidocaine was protective when applied 45 minutes after the onset of a 90-minute middle cerebral artery occlusion (22). In that study, the infarct size was not reduced. However, the number of intact neurons was increased in both the penumbra and core and the neurological outcome was improved. Several clinical studies have also indicated that lidocaine may be neuroprotective (23,24).

Lidocaine is a local anesthetic and antiarrhythmic drug that expresses use-dependent block of Na+ channels. In the presence of the low lidocaine concentration (10 µM), we observed normal synaptic transmission and excitability before hypoxia (1,3). Hypoxia led to a small and slow depolarization, which was followed by a rapid complete depolarization; this rapid depolarization has been associated with neuronal damage (3,15). The low lidocaine concentration blocks Na+ channels in the hypoxic neurons during the slow depolarization, probably by a process similar to use-dependent block, and thereby delays the hypoxic rapid and complete depolarization as well as limiting Na+ influx (3).

Thiopental is a barbiturate anesthetic that has been shown to provide protection both in vivo and clinically if given in barbiturate coma doses (25,26). Its clinical use has the major disadvantage of precluding neurological examination of the patient because of the large doses required for efficacy. Thiopental protected hippocampal slice cultures if applied before OGD. Our previous results using acutely prepared hippocampal slices demonstrated that, during hypoxia, thiopental blocked the neuronal depolarization, the increase of cytosolic Na+ and Ca++, and the decrease of cytosolic concentrations of potassium and adenosine triphosphate (ATP) (15). Thiopental also decreased excitatory amino acid release during and after in vivo ischemia (27,28). We found that thiopental reduced damage to slice cultures if applied after OGD; others have found postischemic treatment to be protective in vivo (27).

The mechanisms are unclear for protection with post-OGD thiopental or lidocaine treatment. Thiopental reduces the time after ischemia when large excitatory amino acid concentrations are present (27). This could be a direct mechanism of protection, but it may also indicate a more rapid return of ionic and energetic homeostasis; lidocaine may act via the same mechanism. Reperfusion injury may be important for enhancing neuronal damage after hypoxia and ischemia; having a protective drug present during this period appears to be beneficial. A clinical study with thiopental after cardiac arrest did not find improved recovery; however, thiopental was not administered to the patients until 15 minutes after resuscitation (29). It may be that the period immediately after ischemia is critical, because at this time oxygen concentrations recover rapidly but ATP, intracellular Na+ and Ca+, and reducing equivalents are still at their ischemic levels. This may be a factor enhancing reperfusion injury and a protective drug may be crucial at this time. Indeed, in the current study, we administered thiopental and lidocaine for 10 minutes beginning with the onset of reoxygenation. The drugs were removed from the solution at 10 minutes after the OGD.

OGD, an experimental model of ischemia, induces delayed neuronal loss in slice cultures. Lidocaine and thiopental, if administered either before or immediately after OGD, can attenuate delayed neuronal loss. Few drugs, aside from lidocaine and thiopental, can reduce neuronal damage if administered immediately after OGD. Lidocaine may prove useful clinically because it prevents damage at a dose that would allow neurological status testing. Additional studies are required to determine if antiarrhythmic concentrations of lidocaine provide clinical brain protection.


   Footnotes
 
Accepted for publication March 22, 2005.

This work was supported by a National Institutes of General Medical Sciences Grant to ISK and a Brooklyn Anesthesia Research Grant to HC and ISK.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press