Journal of Cerebral Blood Flow and Metabolism 12:223-229 © 1992 The International Society of Cerebral Blood Flow and Metabolism Published by Raven Press, Ltd., New York

The Effect of Glutamate Receptor Blockade on Anoxic Depolarization and Cortical Spreading Depression

*tMartin Lauritzen and *:j:Anker Jon Hansen *Department of General Physiology and Biophysics, Panum Institute, University of Copenhagen, Copenhagen, tDepartment of Clinical Neurophysiology, Hvidovre Hospital, Hvidovre, and tCNS Division, Novo Nordisk Inc., S¢borg, Denmark

Summary: We examined the effect of blockade of N­ methyl-D-aspartate (NMDA) and non-NMDA subtype glutamate receptors on anoxic depolarization (AD) and cortical spreading depression (CSD). [K +le and the direct current (DC) potential were measured with microelec­ trodes in the cerebral cortex of barbiturate-anesthetized rats. NMDA blockade was achieved by injection of (+)5-methyl-to, II-dihydro-5H-dibenzo[a, dlcyclohepten5,10-imine maleate [MK-801; 3 and to mg/kgl or amino7-phosphonoheptanoate (APH; 4.5 and to mg/kg). Non­ NMDA receptor blockade was achieved by injection of 2, 3-dihydroxy-6-ni tro-7-sulfamoyIbenzo(F)quinoxaline (NBQX; 10 and 20 mg/kg). MK-801 and APH blocked CSD, while NBQX did not. In control rats, the latency

from circulatory arrest to AD was 2.1 ± 0.1 min, while the amplitude of the DC shift was 21 ± 1 m V, and [K + le increased to 50 ± 6 mM. All variables remained un­ changed in animals treated with MK-801, APH, or NBQX. Finally, MK-801 (14 mg/kg) and NBQX (40 mg/ kg) were given in combination to examine the effect of total glutamate receptor blockade on AD. This combina­ tion slightly accelerated the onset of AD, probably owing to circulatory failure. In conclusion, AD was unaffected by glutamate receptor blockade. In contrast, NMDA re­ ceptors play a crucial role for CSD. Key Words: Cerebral ischemia-Glutamate receptors-Ion homeostasis­ Migraine-Spreading depression.

The aim of this study was to examine the mech­ anism of depolarization associated with cortical spreading depression (CSD) (Leao, 1944) and cere­ bral ischemia (anoxic depolarization; AD) (Leao, 1947). CSD and AD are two conditions in which brain function is perturbed, with a number of inter­ esting similarities and differences. In both condi­ tions spontaneous and evoked brain activity is de­ pressed, the direct current (DC) potential under-

goes a predominantly negative change of 10-40 mV, and brain ion homeostasis fails owing to increased membrane permeability (Hansen and Zeuthen, 198 1; Nicholson and Kraig, 198 1; Hansen, 1985). Important differences are that in CSD the electro­ physiological and metabolic changes revert sponta­ neously within a couple of minutes, while in cere­ bral ischemia blood flow is required to restore en­ ergy and ion metabolism to normal. Furthermore, in CSD the depolarization successively invades adja­ cent tissue (Leao, 1944), while the AD occurs asyn­ chronously in widespread brain regions (Leao, 1947), without evidence of interaction between de­ polarized and nondepolarized regions (Hernandez­ Caceres et aI., 1987). The mechanisms of depolarization and membrane failure during CSD and AD are incompletely under­ stood. The possibility that glutamate plays an active role in CSD and AD was originally suggested by Van Harreveld ( 1959). Glutamate, aspartate, and agonists of the glutamate subtype receptors [N­ methyl-D-aspartate (NMDA), quisqualate, and

Received February 22, 1991; revised July 19, 1991; accepted July 23, 1991. Address correspondence and reprint requests to Dr. M. Lauritzen at Department of General Physiology and Biophysics, Panum Institute, University of Copenhagen, Blegdamsvej 3c, 2100-DK Copenhagen, Denmark. Abbreviations used: AD, anoxic depolarization; APH, amino7-phosphonoheptanoate; APV, amino-5-phosphonovalerate; CSD, cortical spreading depression; DC, direct current; MK801, (+ )-5-methyl-10,II-dihydro-5H-dibenzo[a,dlcyclohepten5,IO-imine maleate; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoyl­ benzo(F)quinoxaline; NMDA, N-methyl-D-aspartate. Part of the data presented here have been published as pre­ liminary communications (Hansen et al., 1988; Lauritzen et al., 1991).

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kainate] trigger CSD (Van Harreveld, 1959; Curtis and Watkins, 1963; Bures et aI., 1974; Lauritzen et aI., 1988). It is controversial whether glutamate, and to a lesser extent aspartate, is released during CSD (Van Harreveld and Kooiman, 1965; Van Har­ reveld and Fifkova, 1970; Gardino and do Carmo, 1983; Scheller et aI., 1990). On the other hand, ce­ rebral anoxia is accompanied by the release of glu­ tamate, aspartate, and -y-aminobutyrate (Ben­ veniste et aI., 1984). Artificial CSF with a low magnesium concentra­ tion triggers the opening of the NMDA receptor­ channel complex and the production of CSD in the hippocampus and the cerebellum in vitro (Mody et aI., 1987; Lauritzen et aI., 1988). On some occa­ sions the tissue remains depolarized much in the same manner as during AD (Lauritzen et aI., 1988). It is possible that NMDA receptor activation per se is sufficient to cause AD. NMDA receptor blockade inhibits CSD, both in vitro (Mody et aI., 1987; Lau­ ritzen et aI., 1988) and in vivo (Gorelova et aI., 1987; Marrannes et aI., 1988). The role of NMDA receptor blockade in AD is controversial, since ke­ tamine failed to influence AD in the neocortex (Her­ nandez-Caceres et aI., 1987; Amemori and Bures, 1990) while amino-5-phosphonovalerate (APV) cur­ tained hippocampal AD (Benveniste et aI., 1988). To elucidate the contribution of glutamate­ mediated neurotransmission further, we examined the effects on CSD and AD of (+ )-5-methyl-IO,Il­ dihydro-5H-dibenzo[a ,d]cyciohepten-5, 10-imine maleate (MK-80 1) and amino-7 -phosphono­ heptanoate (APH), both NMDA antagonists (Simon et aI., 1984; Wong et aI., 1986; Park et aI., 1988; Albers et aI., 1989), and 2,3-dihydroxy-6-nitro-7sulfamoylbenzo(F)quinoxaline (NBQX), a newly developed non-NMDA receptor antagonist with preference for a-amino-3-hydroxy-5-methyl-4isoxazole propionic acid receptors and cerebro­ protective properties for cerebral ischemia (Shear­ down et aI., 1990).

croelectrodes as described previously (Hansen and Zeuthen, 1 98 1 ). Spread of the CSD was monitored with a single-barreled microelectrode measuring the DC poten­ tial in the frontal cortex. An Ag/AgCI wire located under the skin of the hind leg served as reference electrode. CSD was induced electrically in the parietal cortex by bipolar stimulation using two bared silver wires attached to the bottom of a cup placed on the dura (Fig. I). The recording electrode was positioned midway between the two stimulating wires. Stimulation consisted of a train of 5-ms pulses at 40 Hz lasting for 2 s at 8- 1 0 V. The thresh­ old stimulation for CSD elicitation was defined by varying the voltage, but the stimulus parameters varied very little between animals. The reliability of the threshold stimulus was tested by inducing CSD a couple of times before MK-80 1 at 3 or 1 0 mg/kg, APH at 4.5 or 1 0 mg/kg, or NBQX at 10 or 20 mg/kg was injected. Slow injection rates were used to avoid drop of arterial blood pressure. Stimulation was resumed after another few minutes, first at the threshold level. If CSD was blocked, stimulation was increased with respect to voltage ( 1 5-25 V) and stim­ ulus duration (up to 4 s) so as to produce a local response of the DC potential andlor [K + le as during the preceding CSD under control conditions. The speed of the CSD spread was calculated from the latency difference of the negative DC shift at the elec­ trodes in the parietal and frontal cortices and the distance between the electrodes. The amplitude of the DCI potassium shift was measured from the baseline to the largest deflection. Animals were killed with an intravenous injection of concentrated KCI. The AD latency was measured from the moment of circulatory arrest to the onset of the rapid part of the depolarization. Amplitudes were measured peak to peak from the positive shift occurring during the first phase of the AD to the negative peak terminating the AD.

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MATERIALS AND METHODS Male Wistar rats (300-350 g) were anesthetized with an initial dose of Nembutal (50 mg/kg) and supplementary doses as required later. Catheters were placed in one fem­ oral artery and one femoral vein. The spontaneously breathing rats were placed in a headholder and cranioto­ mies were performed ipsilaterally over the frontal and parietal cortices. The mean arterial blood pressure was monitored continuously while respiratory steady state was ensured by frequent sampling of arterial blood and measurements of Pa02, Pac02, and arterial pH. Rectal temperature was servo-controlled at 37°C with a heating pad. [K +]e and/or the DC potential were measured in the parietal cortex using single- or double-barreled glass mi-

J Cereb Blood Flow Metab, Vol. 12, No.2, 1992

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FIG. 1. Schematic drawing of arrangement of stimulating and recording electrodes. Stimulating electrodes were two bared silver wires extending 1-2 mm out of the bottom of a cup placed at the dura over the parietal cortex. One record­ ing electrode was placed between the two stimulating elec­ trodes to monitor the triggering of cortical spreading depres­ sion (CSD) and the local response to electrical stimulation following injection of drugs. A second recording electrode was placed in the frontal cortex to monitor the spread of the CSD. DC, direct current.

GLUTAMATE IN SPREADING DEPRESSION AND ISCHEMIA

Values in the text are means ± 1 SD. Student's t test (paired and unpaired) was used for statistics.

tion produced local changes of DC potential and [K +]e as during the CSD recorded previously, but there was no spread to the electrode in the frontal cortex. In two rats a cottonball soaked in KCI at 1 M was applied to the cortex, but failed to produce a CSD. CSD was also inhibited when MK-SOI at 1 fA-M was applied directly to the cortex; however, the effect was irreversible and this type of experiment was pursued no further. Circulatory failure was instigated by intravenous injection of 1 ml of 1 M KCI, typically at 30-45 min after injection of MK-SOI. NMDA receptors were still blocked at this time as evidenced by complete inhibition of CSD in response to electrical stimula­ tion. The latency to the AD was 2.2 ± 0.2 min, while the DC potential change was 23 ± 3 mV, and [K +]e increased to 52 ± 6 mM, not different from controls (NS, n S). Thus, MK-SOI interferes with both the triggering and the spreading of CSD, but has no effect on AD. APR was tested in four rats. Intravenous injec­ tion of 4.5 mg/kg (n 1) induced incomplete block­ ade since suprathreshold stimulation induced a CSD on one occasion (Fig. 4). APR at 10 mg/kg (n 1) blocked CSD completely. APR at 0.5 mM applied to the brain surface at the site of electrical stimulation inhibited CSD completely, but CSD re-

RESULTS Under control conditions, the rate of the CSD spread was 3.S ± 0.9 mm/min while the amplitude 17 episodes). of the DC shift was 23 ± 6 mV (n The latency to the onset of the AD was 2. 1 ± 0. 1 min, while the amplitude of the DC shift was 2 1 ± 1 4 rats). mV and [K +]e increased to 50 ± 6 mM (n In eight rats treated with NBQX at 10 or 20 mg/ kg, the rate of CSD spread was 4. 1 ± 1.2 mm/min before and 3.7 ± O.S mm/min after injection of the drug (n 13; NS), while the change of the DC potential was 24 ± 7 mV before and 23 ± 5 mV after the drug (NS) (Fig. 2). The latency to the AD was 1.9 ± 0.3 min and the amplitude of the DC shift was 17 ± 4 mV (NS). Thus, CSD and AD are unaffected by NBQX. CSD was completely blocked in another 12 rats treated with MK-SOI at 3 or 10 mg/kg CSD from a few minutes after the injection (Fig. 3). We tested the animals for up to 5 h after administration of MK-SOl, but found no evidence of adaptation. Threshold stimulation caused local changes of the DC potential and [K +]e' which were drastically re­ duced. Increasing the stimulus strength and dura=

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tial at electrodes in frontal cor­ tex (upper trace) and parietal cortex (lower trace) of rats ex­ posed to CSD and cerebral isch­ emia. CSD was elicited by local electrical stimulation of the pa­ rietal cortex. Ischemia was in­ duced by intravenous injection of KCL After the second CSD episode, NBQX, a non-NMDA antagonist, was given at 10 mg/ kg Lv. The drug had no effect on the triggering or spread of CSD, or the latency or amplitude of the AD. For abbreviations see the text.

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J Cereb Blood Flow Metab. Vol. 12, No.2, 1992

M. LAURITZEN AND A. 1. HANSEN

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FIG. 3. [ K+le in parietal cortex (upper trace) and DC potential change in frontal cortex (lower trace) in rats exposed to CSD and cerebral ischemia. After the fourth CSD, MK-801, an NMDA­ antagonist, was given at 10 mg/ kg i. v. ( a r r o w ) . T h e dru g blocked CSD completely, but did not delay or curtail the [ K+le changes during AD induced by intravenous injection of KCI. For abbreviations see the text.

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appeared following prolonged drug outwash (n 2). Circulatory arrest was induced at a time when CSD remained inhibited owing to NMDA receptor blockade. The AD for all four rats followed with a latency of 2.3 ± 0.4 min and the amplitude of the DC shift was 2 1 ± 1 mY (NS). The variables for AD were the same whether the drug was applied locally or by intravenous injection. Finally, MK-80 1 at 14 mg/kg i.v. and NBQX at 40 mg/kg i. v. were given simultaneously to three rats over a 10-min period. The blood pressure-lowering effect of this rather high dose was dramatic and killed one of the rats, while the remaining two sur­ vived with a blood pressure at 50-60 mm Hg for a few minutes. The latency from circulatory arrest to the AD was 1.6 ± 0.3 min, slightly faster than in controls (p < 0.05), while the amplitude of the DC shift in the parietal cortex was 16 ± 5 mY, not sig­ nificantly different from control rats. The shorter J Cereb Blood Flow Metab, Vol. 12, No.2, 1992

'...._--latency to AD is explained by the preischemic low mean arterial blood pressure, which induces brain hypoxia before cardiac arrest. DISCUSSION The main result of the present study is that AD in the cortex is unaffected by NBQX, MK-80 1, and APH alone and in combination. The results confirm the observations of Hernandez-Caceres et al. ( 1987) and Amemori and Bures ( 1990) that systematically administered NMDA antagonists in high doses are ineffective in blocking cortical AD. In the rat hip­ pocampus, on the other hand, local injection of the competitive NMDA antagonist APY into the CAl region curtailed AD and the associated cellular in­ flux of calcium (Benveniste et al., 1988). AD and the calcium flux were also prevented by removal of the glutamatergic input to the CAl region (by killing

GLUTAMATE IN SPREADING DEPRESSION AND ISCHEMIA

FIG. 4. Shifts of the potential at electrodes in the parietal cortex (upper trace) and frontal cortex (lower trace) of rats exposed to CSD and cerebral ischemia. Af­ ter the third CSD, APH, an NMDA antagonist, was given at 4.5 mg/kg i.v. (arrow) . APH blocked CSD rather effectively even in response to supra­ threshold stimulation when the local response was of higher amplitude and longer duration than during control conditions. Numbers at arrows indicate the multiplication factor of the stim­ ulus threshold voltage that was applied. The electrical stimula­ tion induced CSD on one occa­ sion following administration of the drug (bottom panel), but not during the following supra­ threshold stimulations. For ab­ breviations see the text.

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CA3 neurons with kainic acid) during a lO-min pe­ riod of ischemia (Benveniste et aI. , 1988). This may suggest that cortical and hippocampal ADs have dif­ ferent mechanisms. The latency from heart arrest to AD has previ­ ously been changed by varying the glucose stores of the brain or the cerebral metabolic rate (Bures et aI., 1974; Hansen, 1978; Astrup et aI., 1980; Schaef­ fer and Lazdunski, 199 1). Antagonists of the ATP­ dependent K + channel are, however, without effect on the K + efflux during hippocampal ischemia (Schaeffer and Lazdunski, 199 1), despite the fact that the large ionic shifts are linked to a decline of energy charge (Siesjo and Bengtsson, 1989). Energy charge remains constant during CSD, suggesting that energy failure is not a condition for membrane failure (Lauritzen et aI., 1990). MK-80 1 and APH blocked CSD, while NBQX did not. MK80 1 and APH interfered with both the triggering and the spreading mechanisms since a higher stimula­ tion strength was required to obtain a local response of the same amplitude as in the untreated animal, and spread of the CSD occurred on only one occa­ sion in one rat. The experimental setup with one recording electrode positioned between the two stimulating wires and the second electrode at a re­ mote position appeared well suited for pharmaco-

logical studies of CSD since both the triggering and the spreading process were monitored. Our data strengthen the viewpoint that NMDA antagonists play a special role in CSD (Gorelova et aI., 1987; Mody et aI., 1987; Lauritzen et aI., 1988; Marrannes et aI., 1988; Sheardown, 1989). Despite the similarities of CSD and AD with re­ spect to ionic changes and DC shift, nerve cell de­ polarization, and electroencephalographic silence, the basic mechanisms appear entirely different. The different susceptibility to the NMDA antagonists may reflect quantitative aspects of transmitter re­ lease in the two conditions. Glutamate and aspar­ tate are released in large quantities during ischemia (Benveniste et aI., 1984), while trace amounts are released during CSD (Van Harreveld and Kooiman, 1965; Van Harreveld and Fifkova, 1970; Gardino and do Carmo, 1983; Scheller et aI., 1990). The dra­ matic increase of extracellular glutamate during ce­ rebral ischemia occurs, however, much later than AD (Benveniste et aI., 1984) and has no immediate bearing on the ion fluxes associated with AD. Also the fact that the noncompetitive NMDA antagonist MK-80 1 was inefficient as a blocker of AD speaks against the importance of a larger efflux of gluta­ mate during AD as compared to CSD. Studies of cultured hippocampal and cortical J Cereb Blood Flow Metab, Vol. 12, No.2, 1992

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nerve cell cultures have demonstrated that acidosis inhibits the NMDA-induced Ca2+ current (Giffard et aI., 1990), that mild acidosis protects the neurons from NMDA-mediated damage (Tombaugh and Sa­ polsky, 1990), and that preservation of intracellular high-energy phosphates prevents the rundown of NMDA-gated channels (Mody et aI. , 1988). This suggests that the NMDA receptor channel complex changes properties during ischemia. If so, NMDA receptor blockade by, e.g. , MK-80 1 and APH may be neutralized or unimportant during the ischemic period when acidosis and energy depletion occur. During reperfusion, the "intrinsic" NMDA recep­ tor blockade is expected to disappear concomi­ tantly with the return to normal of pH and energy metabolism. The therapeutic time window of NMDA receptor blockers may be during this latter period. NBQX effectively inhibits the delayed neu­ ronal death in the hippocampus following complete cerebral ischemia (Sheardown et aI. , 1990), but has no effect on AD. Whether AD and the associated ion fluxes play any role in the development of neu­ ronal cell death remains unknown. Finally, CSD may be a trigger mechanism of mi­ graine attacks in humans (Lauritzen, 1987). Consid­ ering the extreme sensitivity of CSD to NMDA an­ tagonism, it is possible that NMDA receptor block­ ade could be a new therapeutic strategy for migraine.

Curtis DR, Watkins JC (1963) Acidic amino acids with strong excitatory actions on mammalian neurons. J Physiol 166:114

Gardino FG, do Carmo RJ (1983) Glutamate and spreading de­ pression in chick retina. An Acad Bras Cienc 55:297-307 Giffard RG, Monyer H. Christine CW, Choi DW (1990) Acidosis reduces receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cul­ tures. Brain Res 506:339-342 Gorelova NA. Koroleva VI, Amemori T, Pavlik V, Bures J (1987) Ketamine blockade of cortical spreading depression in rats. Electroencephalogr Clin Neurophysiol 66:440-447 Hansen AJ (1978) The extracellular potassium concentration in brain cortex following ischemia in hypo- and hyperglycemic rats. Acta Physiol Scand 102:324-329 Hansen AJ (1985) Effect of anoxia on ion distribution in the brain. Physiol Rev 66:101-148 Hansen AJ, Zeuthen T (1981) Changes of brain extracellular ions during spreading depression and ischemia in rats. Acta Phys­ iol Scand 113:437--445 Hansen AJ, Lauritzen M, Wieloch T (1988) NMDA antagonists block cortical spreading depression but not anoxic depolar­ ization. In: Frontiers in f.xcitatory Amino Acid Research (Cavalheiro EA. Lehmann J, Turski L, eds), New York, Alan R Liss, pp 661-665 Hernandez-Caceres J, Macias-Gonzales R, Brozek G. Bures J (1987) Systemic ketamine blocks cortical spreading depres­ sion, but does not delay the onset of terminal anoxic depo­ larization in rats. Brain Res 437:360-364 Lauritzen M (1987) Cortical spreading depression as a putative migraine mechanism. Trends Neurosci 10:8-13 Lauritzen M, Rice ME, Okada YC Nicholson C (1988) Quis­ qualate, kainate and NMDA can Initiate spreading depres­ sion in the turtle cerebellum. Brain Res 475:317-327 Lauritzen M, Hansen AJ, Kronborg D, Wieloch T (1990) Corti­ cal spreading depression is associated with arachidonic acid

accumulation and preservation of energy charge. J Cereb

Blood Flow Metab 10:115-122

Lauritzen M. Sheardown M, Hansen AJ (1991) The neuropro­

Acknowledgment: This work was supported by the

Medical Research Council (Denmark), the Danish Mi­ graine Society, the Foundation of 1 870, the Carlsberg Foundation, and the Foundation for Experimental Re­ search in Neurology.

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