Abstract
In many brain disorders reduced binding of central benzodiazepine receptor ligands indicates irreversible neuronal damage. The data presented by Koizumi et al (2010) demonstrate that this is not the case in traumatic brain injury suggesting different pathogenetic mechanisms leading to tissue damage. The proof for this hypothesis requires further studies that should also consider thresholds of ligand binding as indicators of irreversible damage.
In their study, Koizumi et al (2010) demonstrate that reduced binding of the central benzodiazepine receptor ligand 123I-iomazenil (IMZ) can be reversible in patients with traumatic brain injury (TBI), suggesting that loss of accumulation of this tracer is not a definite sign of irreversible neuronal damage. This finding is surprising, since all previous data indicate that the central benzodiazepine receptor, which is a subunit of the postsynaptic GABAergic complex (Olsen and Tobin, 1990), is highly sensitive to damage of the neuronal membrane. Studies with radioligands for imaging the distribution of this receptor by positron emission tomography (11C-flumazenil) or single photon emission computed tomography (IMZ) have shown a reduction suggestive of neuronal loss (Pappata et al, 1988) in various brain disorders affecting predominantly cortical cells, including focal epilepsy, Alzheimer's disease, and degenerative disorders of the basal ganglia and cerebellum, but also in experimental ischemia and ischemic stroke, where it may be used to predict irreversible morphological damage early after the attack (Heiss et al, 2007).
It is difficult to explain why this concept is not valid in TBI, and the authors propose several mechanisms by which TBI is different from other brain disorders. Whereas in degenerative disorders the molecular changes might primarily affect membrane or cellular structures and thereby cause selective loss of neurons, ischemia reduces supply of oxygen and metabolic substrates and has its primary effect on those structures with the highest energy demand, which is the synaptic region. In ischemia, inhibitory postsynaptic potentials are more sensitive than excitatory postsynaptic potentials (Xu and Pulsinelli, 1994), and the alteration of gamma aminobutyric acid (GABA) transmission—GABAergic synapses are present in high concentration on cortical neurons and found in a lesser density in basal ganglia and cerebellum (Krnjevic, 1984)—is the cause of various cellular events, including changes in Cl− gradient, increase in intracellular Ca2+ concentration, reduction of adenosine triphosphate, and generation of reactive oxygen species, to name a few, which lead to synaptic disruption that can be demonstrated at the ultrastructural level before the neuronal somata are disintegrated (Garcia et al, 1997). In contrast, lack of oxygen and metabolic substrates is not the primary mechanism leading to damage in TBI, as in tissues in the vicinity of brain hemorrhages the compression of the tissue and perifocal edema are important and, as a consequence, may lead to metabolic disturbance of the GABAergic complex without irreversible damage. With reduction of pressure and perifocal edema oxygen supply is improved and metabolism might recover, receptor function is re-established, and permanent neuronal damage is prevented. However, this hypothesis requires validation in studies combining serial metabolic evaluation with assessment of receptor function and morphological imaging. In this context it will be important to establish a quantitative relationship between reduction of radiotracer accumulation/receptor binding and functional (reversible) versus irreversible neuronal damage. As in cerebral ischemia, there might be a threshold of decreased radioligand accumulation for morphological integrity (Heiss et al, 2001) as indicated by the reversibility of lesions in diffusion-weighted imaging as long as flumazenil (FMZ) binding is above the threshold.