Ceftriaxone Treatment of TBI

Traumatic Brain Injury and Glutamate Excitotoxicity

Traumatic brain injury (TBI) is among the most common causes of morbidity and mortality in the USA across all age groups ( ). Beyond the mechanical injury, TBI triggers a cascade of biochemical events that, while incompletely understood, offers prospects for therapeutic intervention. Among such posttraumatic consequences is disruption of glutamate homeostasis and glutamate excitotoxicity. Progressively increasing levels of extracellular glutamate leaking from dead and dying neurons in the acute and subacute posttraumatic period ( ), coupled with downregulation of glial membrane glutamate transporters in the lesional cortex ( ), lead to the overexcitation of neurons and increased intracellular calcium via calcium-permeable glutamate receptors. Calcium accumulation in turn impacts mitochondrial function and causes increased caspase activation, radical oxygen species (ROS) release, and oxidative injury ( ), eventually leading to cell death. This excitotoxic cycle appears causally related to a range of posttraumatic symptoms, including posttraumatic epilepsy (PTE) as seen by epileptogenic cortical changes that follow TBI ( ).

Long-term posttraumatic sequelae, such as PTE and mnemonic disability are common TBI complications ( ) and are due in large part to neuronal and synaptic dysfunction that is delayed from the time of injury by prolonged time periods ( ). For instance, in human patients and in animal PTE models, epilepsy does not immediately follow TBI. Rather, spontaneous posttraumatic seizures follow a several-week-long seizure-free “latent period” of posttraumatic epileptogenesis ( ). Notably, prospective trials of PTE prophylaxis with common antiepileptic drugs have consistently failed to find an antiepileptogenic benefit ( ) and thus mitigating glutamate excitotoxicity in the latent period is a major area of interest.

Like many aspects of TBI biology, posttraumatic epileptogenesis is incompletely described at the cellular level. However, some aspects appear well-coupled to aberrant posttraumatic glutamate handling. For instance, delayed neuronal apoptosis and exaggerated long-term potentiation of glutamatergic synapses appear to contribute to both PTE and related neurocognitive symptoms. A proximal mechanism for these may be excitotoxic activation of the N -methyl- d -aspartate (NMDA)-type receptor (NMDAR) by free glutamate; and NMDAR-mediated intracellular signaling that leads to transcription genes related to synaptic plasticity and apoptosis appears to be a critical step toward long-term neurodegeneration and abnormal synaptic plasticity that follows TBI ( ).

Glutamate Physiology and Homeostasis

Glutamate is critical for normal brain function ( ). It is synthesized from glutamine in glutamatergic neurons and then stored in presynaptic vesicles. Glutamate release from the vesicles into the synaptic cleft is triggered by calcium influx via voltage-gated ion channels ( ). It is then actively removed from the synapse by astrocytes through membrane transporters ( ), before being converted to glutamine by glutamine synthase and shuttled back to neurons ( Fig. 15.1A ) ( ).

Glutamate acts on both ionotropic (NMDA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainite) and metabotropic G protein-coupled receptors, prompting intracellular signaling cascades. NMDARs are glutamate-regulated calcium channels that require the binding of glutamate as well as postsynaptic membrane depolarization to remove the magnesium ion blocks the channel at rest, to allow calcium ion influx ( ). Activation of NMDARs and calcium-permeable AMPA receptors (AMPARs) in particular leads to intracellular signaling that promotes potentiation of excitatory synaptic strength, and, if in excess, also triggers apoptotic neuronal death ( ).

Precise control of extracellular glutamate levels is essential for normal synaptic function and for protection against excitotoxicity. Extracellular mechanisms for the enzymatic deactivation of glutamate have not been identified, and so excitatory amino acid transporters (EAAT1–5 in humans) provide the only known endogenous mechanism for rapid glutamate clearance in mammals, by shunting it into the intracellular space ( ).

Glutamate transporter 1 (GLT-1), the rodent analog of human excitatory amino acid 2 (EAAT2), provides 95% of the total glutamate clearance capacity in the mammalian brain ( ). It is a sodium-dependent transmembrane protein that relies on ion gradients across cell membranes generated primarily by the Na/K ATPase as the driving force for glutamate uptake and is present predominantly on glial membranes but is also expressed in oligodendrocytes, presynaptic neuronal terminals, and dendritic spines ( ). GLT-1 (EAAT2) is highly expressed and accounts for as much as 1% of total brain protein ( ).

Astrocytic glutamate transport (hereafter we will use the term GLT-1, as more basic research has been done in rodents than in humans) thus constitutes a powerful mechanism protecting the normal brain from glutamate excitotoxicity. For instance, astrocyte-rich neuronal cultures survive exposure to much higher concentrations of glutamate as compared to astrocyte-poor cultures and both cultures are equally vulnerable to injury after glutamate uptake is blocked ( ). Antisense knockdown of GLT-1 also worsens hippocampal neuronal survival a week after controlled cortical impact (CCI) injury ( ). Loss of glutamate transporters is also associated with neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) ( ), Alzheimer’s disease ( ), and an experimental model of Huntington’s disease ( ).