Increases in GABA concentrations during cerebral ischaemia: a microdialysis study of extracellular amino acids

The excitatory amino acids glutamate and aspartate are thought to play an important part in the pathogenesis of neuronal damage and death in acute cerebral ischaemia. ^{1- 9} In association with reduced oxygen and substrate (glucose) delivery and increased production of protons and lactate, excessive accumulation of these amino acids results in potential pathological activation of receptors and increased calcium entry into cells. Cytoplasm swelling, mitochondrial dysfunction, and membrane disintegration occur, culminating in cell death. These processes were initially demonstrated in animal models and are currently undergoing investigation in humans. Microdialysis is currently being applied to monitor the extracellular chemistry of the brain of neurosurgical patients. ^{10- 17} Studies in patients with head injury and subarachnoid haemorrhage have disclosed increases of the extracellular concentrations of excitatory amino acids in response to secondary ischaemic events such as intracranial hypertension, systemic hypotension, seizures, and contusions. ^{11- 13, 16, 18- 20}

By contrast, less attention has been applied to the inhibitory amino acids, notably [GAMMA]-aminobutyric acid (GABA), despite experimental studies of cerebral ischaemia showing that glutamate and aspartate rises may be accompanied by changes in the concentration of other amino acids ^{21- 36} and increases in GABA concentrations in the CSF of patients with head injury. ³⁷ Although GABA was measured in the first reported human brain microdialysis study performed during thalamotomy ³⁸ and changes in GABA concentrations have been shown during seizures, ^{16, 39} after trauma, ⁴⁰ and in lobectomy models of ischaemia, ^{41, 42} clinical microdialysis studies have concentrated on the excitatory amino acids.

The objective of this study was to apply microdialysis to measure the extracellular concentrations of inhibitory, excitatory, and non-transmitter amino acids in patients at risk of cerebral ischaemia after head injury and subarachnoid haemorrhage. We aimed to establish normal values of amino acids under basal conditions and changes in concentrations during episodes of cerebral ischaemia.

METHODS

Patient selection

The study was approved by the local research ethics committee and consent was obtained from the patient or next of kin. Patients with severe head injury and subarachnoid haemorrhage were eligible. Patients with severe head injury were monitored on the neurointensive care unit. Those with aneurysmal subarachnoid haemorrhage were monitored during aneurysm clipping in the operating theatre, and were preselected on the basis of...