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Introduction
Traumatic brain injury (TBI), a major public health problem globally, is the leading cause of mortality and morbidity in adults and children (1). TBI is caused by primary as well as secondary injury mechanisms. Primary damage is as a result of mechanical factors immediately following trauma, while secondary injury is produced by complicating processes which are initiated at the moment of impact but do not present clinically for a period of time. Moreover, TBI induces an amount of inflammatory responses that are believed to participate in the pathogenesis of secondary injury (2). In particular, these inflammatory responses incorporate the upregulation of adhesion cytokines, permeation of neutro-phils and macrophages as well as activation of glia and neurons (3). Tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and IL-6 are crucial pro-inflammatory cytokines involved in the in flammatory responses after TBI (4–6). In the serum and cerebral spinal fluid of TBI patients and in brain parenchyma of animals with experimental brain injuries, elevated levels of these cytokines have been detected (7–9). In spite of the potential pathophysiological function of these cytokines in TBI, their role has remained controversial. Evidence from animal experiments has implied that in the initial post-trauma period, elevated levels of TNF-α, IL-1β and IL-6 are harmful, and suppressing the expression of these cytokines may reduce tissue damage and brain edema, and improve the functional outcome (3,10).
Furthermore, multiple previous studies have shown that glutamate is the major excitatory neurotransmitter in the brain (2,11). Accumulation of additional extracellular glutamate and succeeding overstimulation of glutamatergic receptors increases the production of excitotoxic oxygen/nitrogen species, which induce oxidative stress resulting in neuronal death (12). Moreover, high-affinity glutamate transporters are able to clear the majority of the glutamate from the extracellular space under physiological conditions (13). There are five different proteins within the glutamate transporter family in the mammalian central nervous system (13). Excitatory amino acid transporter (EAAT)1 and EAAT2, known as glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1), respectively, are predominantly expressed in astrocytes and account for 80% of the total glutamate uptake in the brain (14). The potential of GLAST and GLT-1 to limit extracellular glutamate levels makes them a potential target in diseases associated with glutamate excitotoxicity (11,15). Therefore, a pharmacological approach aimed at increasing glutamate...