Artikel
Induction of GLT-1 by ceftriaxone reduces neuronal activity and affects neurometabolic coupling of cortical glutamate clearance in isoflurane-anaesthetized rats
Die Ceftriaxon-vermittelte Induktion von GLT-1 vermindert neuronale Spontanaktivität und beeinflusst die neurometabolische Kopplung der Glutamat-Clearance in Isofluran-anaesthesierten Ratten
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Veröffentlicht: | 11. April 2007 |
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Objective: Excessive glutamate concentrations may lead to excitotoxic secondary brain injury. Physiological extracellular concentrations of glutamate are maintained by active transport through glial membrane proteins, e.g. GLT-1. Betalactam-antibiotics, such as ceftriaxone (CTX) are known to increase GLT-1 expression in vivo. Does this mechanism improve cerebral glutamate clearance and associated neurometabolism?
Methods: In total, 35 male Sprague-Dawley rats (317±35g) were pretreated over 5 days, receiving either CTX (200mg/kg/d, i.p.) or saline. Through a craniotomy window, a microdialysis catheter (CMA/12, 2mm, 100kD) was inserted into non-traumatized tissue. In reverse microdialysis-technique, 35µM glutamate followed by 10-1000µM DL-threo-beta-benzyloxyaspartate (DL-TBOA; non-competetive GLT-1 antagonist) was infused cortically. Twenty-minute samples were collected and e.c. concentrations of glutamate, glucose, lactate and pyruvate were determine ed byspectrophotometry. Systemic blood pressure, arterial blood gases, core temperature and EEG were monitored continuously. Differences were assumed to be significant at p<0.05.
Results: The vital signs remained stable in all animals. Under similar levels of anaesthesia, alpha- and beta-EEG-activity was reduced in the treatment group (p<0.05). Glutamate infusion increased EEG-activity in control animals, an effect seen with DL-TBOA only in the CTX group. In both groups cortical glutamate was cleared completely, though associated glycolysis was lower in pretreated animals (e.c. lactate: 119±19 vs 106±17%, p<0.1). In these, anaerobic metabolism was increased upon DL-TBOA (lactate/pyruvate-ratio: 135±13 vs 88±11%, p<0.05).
Conclusions: CTX-induced expression of GLT-1 reduces neuronal activity, responsiveness to cortical glutamate infusion and neurometabolic coupling of glutamate-clearance in isoflurane-anaesthetized rats. Whether this mechanism results in post-traumatic neuroprotection is currently being investigated.