Research reportNeuroprotection of S(+) ketamine isomer in global forebrain ischemia
Introduction
Focal and global cerebral ischemia are critical events in many clinical situations, such as stroke, cardiac arrest, and cerebral trauma [39]. There is ample evidence that glutamate and other excitatory amino acids are at least partly responsible for the selective neuronal death after cerebral ischemia/anoxia [12], [20], [25], [30]. Glutamate is an excitatory neurotransmitter in the central nervous system (CNS) [20], [30]. Three ionotropic subtypes of the glutamate receptors have been identified: N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate [25]. Energy depletion after brain ischemia results in an increased synaptic release and decreased cellular reuptake of glutamate [20], [29]. The accumulation and interaction of glutamate with its receptors contributes to a variety of pathological processes such as intracellular sodium/calcium influx, cellular swelling, and activation of enzymes, that catalyze the breakdown of proteins, lipids and nucleic acids leading to neuronal death [12], [41]. Therefore, antagonists of the NMDA receptor are thought to be an effective therapeutic approach in the treatment of secondary neuronal injury after cerebral ischemia. However, despite numerous experimental studies investigating different substances [19], [22], [41], ketamine and dextrorphan are currently the only clinically available NMDA antagonists. Ketamine hydrochloride is an established dissociative anesthetic used in selected clinical procedures for over 25 years [13]. Ketamine interacts with the phencyclidine (PCP) binding site which is located in the NMDA receptor associated ion-channel [1]. It inhibits the influx of Na+ and Ca2+ cations through this channel thus noncompetitively antagonizing the actions of NMDA agonists like glutamate [1], [7], [17]. There is evidence that ketamine-induced anesthesia is in part mediated by the interaction with the NMDA receptor complex [17], [44]. This pharmacological action could provide therapeutical benefit in the treatment of glutamate induced mediated neuronal injury after cerebral ischemia. Ketamine has been shown to protect neurons from NMDA induced damage in vivo after ischemia [1], [7], [16], [27], seizures [8], cerebral trauma [38] and after intracerebroventricular injection of excitotoxins [22], [23], [24] as well as in vitro [1], [15]. However, unlike other anesthetics, which are CNS depressants, ketamine is reported to increase cerebral metabolism, with subsequent increase of local glucose utilization, cerebral blood volume and cerebrospinal fluid (CSF) pressure [3]. Thus, the overall effects of ketamine might reflect an interplay between the parenchymal neuroprotective effects and its prometabolic action [5]. Because of its chiral center at the C2 atom of the cyclohexanone ring, ketamine exists as two isomers, the R(−) and the S(+) form [28], [36]. The S(+) isomer shows approximately 2–3 times higher analgetic and hypnotic potency than the R(−) isomer [15], [26]. Furthermore it has been shown that certain locomotor and psychomimetic side effects are less intense in the S(+) form [36], [42], [43] and the therapeutic index is greater compared with the racemate [28], [42]. As recently demonstrated, S(+) ketamine also has a higher neuroprotective potency in vitro against NMDA-induced injury compared with the racemate and the S(−) form and can induce neuronal regeneration after axonal transection [15], [45]. However, no studies evaluating the potential neuroprotective effects of the S(+) isomer in vivo have been performed so far. The purpose of the current study is to determine the differences in the neuroprotective properties of the ketamine isomers in vivo in a rat model of global forebrain ischemia induced by hypobaric hypotension. To assess the potential prometabolic effects of ketamine and its influence on cerebral microperfusion and oxygenation the present study was carried out with special focus on cerebral blood flow, cortical oxygen saturation, functional and histopathological outcome.
Section snippets
Animals
30 adult male Wistar rats weighing 401±68.0 g (mean±S.D.) were used. The animals were housed at constant temperature and humidity with free access to food and water.
Ketamine stereoisomer
The substance was obtained as sterile dry powder (Parke Davis, Detroit, MI, USA). The solution was prepared freshly before injection in sterile saline and the pH was adjusted to 7.0. S(+) ketamine was given in three different dosages 30, 60, 90 mg/kg body weight (groups A, B, C), group D received 90 mg/kg of the R(−) ketamine, the
Results
All experimental animals included in the study had physiologic baseline parameters (pO2=93.4±4.8 mmHg; pCO2=39.2±1.5 mmHg, SO2=96.2±0.3%, pHa=7.35±0.01, MAP=74.9±2.8 mmHg). The baseline rCBF value before induction of cerebral ischemia was 37.06±3.97 LDU. No significant difference between the baseline values of the different treatment groups was observed (P>0.05, Fig. 1a). During cerebral ischemia the CBF values dropped significantly to 10.43±1.11 LDU (P<0.001). The treatment groups showed no
Discussion
In the present study we compared the potential neuroprotective effects of different dosages of S(+) ketamine and of the stereoisomer R(−) ketamine given after global forebrain ischemia. Although no significant neuronal protection could be observed in the hippocampus, S(+) ketamine significantly reduced neuronal cell loss in the cortex. The R(−) stereoisomer did not induce this effect.
Several studies demonstrated neuronal protection by ketamine after global or focal brain ischemia [7], [16]. In
Acknowledgements
The excellent assistance by Andrea Schollmayer, Michael Malzahn and Laszlo Kopacz is gratefully acknowledged.
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Present address: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.