This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Paris, A. Articles by Gressens, P. Search for Related Content PubMed PubMed Citation Articles by Paris, A. Articles by Gressens, P.

---

ANESTHETIC PHARMACOLOGY

The Effects of Dexmedetomidine on Perinatal Excitotoxic Brain Injury are Mediated by the _2A-Adrenoceptor Subtype

Andrea Paris, MD^*, Jean Mantz, MD, PhD, Peter H. Tonner, MD^*, Lutz Hein, MD, Marc Brede, MD, and Pierre Gressens, MD, PhD^||

*Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel; Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg; Department of Anaesthesia and Critical Care, University of Wuerzburg Hospitals, Germany; Hôpital Beaujon, Assistance Publique des Hôpitaux de Paris; and ||INSERM U 676 & Service de Neuropédiatrie, Hôpital Robert Debré, Paris, France

Address correspondence to Andrea Paris, MD, Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Schwanenweg 21, D-24105 Kiel, Germany. Address e-mail to paris{at}anaesthesie.uni-kiel.de.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
We performed the current study in mice lacking individual ₂-adrenoceptor subtypes to elucidate the contribution of ₂-adrenoceptor subtypes to the neuroprotective properties of dexmedetomidine in a model of perinatal excitotoxic brain injury. On postnatal Day 5, wild-type mice and mice lacking _2A-adrenoceptor (_2A-KO) or _2C-adrenoceptor subtypes (_2C-KO) were randomly assigned to receive dexmedetomidine (3 µg/kg) or phosphate-buffered saline intraperitoneally. Thirty minutes after the intraperitoneal injection, the glutamatergic agonist ibotenate (10 µg) was intracerebrally injected, producing transcortical necrosis and white matter lesions that mimic perinatal human hypoxic-like lesions. Quantification of the lesions was performed on postnatal Day 10 by histopathologic examination. Dexmedetomidine reduced mean lesion size in the cortex of wild-type mice and _2C-KO mice by 44% and 49%, respectively. Ibotenate-induced white matter lesions were reduced by 71% (wild-type mice) and 75% (_2C-KO mice) after pretreatment with dexmedetomidine. In contrast, in _2A-KO mice, dexmedetomidine did not protect against the cortical excitotoxic insult, and white matter lesions were even more pronounced (82% increase of mean lesion size). Dexmedetomidine provides potent neuroprotection in a model of perinatal excitotoxic brain damage. This effect was completely abolished in _2A-KO mice, suggesting that the neuroprotective effect is mediated via the _2A-adrenoceptor subtype.

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Perinatal brain damage potentially leading to permanent disability is a health care priority (1). Besides the concern for individuals, the need for long-term care represents an economic factor (2). The pathophysiology of cerebral damage usually differs in preterm neonates and full-term babies. Whereas the brain of premature neonates most often displays periventricular leukomalacias (white matter cystic lesions) (3), the leading cause of cerebral palsy in this population (1), cortical damage (transcortical necrosis) is more frequently observed in full-term infants (4). The hypothesized origin of perinatal brain damage is multifactorial, but increased glutamate release and consecutively triggered excitotoxic pathways seem to play a critical role, and they may present a common final pathway for several causative factors leading to perinatal neuronal damage (5).

Intracerebral injection of ibotenate, a glutamatergic agonist, in newborn mice has been used as a well-characterized murine model of excitotoxic brain lesions, displaying striking similarities to human perinatal hypoxic brain lesions (6). Ibotenate administration on postnatal Day 5, when all neurons have completed their migration into the neocortex, produces a spectrum of cortical and white matter injuries, resembling cortical damage observed more frequently in full-term babies (4) and mimicking certain types of periventricular leukomalacias most often observed in premature neonates (3). In this murine model, ₂-adrenoceptor agonists, such as dexmedetomidine, have been shown to be neuroprotective and provided a dose-dependent protection against cortical and white matter lesions (7).

Three subtypes of ₂-adrenoceptors, termed _2A, _2B, and _2C, were initially revealed by pharmacological means and were cloned from several species, including mice and humans (8). Dexmedetomidine is a highly specific ₂-adrenoceptor agonist with a high affinity to each of the ₂-adrenoceptor subtypes. The _2A-adrenoceptor subtype has been reported to be the predominant subtype in the brain and is involved in a variety of physiological functions including antinociceptive, sedative, hypotensive, hypothermic, and behavioral actions of ₂-adrenoceptor agonists (9,10). Stimulation of _2B-adrenoceptors in vascular smooth muscle leads to vasoconstriction, which causes the initial hypertension after the administration of ₂-adrenoceptor agonists (11). In addition, the _2B-adrenoceptor subtype is involved in mediation of the antinociceptive action of nitrous oxide (12) and in central thermoregulation (13). The _2C-adrenoceptor subtype has been shown to modulate dopaminergic neurotransmission, as well as various behavioral responses, and to induce hypothermia (14). In addition, this subtype contributes to spinal antinociception of the imidazoline moxonidine in mice (15).

To further characterize which of the adrenoceptor subtypes mediates the neuroprotective effect of ₂-adrenoceptor agonists, we studied the effect of dexmedetomidine in a murine model of perinatal excitotoxic brain injury in vivo in mice carrying targeted deletions of the _2A-adrenoceptor or _2C-adrenoceptor genes (8).

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Ibotenate (Sigma, St Louis, Missouri), a glutamate analog, activates both N-methyl-d-aspartate and metabotropic receptors but not the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate and kainate receptors. Dexmedetomidine (Orion Pharmos, Turku, Finland) was diluted in 0.1 M of phosphate-buffered saline (PBS), and ibotenate was diluted in PBS containing 0.02% acetic acid.

Wild-type mice and transgenic mice lacking _2A-adrenoceptor or _2C-adrenoceptor subtypes were used for the experiments. All mouse lines used in this study were maintained on a C57BL6J/OlaHsd background. For this purpose, the _2A and _2C deletions were backcrossed for >10 generations with C57BL6 wild-type mice. The generation of mouse lines lacking single ₂-adrenoceptor subtypes has been previously described (11,16). Pregnant mice were housed in groups in a specified pathogen-free facility given free access to water and food, with a 12-h light-dark cycle. The experimental protocol received approval from the IRB of the Hôpital Robert Debré (Paris, France) and complied with the guidelines of the Institut National de la Santé et de la Recherche Médicale.

Pups of both sexes from at least 2 different litters per genotype were used for experiments on postnatal Day 5. Dexmedetomidine 5 µL or PBS 5 µL was intraperitoneally injected 30 min before a stereotactic intracerebral injection of ibotenate. As previously described (6,7), pups were anesthetized using ether inhalation and maintained under a warming lamp. Intracerebral injection of ibotenate was performed using a 26-gauge needle on a 50-µL Hamilton syringe mounted on a calibrated microdispenser. The needle was inserted 2 mm under the external surface of the scalp skin in the frontoparietal area of the right hemisphere, 2 mm from the midline in the lateral-medial plane, and 3 mm from the junction of the sagittal and lambdoid sutures in the rostrocaudal plane. Histological analysis from previous experiments in >1500 animals confirmed that this technique results in highly reproducible injections (6,7). Two 1-µL boluses were injected 30 s apart into the cortex and into the periventricular white matter. The needle was left in place for 30 s after the second bolus. After the injection, the pups were allowed to return to their dams.

Wild-type mice, transgenic mice lacking _2A-adrenoceptor subtypes (_2A-KO), and mice lacking _2C-adrenoceptor subtypes (_2C-KO) were used. In all experimental groups, a stereotactic intracerebral injection of ibotenate (10 µg) was given on postnatal Day 5. Thirty minutes before intracerebral injection, pups were randomly assigned to receive an intraperitoneal injection (5 µL) of dexmedetomidine (3 µg/kg of body weight) or PBS. Eight to 32 pups from at least 2 different litters were used in each experimental group. The numbers of pups used in each experimental group are given in Figure 1.

View larger version (29K): [in this window] [in a new window]   Figure 1. Quantitative analysis of ibotenate-induced cortical and white matter lesions in wild-type mice (WT) and mice lacking 2A-adrenoceptor ( 2-A) or 2C-adrenoceptor ( 2-C) subtypes. Bars represent mean lesion size along the sagittal frontooccipital axis ± sem in animals treated with phosphate-buffered saline (PBS; filled bars) or dexmedetomidine (3 µg/kg; open bars). Numbers in parentheses represent the numbers of pups used in each experimental group. *P < 0.05 versus pretreatment with PBS in Mann-Whitney test.

On postnatal Day 10, surviving pups were killed by decapitation. Brains were removed, fixed in 4% formalin for 7 days, and embedded in paraffin subsequently. Coronal serial sections, 15-µm thick, were cut along the entire brain from the frontal to the occipital pole, and every third section was stained with cresyl violet. In theory, neocortical and white matter lesions can be defined based on the maximal length in three orthogonal axes: the lateral-medial axis (in the coronal plane), the radial axis (also in the coronal plane, from the pial surface to the lateral ventricle), and the frontooccipital axis (in the sagittal plane). In preliminary studies, there was a high correlation between the maximal size of the lateral-medial, radial, and frontooccipital diameters of the ibotenate-induced lesions (6). Based on these findings, the entire brain was serially sectioned in the coronal plane. This permitted an accurate and reproducible measurement of the maximal sagittal frontooccipital diameter of the lesion. The number of sections demonstrating the lesion, multiplied by 15 µm, served as an index of the lesion size. Lesion size determination was performed in a blinded manner by an investigator unaware of the experimental group to which the animal was assigned.

Data are presented as mean ± sem. Kruskal-Wallis nonparametric analysis of variance was used to analyze effects between different genotypes given the same pretreatment (dexmedetomidine or PBS, respectively). The Mann-Whitney test was used to compare pups treated with ibotenate + dexmedetomidine with pups of the same genotype but treated with ibotenate + PBS. A value of P < 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Overall mortality was low in the present study, with <3% of the pups injected with ibotenate. No significant difference was observed in a test of contingency (Fisher Exact test) when the different experimental groups were compared with wild-type mice.

The stereotactic, intracerebral injection of ibotenate caused dramatic cortical lesions characterized by loss of neurons affecting all cortical layers and large periventricular white matter cysts (Fig. 2).

View larger version (157K): [in this window] [in a new window]   Figure 2. Influence of dexmedetomidine on ibotenate-induced lesions in wild-type mice (A and B) and mice lacking 2A-adrenoceptor (2A-KO mice) subtypes (C and D). Cresyl violet-stained sections show brain lesions induced by intracerebral injection of the glutamatergic agonist ibotenate on postnatal Day 5 and histopathological examination on postnatal Day 10. (A) Brains of wild-type mice and (C) 2A-KO mice injected with ibotenate and pretreatment with phosphate-buffered saline (PBS) show typical transcortical necrosis (arrow) and white-matter lesions (*). (B) Pretreatment with dexmedetomidine in wild-type mice and (D) 2A-KO mice. Bar = 40 µm.

In wild-type pups injected with intraperitoneal PBS and intracerebral ibotenate, the mean cortical lesion size was 898 ± 56 µm (Fig. 1). Comparable cortical lesion size was found in the brains of _2A-KO mice (816 ± 55 µm) and _2C-KO mice (815 ± 64 µm) pretreated with PBS. When compared with PBS-pretreated controls, pretreatment with dexmedetomidine significantly reduced mean cortical lesion size in wild-type mice by 44% (500 ± 39 µm; P < 0.05) and in _2C-KO mice by 49% (418 ± 69 µm; P < 0.05). In contrast, dexmedetomidine did not significantly reduce mean cortical lesion size in _2A-KO mice (772 ± 71 µm).

In pups pretreated with PBS, ibotenate-induced white matter lesion size did not differ between groups and was 590 ± 52 µm in wild-type mice, 384 ± 60 µm in _2A-KO mice, and 530 ± 57 µm in _2C-KO mice. When compared with PBS-pretreated controls, pretreatment with dexmedetomidine significantly reduced mean white matter lesion size in wild-type mice by 71% (170 ± 44 µm; P < 0.05) and in _2C-KO mice by 75% (134 ± 39 µm; P < 0.05). In contrast, pretreatment with dexmedetomidine did not afford neuroprotection but significantly increased mean white matter lesion size in _2A-KO mice by 82% (701 ± 97 µm; P < 0.05).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In wild-type mice and mice lacking _2C-adrenoceptor subtypes, dexmedetomidine potently protects the developing brain from transcortical necrosis and white matter lesions induced by intracerebral injection of the glutamatergic agonist ibotenate in newborn mice. In contrast, dexmedetomidine did not prevent excitotoxic cortical neuronal loss and produced even more pronounced white matter cystic lesions in mice lacking the _2A-adrenoceptor subtype.

Dexmedetomidine has neuroprotective properties in various experimental designs, mainly conducted as models of cerebral ischemia in adult animals (17). Moreover, it was effective in a model of excitotoxic neuronal injury protecting against kainic acid-induced neuronal damage (18). However, there are only few models investigating neuroprotective properties of ₂-adrenoceptor agonists in developing brains that are highly susceptible to neuronal damage. In neonatal rats, dexmedetomidine (19) attenuated hypoxic-ischemic brain injury. Previous studies in our murine model of perinatal excitotoxic brain injury revealed that clonidine and dexmedetomidine provided potent neuroprotection (7). However, the respective contribution of ₂-adrenoceptor subtypes has not yet been determined. Therefore, we studied wild-type mice and transgenic mice lacking single ₂-adrenoceptor subtypes (11,16) to elucidate the contributions of different ₂-adrenoceptor subtypes to the neuroprotective effect of dexmedetomidine in this model of excitotoxic perinatal brain injury. We confirmed the neuroprotective properties of dexmedetomidine in wild-type mice and _2C-KO mice. In contrast, the neuroprotective effects of dexmedetomidine were completely abolished in _2A-KO mice, suggesting that the neuroprotective properties of dexmedetomidine are mediated by the _2A-adrenoceptor subtype.

These results are in accordance with the results of Ma et al. (19). In vitro dexmedetomidine did not exert a protective effect on neuronal injury (exposure to oxygen and glucose deprivation) in mixed neuronal-glial cultures derived from transgenic mice (D79N) expressing dysfunctional _2A-adrenoceptors. In a model of neonatal hypoxia-ischemia in vivo, the dose-dependent protection against brain matter loss by dexmedetomidine was reversed by an _2A-adrenoceptor subtype-preferring antagonist (BRL44408) (19). However, ₂-adrenoceptor antagonists lack high subtype specificity. Thus, the results of the present in vivo study in _2A-KO mice present an important confirmation of the crucial role of the _2A-adrenoceptor subtype in mediating neuroprotective effects of ₂-adrenoceptor agonists.

We used a well-characterized murine model of excitotoxic brain injury displaying remarkable histopathological similarities to human neuronal injuries described after hypoxia occurring in human fetuses and neonates (6). Several drugs including ₂-adrenoceptor agonists have been shown to be neuroprotective in this model and provided insight into the pathophysiology of neuronal damage and neuroprotection in the developing brain (7). However, the exact mechanisms of ₂-adrenoceptor-mediated neuroprotection still remain unclear. Studies using models of cerebral ischemia showed that a massive release of glutamate and catecholamines during ischemia may play a key role in ischemic neurologic damage (17,20). An in vivo positive correlation between circulating norepinephrine and neurologic outcome was revealed after cerebral ischemia (17,21). ₂-adrenoceptors modulate neurotransmitter release in the central and peripheral sympathetic nervous system (16), and genetic mouse models indicate that the _2A-adrenoceptor subtype is the major subtype regulating sympathetic neurotransmission (8,16), thus offering a possible explanation for the neuroprotective properties of dexmedetomidine. Furthermore, in vitro ₂-adrenoceptor agonists were able to reduce hypoxia-evoked glutamate release from hippocampal slices (22). In contrast, in an in vivo model of cerebral ischemia, dexmedetomidine failed to suppress brain norepinephrine and glutamate concentrations (23). However, these findings cannot be simply extrapolated to our model of excitotoxic brain lesions. Even if a secondary release of catecholamines and glutamate, triggered by excitotoxic brain damage in our model, seems likely, the initial intracerebral injection of the glutamatergic analog ibotenate may directly activate local N-methyl-d-aspartate receptors (7). Thus, the mechanism of neuroprotection by ₂-adrenoceptor agonists may differ depending on experimental design.

There are some limitations to our study. We did not investigate mice lacking _2B-adrenoceptor subtypes. At present, _2B-adrenoceptor–deficient mice cannot be maintained on a congenic C57BL6 background because of embryonic lethality of homozygous _2B-KO mice (Hein and Brede, unpublished observation). To avoid developmental effects or influences of mixed genetic backgrounds, we chose not to include _2B-KO mice in this study. Each subtype has a distinct tissue distribution. In the brain, the _2A-adrenoceptor is the predominant receptor subtype and can be found ubiquitously. Disruption of the _2A-adrenoceptor gene resulted in a 90% reduction in total ₂-adrenoceptor binding in mouse brains (16). Residual binding can primarily be attributed to the _2C-adrenoceptor subtype found in basal ganglia, olfactory tubercle, hippocampus, and cerebral cortex, whereas the distribution of the _2B-adrenoceptor subtype in the brain is quite limited and mainly restricted to the thalamic nuclei (8,9,16); however, species differences have been described. Moreover, the _2A-adrenoceptor is the major subtype regulating sympathetic neurotransmission and mediating sedative and antinociceptive effects (8,9,16). Therefore, it seems unlikely that _2B-adrenoceptors contribute substantially to the neuroprotective effect of ₂-adrenoceptor agonists. Consistently, in the current study, the neuroprotective action of dexmedetomidine was completely abolished in _2A-KO mice, indicating that _2B-adrenoceptors are not involved in neuroprotection.

In the current study, it was found that white matter lesions were even more pronounced after dexmedetomidine in _2A-KO mice. The reason for this finding is unclear. The dexmedetomidine dose we used provided potent neuroprotective effects on excitotoxic brain injury in previous investigations (7). Dexmedetomidine displayed a U-shaped dose-response curve showing decreasing neuroprotective properties with large doses (7,18,19). After permanent occlusion of the middle cerebral artery in the rat, large doses of dexmedetomidine were reported to worsen outcome (24). However, studies in neuronal and glial co-cultures from D79N transgenic mice expressing dysfunctional _2A-adrenoceptors did not report any direct neurotoxic-like effects of dexmedetomidine (19). Studies in _2A-deficient mice have shown that dexmedetomidine resulted in a pronounced initial hypertension accompanied by a reduction in heart rate, whereas the hypotensive effect of dexmedetomidine was completely absent (16). _2A-adrenoceptors are the predominant subtypes involved in the sedative, antinociceptive, and hypothermic effects of dexmedetomidine (9,16). Consequently, dexmedetomidine may cause complex changes in physiological pathways possibly harmful or beneficial in cases of neuronal damage. Additionally, previous studies in this model of neonatal excitotoxic brain injury strongly suggest that ibotenate-induced white matter and cortical lesions develop independently from each other and may differ with respect to their pathophysiology (25).

Another limitation and a common criticism of studies in transgenic mice is the possible induction of compensatory mechanisms that are not operational in wild-type mice, and that may mask the functional results of a targeted mutation. Accordingly, such influences cannot be excluded in the present study. However, studies using pharmacological approaches and studies in transgenic mice can complement each other, although both strategies have their own drawbacks. The fact that the results of our study are in accordance with other studies using pharmacological approaches (19) clearly suggests a key role for the _2A-adrenoceptor subtype in the neuroprotective action of dexmedetomidine.

In conclusion, in a model of neonatal excitotoxic brain damage, dexmedetomidine exerts potent neuroprotection in wild-type and _2C-KO mice but not in _2A-KO mice, suggesting that this effect is mediated via the _2A-adrenoceptor subtype.

	Footnotes

 
Accepted for publication September 20, 2005.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Hagberg B, Hagberg G. The changing panorama of cerebral palsy: bilateral spastic forms in particular. Acta Paediatr Suppl 1996;416:48–52.[Medline]
2. Centers for Disease Control and Prevention. Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment: United States, 2003. MMWR Morb Mortal Wkly Rep 2004;53:57–9.[Medline]
3. Zupan V, Gonzalez P, Lacaze-Masmonteil T, et al. Periventricular leukomalacia: risk factors revisited. Dev Med Child Neurol 1996;38:1061–7.[Web of Science][Medline]
4. Volpe JJ. Perinatal hypoxic-ischemic brain injury: an overview. In: Fukuyama Y, Suzuki Y, Kamoshita S, Caesaer P, eds. Fetal and perinatal neurology. Basel, Switzerland: Karger, 1992:232–52.
5. McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Brain Res Rev 1990;15:41–70.[Medline]
6. Marret S, Mukendi R, Gadisseux JF, et al. Effect of ibotenate on brain development: an excitotoxic mouse model of microgyria and posthypoxic-like lesions. J Neuropathol Exp Neurol 1995;54:358–70.[Web of Science][Medline]
7. Laudenbach V, Mantz J, Lagercrantz H, et al. Effects of alpha(2)-adrenoceptor agonists on perinatal excitotoxic brain injury: comparison of clonidine and dexmedetomidine. Anesthesiology 2002;96:134–41.[Web of Science][Medline]
8. Hein L, Limbird LE, Eglen RM, Kobilka BK. Gene substitution/knockout to delineate the role of alpha2-adrenoceptor subtypes in mediating central effects of catecholamines and imidazolines. Ann N Y Acad Sci 1999;881:265–71.[Web of Science][Medline]
9. Hunter JC, Fontana DJ, Hedley LR, et al. Assessment of the role of alpha2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Br J Pharmacol 1997;122:1339–44.[Web of Science][Medline]
10. MacMillan LB, Hein L, Smith MS, et al. Central hypotensive effects of the alpha2a-adrenergic receptor subtype. Science 1996;273:801–3.[Abstract]
11. Link RE, Desai K, Hein L, et al. Cardiovascular regulation in mice lacking alpha2-adrenergic receptor subtypes b and c. Science 1996;273:803–5.[Abstract]
12. Sawamura S, Kingery WS, Davies MF, et al. Antinociceptive action of nitrous oxide is mediated by stimulation of noradrenergic neurons in the brainstem and activation of [alpha]2B adrenoceptors. J Neurosci 2000;20:9242–51.[Abstract/Free Full Text]
13. Paris A, Ohlendorf C, Marquardt M, et al. Effect of meperidine on thermoregulation in mice: involvement of alpha2-adrenoceptors. Anesth Analg 2005;100:102–6.[Abstract/Free Full Text]
14. Sallinen J, Link RE, Haapalinna A, et al. Genetic alteration of the alpha2C-adrenoceptor expression in mice: influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective alpha 2-adrenoceptor agonist. Mol Pharmacol 1997;51:36–46.[Abstract/Free Full Text]
15. Fairbanks CA, Stone LS, Kitto KF, et al. alpha(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther 2002;300:282–90.[Abstract/Free Full Text]
16. Altman JD, Trendelenburg AU, MacMillan L, et al. Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice. Mol Pharmacol 1999;56:154–61.[Abstract/Free Full Text]
17. Hoffman WE, Kochs E, Werner C, et al. Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat: reversal by the alpha 2-adrenergic antagonist atipamezole. Anesthesiology 1991;75:328–32.[Web of Science][Medline]
18. Halonen T, Kotti T, Tuunanen J, et al. Alpha 2-adrenoceptor agonist, dexmedetomidine, protects against kainic acid-induced convulsions and neuronal damage. Brain Res 1995;693:217–24.[Web of Science][Medline]
19. Ma D, Hossain M, Rajakumaraswamy N, et al. Dexmedetomidine produces its neuroprotective effect via the alpha2A-adrenoceptor subtype. Eur J Pharmacol 2004;502:87–97.[Web of Science][Medline]
20. Werner C, Hoffman WE, Thomas C, et al. Ganglionic blockade improves neurologic outcome from incomplete ischemia in rats: partial reversal by exogenous catecholamines. Anesthesiology 1990;73:923–9.[Web of Science][Medline]
21. Hoffman WE, Cheng MA, Thomas C, et al. Clonidine decreases plasma catecholamines and improves outcome from incomplete ischemia in the rat. Anesth Analg 1991;73:460–4.[Abstract/Free Full Text]
22. Talke P, Bickler PE. Effects of dexmedetomidine on hypoxia-evoked glutamate release and glutamate receptor activity in hippocampal slices. Anesthesiology 1996;85:551–7.[Web of Science][Medline]
23. Engelhard K, Werner C, Kaspar S, et al. Effect of the alpha2-agonist dexmedetomidine on cerebral neurotransmitter concentrations during cerebral ischemia in rats. Anesthesiology 2002;96:450–7.[Web of Science][Medline]
24. Kuhmonen J, Haapalinna A, Sivenius J. Effects of dexmedetomidine after transient and permanent occlusion of the middle cerebral artery in the rat. J Neural Transm 2001;108:261–71.[Web of Science][Medline]
25. Tahraoui SL, Marret S, Bodenant C, et al.. Central role of microglia in neonatal excitotoxic lesions of the murine periventricular white matter. Brain Pathol 2001;11:56–71.[Web of Science][Medline]

This article has been cited by other articles:

				M. A. Nikolaeva, S. Richard, A. Mouihate, and P. K. Stys Effects of the Noradrenergic System in Rat White Matter Exposed to Oxygen-Glucose Deprivation In Vitro J. Neurosci., February 11, 2009; 29(6): 1796 - 1804. [Abstract] [Full Text] [PDF]

				R. D. Sanders, D. Ma, P. Brooks, and M. Maze Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity Br. J. Anaesth., November 1, 2008; 101(5): 597 - 609. [Abstract] [Full Text] [PDF]

				R. D. Sanders and M. Maze Translational Research: Addressing Problems Facing the Anesthesiologist Anesth. Analg., October 1, 2007; 105(4): 899 - 901. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Paris, A. Articles by Gressens, P. Search for Related Content PubMed PubMed Citation Articles by Paris, A. Articles by Gressens, P.