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J Neurophysiol 96: 2809-2814, 2006. First published August 2, 2006; doi:10.1152/jn.00466.2006
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REPORT

Endogenous Activation of Adenosine A1 Receptors Accelerates Ischemic Suppression of Spontaneous Electrocortical Activity

Andrei Ilie1, Dragos Ciocan1, Ana-Maria Zagrean1, Dragos Alexandru Nita2, Leon Zagrean1 and Mihai Moldovan3,1

1Center for Excellence in Neuroscience, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; 2Neurophysiology Laboratory, Medical School, Laval University, Quebec, Canada; and 3Division of Neurophysiology, Panum Institute of Medical Physiology, University of Copenhagen, Denmark


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Cerebral ischemia induces a rapid suppression of spontaneous brain rhythms prior to major alterations in ionic homeostasis. It was found in vitro during ischemia that the rapidly formed adenosine, resulting from the intracellular breakdown of ATP, may inhibit synaptic transmission via the A1 receptor subtype. The link between endogenous A1 receptor activation during ischemia and the suppression of spontaneous electrocortical activity has not yet been established in the intact brain. The aim of this study was to investigate in vivo the effects of A1 receptor antagonism by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) on the time to electrocortical suppression during global cerebral ischemia. Adult male Wistar rats under chloral hydrate anesthesia were subjected to 1-min transient "four-vessel occlusion" ischemic episodes, separated by 20-min reperfusion. The rats were injected intraperitoneally with either 1.25 mg/kg DPCPX dissolved in 2 ml/kg dimethyl sulfoxide (DMSO) or the same volume of DMSO alone, 15 min before the third ischemic episode. Time to electrocortical suppression was estimated based on the decay of the root mean square of two-channel electrocorticographic recordings. During the first two ischemic episodes, electrocortical suppression appeared after ~12 s in both groups. After DMSO administration, ischemic suppression remained unchanged. After DPCPX administration, the time to electrocortical suppression was increased by ~10 s, and bursts of activity were recorded during the entire ischemia. These effects disappeared within 15 h after DPCPX administration. Our data provide evidence that during cerebral ischemia endogenous activation of A1 receptors accelerates the electrical "shut-down" of the whole brain.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
It has been recognized for a long time that cerebral ischemia induces a rapid suppression of spontaneous brain rhythms prior to major alterations in ionic homeostasis reflected by the anoxic depolarization (Leão 1947Go). To date, the early factors responsible for the ischemic "shut-down" of the electrocortical activity remain poorly understood. During cerebral ischemia/hypoxia, the rapidly formed adenosine, resulting from the intracellular breakdown of ATP, was found to suppress electrically evoked synaptic transmission through the activation of A1 receptor subtype (A1R) in the rat hippocampus in vitro (Dale et al. 2000Go; Fowler 1989Go, 1990Go; Gribkoff et al. 1990Go; Sebastião et al. 2000Go) and, more recently, in vivo (Fowler et al. 2003Go; Gervitz et al. 2001Go, 2003Go). The possible link between endogenous A1R activation during ischemia and suppression of spontaneous electrocortical activity has not yet been established in the intact brain.

Global cerebral ischemia (GCI) in rat is followed by a rapid suppression of spontaneous electrocortical activity (Barzaghi et al. 1982Go; Pulsinelli and Brierley 1979Go; Zagrean et al. 1995Go). In the rat brain, A1Rs were found with high densities on the large cortical pyramidal neurons (Rivkees et al. 1995Go) and in some thalamic neurons (Fastbom et al. 1987Go), structures that are directly involved in the generation of spontaneous brain rhythms (reviewed in Steriade 2006Go). Because a massive ischemic increase of interstitial adenosine was reported in the rat brain (Van Wylen et al. 1986Go), we hypothesize that ischemic A1R activation may contribute to the suppression of electrocortical activity.

We have recently developed a method to detect small changes in the time to electrocortical suppression (TES) (Ilie et al. 2006Go) during transient GCI episodes under anesthesia in rat (Moldovan et al. 2004bGo). The aim of the present study was to investigate the effect of A1R antagonism on TES. The xanthine derivative 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) is a very potent and selective antagonist for rat A1Rs (Bruns et al. 1987Go). In vitro, DPCPX abolished the rapid depression of synaptic transmission that appeared during the exposure of hippocampal slices to hypoxia (Canhão et al. 1994Go; Coelho et al. 2000Go; Jin and Fredholm 1997Go; Pearson et al. 2001Go; Zeng et al. 1992Go). Because DPCPX has a very good penetration into the rat brain (Baumgold et al. 1992Go), we tested the in vivo the effect of systemically administered DPCPX on TES during GCI.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals and experimental procedures

The study was carried out in 15 adult male Wistar rats (200–300 g) with free access to food and water. Surgical and experimental procedures were performed under chloral hydrate anesthesia (Sigma, 0.4 g/kg ip maintained with 0.1 g · kg–1 · h–1) with external body temperature regulation.

Our model to investigate the ischemic electrocortical suppression was recently described in detail (Ilie et al. 2006Go). Briefly, the rats were first implanted with two pairs of epidural electrodes for electrocorticographic (ECoG) recordings. After ~1 wk, the rats were subjected to a second surgery to induce transient, nonlethal, GCI by the "four-vessel occlusion" model (Moldovan et al. 2004bGo; Pulsinelli and Brierley 1979Go; Zagrean et al. 1995Go). The animals were then left to recover overnight and subjected to another GCI episode. All rats were killed by cervical dislocation at the completion of experiments. The experiments were carried out with the approval of the local committee for animal research of Carol Davila University of Medicine and Pharmacy (Bucharest, Romania) in accordance with the American Physiological Society ethical policies and procedures regarding animal experimentation.

Pharmacological investigations

To account for individual variability (Pulsinelli and Brierley 1979Go), we tested four consecutive 1-min GCIs, separated by 20-min reperfusion intervals (Ilie et al. 2006Go). We used the first two GCIs to establish a baseline and then injected intraperitoneally DPCPX (Sigma) dissolved in dimethyl sulfoxide (DMSO, Sigma), 15 min (Baumgold et al. 1992Go; Bisserbe et al. 1992Go) prior to the third GCI. We investigated the fourth GCI to test for peak effect and another GCI, ~15 h after drug administration, to investigate recovery (Fig. 1).


Figure 1
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  		FIG. 1. Representative experiments in control (A) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) group (B). Top: electrocorticographic (ECoG) recordings for 5 consecutive global cerebral ischemia episodes (GCIs) are presented at the same scale. Note the time lapse between the 4th and the 5th GCI; 1.25 mg/kg DPCPX in dimethyl sulfoxide (DMSO) vehicle, or DMSO alone, was administered 15 min prior to the 3rd GCI ({downarrow}). Each 1-min GCI is detailed. · · · , time of electrocortical suppression (TES) estimated by the automatic method. *, spontaneous bursts of activity during ischemic suppression. Time origin is set 1 min prior to the 1st GCI.

 
In rats, pharmacological effects of intraperitoneally administered DPCPX were obtained for concentrations as low as 0.1 mg/kg (Liu et al. 2006Go; Simpson et al. 1992Go); however, some DPCPX effects may require as high as 5 mg/kg (Li and Roth 1999Go). To ascertain a maximum effect, we tested both 5 mg/kg (n = 5) and 1.25 mg/kg DPCPX (n = 5). DPCPX was dissolved in 2 ml /kg DMSO, and the control group (n = 5) received a similar volume of DMSO alone.

Electrophysiological signals and statistics

The ECoG signals from two bipolar occipito-frontal leads were recorded using a MP100 Biopac System (Biopac Systems) with EEG100A amplifiers (1- to 35-Hz band-pass filter, –3 dB). Simultaneously with ECoG, the electrocardiogram (ECG) was recorded from two Ag/AgCl electrodes attached to the forepaws using the same MP100 Biopac System. The heart rate (HR) was calculated off-line as previously described in detail (Moldovan et al. 2004aGo).

We recently introduced an automatic method to estimate TES from ECoG during GCI (Ilie et al. 2006Go). Briefly, the root mean square of the signal (RMS) (calculated on consecutive 1-s epochs) was filtered through a low-pass third-order Butterworth filter using a zero-phase forward and reverse algorithm. The TES was then calculated as the time between the clamping of the both common carotid arteries and the decay of the filtered signal <30%.

Signal processing was implemented in MATLAB (MathWorks). Numeric results are given as means ± SE. Nonparametric statistical comparisons were performed by Wilcoxon paired test (SPSS).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Our experimental setup allowed recording of large ECoG (Fig. 1) and ECG (Fig. 2) signals. During GCI there was a complete suppression of the electrocortical activity (Fig. 1). During each GCI we detected a slight (~25%) decrease in HR (Fig. 2A), which peaked after ~30 s (Fig. 2, B and C). This ischemic sinusal bradycardia (Fig. 2, D and E) recovered spontaneously prior to reperfusion with a time course that was reproducible within the same experiment (Fig. 2).


Figure 2
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  		FIG. 2. Electrocardiographic (ECG) recordings from the experiment in Fig. 1B. Instantaneous heart rate (HR) calculated during the entire experiment duration is presented in A. Detailed HR fluctuations are presented during the 2nd (B) and the 3rd (C) global cerebral ischemia (GCI). Each HR point corresponds to 1 R to R interval. The onset of the transient bradycardia (accolades) is detailed in D and E, respectively. Time origin is set 1 min prior to the 1st GCI. Arrow indicates administration of 1.25 mg/kg DPCPX in DMSO vehicle.

 
The ECoG (Fig. 1A) and ECG (data not shown) changes were unaffected by DMSO administration in control group. Prior to the GCI, DPCPX had also no apparent effect on either ECoG (Fig. 1B) or ECG (Fig. 2). During the GCI, DPCPX-induced alterations easily recognizable in all investigated rats: ECoG suppression appeared delayed and interrupted by bursts of activity that could be observed up to the end of the investigated ischemia (Fig. 1B). After 1.25 mg/kg DPCPX, both ECoG (Fig. 1B) and ECG (Fig. 2) recovered fully after each GCI. Nevertheless, after 5 mg/kg DPCPX reperfusion consistently led to malignant arrhythmias (data not shown) and the experiments had to be discontinued.

The automatic TES quantification after DPCPX administration was complicated by the need to distinguish the prolonged persistence of "background" ECoG activity from the "first burst" (Fig. 1B). We found that a 0.01-Hz RMS filter could reasonably predict visual TES estimation both in control and DPCPX groups (Fig. 1). The differences in TES estimation between the two ECoG channels never exceeded 2 s. For consistency we considered the representative TES for one GCI as the shortest value between the two ECoG channels (Fig. 3A).


Figure 3
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  		FIG. 3. TES estimated by the automatic method. In A, the root mean square (RMS) from the 2 ECoG channels recorded during the 3rd GCI in Fig. 1B. Note that TES reflects the fastest normalized RMS decay between the 2 channels. Mean TES values for the 5 consecutive GCIs are presented in B. The 1st 4 GCIs were carried out at 20-min intervals. After the 2nd GCI ( · · · ), the rats were administered either DMSO alone ({square}), or DPCPX dissolved in DMSO. Data for 5 mg/kg DPCPX ({square}) are presented only for the 3rd GCI, as the following investigations had to de discontinued (details in text). The 5th GCI was carried out 15 h after drug administration to investigate recovery. *, significant increase in TES (P < 0.05, Wilcoxon) compared with the 1st GCI. Error bars indicate SE.

 
During the first GCI episode, TES was 12.2 ± 0.3 s in both control and DPCPX groups. No differences in TES were observed between the first and the second GCI episode in either group (Fig. 3B). During the third GCI, 15 min after administration, 1.25 mg/kg DPCPX prolonged TES to 21.3 ± 1.2 s (P < 0.05). This TES prolongation was similar after 5 mg/kg DPCPX (Fig. 3B) in spite of the ECG alterations after the subsequent reperfusion. During the fourth GCI, 36 min after 1.25 mg/ kg DPCPX administration, TES was 20 ± 1.2 s (P < 0.05), which was not significantly different from TES during the third GCI. At 15 h after DPCPX, TES was no different from TES prior to DPCPX administration (Figs. 1B and 3B).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We investigated the effect of systemic administration of the A1R antagonist DPCPX on the suppression of spontaneous electrocortical activity during transient global cerebral ischemia in rat. We found that DPCPX reversibly prolonged TES. Consistent with previous in vitro observations from rat hippocampal slices (Canhão et al. 1994Go; Fowler 1989Go, 1990Go; Pearson et al. 2001Go), it is likely that DPCPX prevented the rapid synaptic depression caused by the ischemic release of adenosine (Dale et al. 2000Go; Valtysson et al. 1998Go; Van Wylen et al. 1986Go). Thus we report here the first evidence that ischemic activation of A1Rs observed in vitro contributes to the suppression of spontaneous ECoG activity recorded from the intact brain in vivo.

Ischemic suppression of spontaneous ECoG activity was found to occur within 15 s in various species including rats (Barzaghi et al. 1982Go; Ilie et al. 2006Go), cats (Hossmann et al. 1990Go), and humans (de Vries et al. 1998Go). The ultimate cause of the ischemic loss of ECoG activity is the wide spread anoxic depolarization resulting from the failure of neuronal energy metabolism (Leão 1947Go). Nevertheless, during the "four-vessel occlusion" ischemia in rats, the suppression of spontaneous ECoG activity precedes anoxic depolarization (Matsumoto et al. 1990Go) with more than a minute (Halaby et al. 2004Go). Furthermore, at the onset of ischemic suppression of spontaneous ECoG, the cortical response to visual stimuli is preserved (Ilie et al. 2006Go). Thus even though our findings are in line with the know inhibitory effects of adenosine at synaptic level (Fowler 1989Go), we bring novel evidence that ischemic A1R activation accelerates the suppression of the "whole brain" most likely by targeting the key cortico-thalamic circuit (Ochiishi et al. 1999Go) responsible for generation of spontaneous brain rhythms (reviewed in Steriade 2006Go).

The impairment in the ischemic ECoG suppression induced by DPCPX was easily identifiable at visual inspection (Fig. 1). In addition to the prolonged persistence of the "background" ECoG activity, DPCPX revealed bursts of activity which could be observed up to the end of the investigated ischemia (Fig. 1B). In this study, we could not directly address whether the persistence of spontaneous ECoG activity and the bursting activity were the consequence of the same altered circuit. In fact, in vitro recordings may suggest that the early ischemic bursting activity may be purely neocortical (Fleidervish et al. 2001Go). Therefore we adjusted the quantification method (Fig. 3A) to measure TES of only the background ECoG activity. While the simple filtered RMS decay may not be appropriate for detecting brief transients like "isolated" bursts, it could accurately distinguish the "first burst" from the suppression of the "background" ECoG activity (Figs. 1B and 3A). Furthermore, the same filter settings could reasonably estimate TES in control group (Fig. 1A) which ensured the consistency of the comparisons.

The rapid suppression of spontaneous ECoG activity after cerebral ischemia was proposed to be a neuroprotective response (Hossmann et al. 1990Go; Nagashima 1994Go). During ischemia/hypoxia lethal neuronal injury occurs largely due to increased levels of glutamate and the subsequent activation of N-methyl-D-aspartate (NDMA) receptors (Simon et al. 1984Go). In vitro, endogenous adenosine release was found to efficiently prevent glutamate release via presynaptic A1Rs (Arrigoni et al. 2005Go; Coelho et al. 2000Go; Hershkowitz et al. 1993Go). Furthermore, recovery of synaptic transmission in hippocampal slices subjected to prolonged ischemia was largely impaired after DPCPX (Sebastião et al. 2001Go). We found that in vivo, DPCPX did not alter ECoG recovery after 1-min GCI (Fig. 1B). Although in vitro A1R antagonists may slightly shorten the delay to anoxic depolarization (Lee and Lowenkopf 1993Go), several minutes of anoxic depolarization may be required to induce neuronal damage in the most ischemic-sensitive neurons (Halaby et al. 2004Go; Sorimachi et al. 1999Go). Thus it is unlikely that DPCPX induced a significant acute neuronal damage during the 1-min transient ischemic episodes used in this study.

Consistent with a low basal adenosine tone (Fulga and Stone 1998Go) we found that DPCPX administration had no effect on the ECoG amplitude outside the GCI. Whereas cerebral A1Rs are primarily neuronal (Ochiishi et al. 1999Go), expression of A1Rs on several nonneuronal tissues, most notably in the heart (for review, see Fredholm et al. 2001Go), may confound the neuronal interpretation of TES changes induced by systemically administered DPCPX. At doses of 1.25 mg/kg, we found that DPCPX prolonged TES (Figs. 1 and 3) without altering the basal HR (Fig. 2). Furthermore, during "four-vessel occlusion" we detected a very slight sinusal bradycardia with a time course that was unaffected by DPCPX (Fig. 2). The observed decrease in HR normalized before the onset of reperfusion, resembling the transient reflex hypoxic bradycardia (Giussani et al. 1993Go) that was also found to be unaffected by DPCPX (Koos and Maeda 2001Go). Therefore we consider it unlikely that cardiovascular actions of DPCPX contributed to the prolongation of TES reported here.

During our repeated ischemia paradigm we found that 5 mg/kg DPCPX had no ECG effects prior to, or during the following 1-min cerebral ischemia; however, it led to malignant arrhythmias early during reperfusion. These cardiac effects were not detected at 1.25 mg/kg DPCPX (Fig. 2). Adenosine is a known modulator of ventricular automaticity (for review, see Hernandez and Ribeiro 1995Go). We may speculate that the high concentrations of DPCPX impaired the anti beta-adrenergic effect of adenosine and increased the ventricular vulnerability to fibrillation (Lubbe et al. 1978Go). Further investigations should be carried out to explore this antiarrhythmogenic, potentially protective, role of A1Rs in the context of cerebral ischemia.

In spite of the differences in the cardiac response, TES prolongation remained unchanged after as much as four times increase in DPCPX concentration (Fig. 2B). We recently reported, on the same ischemic model, that under energy-stress conditions (such as those occurring during rapid repeated cerebral ischemia and kainate-induced seizures), TES could be prolonged to a remarkably similar "plateau" (Ilie et al. 2006Go). Consistent with the "depletable adenosine pool hypothesis" formulated in vitro (Pearson et al. 2001Go), it is likely that the maximal TES prolongation reflects the limit in the plasticity of adenosine release during ischemia (reviewed in Pearson et al. 2003Go). Thus our simple experimental model used to investigate changes in TES may offer a new in vivo window into the ischemic adenosine release and its contribution to the electrical "shut-down" of the whole brain.


   GRANTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
The project was supported by Carol Davila University of Medicine and Pharmacy (Bucharest, Romania) and grants from Viasan National Research Program, Academy of Medical Sciences, Romania.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank T. Vladoiu for taking part in some experimental procedures and two anonymous reviewers for very constructive comments.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests and other correspondence to: M. Moldovan., Dept. of Medical Physiology, Div. of Neurophysiology, The PANUM Institute, University of Copenhagen, Blegdamsvej 3, DK 2200, Copenhagen (E-mail: M.Moldovan{at}mfi.ku.dk)


   REFERENCES
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 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
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T. P. Obrenovitch
Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia
Physiol Rev, January 1, 2008; 88(1): 211 - 247.
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