Neurochemical Characterization of Traumatic Brain Injury in Humans

Abstract

Trauma is the leading cause of death in individuals between the ages of 1 and 44 years. And, in the case of severe head injury mortality can reach as high as 35-70%. Despite this fact, there has been little progress in the development of effective pharmacological agents to protect brain injured patients. To date, there is little data on the mechanisms involved in neuronal cellular insult after severe head injury, especially in humans. Glutamate acts both as a primary excitatory neurotransmitter and a potential neurotoxin within the mammalian brain. Evidence indicates that hyperactivity of the glutamate system contributes to neuronal death in brain trauma. Also, in animal models of neurotrauma, this neural injury is followed by gliosis which has been linked to the severity of brain injury. To investigate the glutamate system in brain trauma, we carried out [3H]glutamate and [3H]MK801 (a noncompetitive NMDA-receptor antagonist) binding and [3H]glutamate uptake assays in human cerebral cortex preparations obtained from severely brain injured and control victims. Additionally, to investigate gliosis following brain injury, we performed GFAP immunohistochemistry. There were no significant differences in [3H]glutamate binding (affinity or density of sites) between the control and head injured groups. In contrast, cerebral cortical [3H]MK801 binding revealed both a significant increase in the density of sites (Bmax) and a decrease in the dissociation constant (Kd) in the head injured group when compared to controls. There were no significant differences in [3H]glutamate uptake between groups. The injured brains presented an increased number of GFAP-positive astrocytes and more intense GFAP reaction in comparison to control brains. In the context of traumatic brain injury, our results encourage further investigation into compounds capable of selective modulation of NMDA receptor subtype in humans while also therapeutically manipulating glial cell responses following brain trauma.

Intestinal Permeability to Glucose after Experimental Traumatic Brain Injury: Effect of Gadopentetate Dimeglumine Administration

“…equilibration period, 3 H-deoxy-glucose (1 μ M), 3 H-3-O-methyl-glucose (25 nM) or 3 H-sorbitol (500 nM) were added to the mucosal chamber for 100 min. Samples (0.5 ml) were removed from the serosal chamber every 10 min.…”

“…Traumatic injury to the central nervous system is regarded as the initial step in a series of biochemical and physiopathological events that may have, as a consequence, irreversible tissue damage. Several factors are involved in this secondary injury process, including ion changes, excitatory amino acids release, formation of reactive oxygen species and metabolic energy perturbations [3,4].…”

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

“…Particularly, excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation are processes that contribute to neurological damage and impairment of neural recovery following TBI (Figure 1). In the injured brain, excitotoxicity derives from an acute increase in extracellular glutamate levels due to excessive release from depolarized neurons, leakage from neuronal and glial cells exhibiting damaged membranes, or the extravasation through a disrupted BBB [53,[62][63][64]. TBI also involves enhanced glutamatergic activity at extrasynaptic sites due to failure of glutamate uptake, gliotransmission, reverse operation of the glutamate transporters, increase in presynaptic glutamate release or increase in the number and/or stability of glutamatergic receptors [53,62,65,66].…”

Biomarcadores prognósticos no traumatismo crânio-encefálico grave

“…(8) Part of this process is mediated by the n-methil-D-aspartate (NMDA) receptor. (3,40) Calcium influx to the cell triggers reactions that, in turn, activate calcium-dependant enzymes. Caspase-3 is a member of the caspases family of the cysteine proteases that may induce apoptosis mechanisms.…”