Pathobiology Of Traumatic Brain Injury Research Articles

Spectrin breakdown products in the cerebrospinal fluid in severe head injury – preliminary observations

Calcium-induced proteolytic processes are considered key players in the progressive pathobiology of traumatic brain injury (TBI). Activation of calpain and caspases after TBI leads to the cleavage of cytoskeletal proteins such as non-erythroid alpha II-spectrin. Recent reports demonstrate that the levels of spectrin and spectrin breakdown products (SBDPs) are elevated in vitro after mechanical injury, in the cerebrospinal fluid (CSF) and brain tissue following experimental TBI, and in human brain tissue after TBI. This study was initiated to detect spectrin and SBDP accumulation in the ventricular CSF of 12 severe TBI-patients with raised intracranial pressure (ICP). Nine patients with non-traumatically elevated ICP and 5 undergoing diagnostic lumbar puncture (LP) served as controls. Intact spectrin and calpain and caspase specific SBDPs in CSF collected once a day over a several day period were assessed via Western blot analysis. Parameters of severity and outcome such as ICP, Glasgow Coma Scale and Glasgow Outcome Scale were also monitored in order to reveal a potential correlation between these CSF markers and clinical parameters. In control patients undergone LP no immunoreactivity was detected. Non-erythroid alpha-II-spectrin and SBDP occurred more frequently and their level was significantly higher in the CSF of TBI patients than in other pathological conditions associated with raised ICP. Those TBI patients followed for several days post-injury revealed a consistent temporal pattern for protein accumulation with the highest level achieved on the 2(nd) -3(rd) days after TBI. Elevation of calpain and caspase specific SBDPs is a significant finding in TBI patients indicating that intact brain spectrin- and SBDP-levels are closely associated with the specific neurochemical processes evoked by TBI. The results strongly support the potential utility of these surrogate markers in the clinical monitoring of patients with severe TBI and provide further evidence of the role of calcium-induced, calpain- and caspase-mediated structural proteolysis in TBI.

Treatment of Traumatic Brain Injury: One Size Does Not Fit All

Treatment of Traumatic Brain Injury: One Size Does Not Fit All

Influence of apoptosis on neurological outcome following traumatic cerebral contusion.

Apoptosis has increasingly been implicated in the pathobiology of traumatic brain injury (TBI). The present study was undertaken to confirm the presence of apoptosis in the periischemic zone (PIZ) of traumatic cerebral contusions and to determine the role of apoptosis, if any, in neurological outcome. Brain tissue harvested at Wentworth Hospital from the PIZ in 29 patients with traumatic supratentorial contusions was compared with brain tissue resected in patients with epilepsy. Immunohistochemical analyses were performed on the tissues to see if they contained the apoptosis-related proteins p53, bcl-2, bax, and caspase-3. The findings were then correlated to demographic, clinical, surgical, neuroimaging, and outcome data. In the PIZ significant increases of bax (18-fold; p < 0.005) and caspase-3 (20-fold; p < 0.005) were recorded, whereas bcl-2 was upregulated in only 14 patients (48.3%; 2.9-fold increase) compared with control tissue. Patients in the bcl-2-positive group exhibited improved outcomes at the 18-month follow-up examination despite an older mean age and lower mean admission Glasgow Coma Scale score (p < 0.03). Caspase-3 immunostaining was increased in those patients who died (Glasgow Outcome Scale [GOS] Score 1, 12 patients) when compared with those who experienced a good outcome (GOS Score 4 or 5, 17 patients) (p < 0.005). Regression analysis identified bcl-2-negative status (p < 0.04, odds ratio [OR] 5.5; 95% confidence interval [CI] 1.1-28.4) and caspase-3-positive status (p < 0.01, OR 1.4, 95% CI 1.1-1.8) as independent predictors of poor outcome. No immunostaining for p53 was recorded in the TBI specimens. The present findings confirm apoptosis in the PIZ of traumatic cerebral contusions and indicate that this form of cell death can influence neurological outcome following a TBI.

Potentiation of GABAA Currents after Mechanical Injury of Cortical Neurons

Numerous studies have implicated glutamate receptors, glutamate neurotoxicity, and hyperexcitation in the pathobiology of traumatic brain injury, yet much less is known about the effects of neurotrauma on inhibitory GABA channels of the brain. Using an in vitro cell injury model, we tested whether mild stretch injury altered the GABA(A) currents of cultured rat cortical neurons. The application of 1-100 microM GABA to single pyramidal neurons voltage clamped to -60 mV activated an inward current that reversed near 0 mV in solutions containing symmetrical [Cl-]. This current was inhibited by bicuculline, consistent with mediation by GABA(A) receptor channels. In injured neurons, 50 microM GABA elicited a peak current density of 41.2 +/- 2.6 pA/pF (n = 82), which was significantly larger than in uninjured control neurons, 20.2 +/- 1.7 pA/pF (n = 69, p < 0.01). The GABA(A) currents of injured neurons did not differ from those of control neurons in their sensitivity to GABA or their reversal potentials, suggesting that GABA current potentiation did not result from changes in the agonist affinity or ionic selectivity of the channels. GABA current potentiation was prevented by injuring neurons in the presence of the NMDA antagonist APV, or the CaMKII inhibitor KN93. These results thus suggest that NMDA receptor activation following neuronal injury may potentiate GABA(A) channels through the activation of CaMKII. The increase in GABA(A) receptor function observed following injury could potentially contribute to dysfunctional synaptic function and information processing as well as unconsciousness and coma following human brain trauma.

Experimental models of brain trauma.

A short review of the most widely used and popular experimental models of traumatic brain injury is presented. This review focuses on current animal models of traumatic brain injury that apply mechanical energy to the skull or, after trephination of the skull, to the intact dura. Recent experimental studies evaluating the pathobiology of traumatic brain injury using these models are also discussed. This article attempts to provide a broad overview of current knowledge and controversies in experimental animal research on brain trauma.

Early treatment with a novel inhibitor of lipid peroxidation (LY341122) improves histopathological outcome after moderate fluid percussion brain injury in rats.

Reactive oxygen species are thought to participate in the pathobiology of traumatic brain injury (TBI). This study determined whether treatment with LY341122, a potent inhibitor of lipid peroxidation and an antioxidant, would provide neuroprotection in a rat model of TBI. To investigate the efficacy of LY341122 in this parasagittal fluid percussion model (1.8-2.1 atm), the rats received oral administration of LY341122 (100 mg/kg) or vehicle 2 hours before and 4 hours after TBI (each group, n = 7). To investigate the therapeutic window for treatment, rats were treated with LY341122 or vehicle for 20 hours by femoral vein infusion starting at 5 minutes, 30 minutes, or 3 hours after TBI (each group, n = 5). Three days after injury, analysis of contusion volumes and the frequency of damaged cortical neurons was conducted. Oral administration of LY341122 before and after TBI led to a significant reduction in overall contusion volume (3.28 mm3+/-0.75 mm3 [mean +/- standard error of the mean] versus 1.32 mm3 +/- 0.33 mm3; P < 0.05) and also reduced the frequency of damaged cortical neurons (1191.7 +/- 267.1 versus 474.6 +/- 80.2; P < 0.05). In the second experiment, rats treated with LY341122 at 5 minutes or 30 minutes after TBI also demonstrated a significant reduction (P < 0.05) in contusion volume (1.92 mm3 +/- 0.64 mm3 or 1.59 mm3 +/- 0.50 mm3, respectively) compared with vehicle-treated rats (4.32 mm3 +/- 1.15 mm3). A significant reduction in total cortical necrotic neuron counts was also demonstrated in the 5-minute group (2243.8 +/- 265.3 versus 1457.8 +/- 265.3; P < 0.05). In contrast, histopathological outcome was not significantly improved when treatment was delayed until 3 hours after TBI. These data reinforce the hypothesis that lipid peroxidation and reactive oxygen species participate in the acute pathogenesis of TBI. Treatment delayed until 3 hours after TBI did not provide significant histopathological protection.

Corticosteroids and traumatic brain injury: status at the end of the decade of the brain.

Although high dose glucocorticosteroid therapy has become the standard of care for hyperacute management of non-penetrating spinal cord injury, it does not enjoy the same prestigious status in traumatic brain injury (TBI). A Brain Trauma Foundation standard concluded that steroids fail to improve outcome and lower intracranial pressure in severe TBI, but in the absence of interventions able to improve the functional outcome, glucocorticosteroid use continues into the present day. This paper summarizes the pathobiology of TBI and provides a methodological critique of the major studies of steroids in TBI. Given the growing appreciation of the complexity and heterogeneity of brain injury, corticosteroid use may find a rational place in management. Alone or in combination with other agents, corticosteroids may have a role in the treatment of severe injury, which so far has remained intractable to all manner of intervention.

The Pathobiology of Traumatic Brain Injury

The recent appreciation that traumatic brain injury is a dynamic process, initiated at the time of injury but not concluded for hours to days afterward, has resulted in the expectation that treatments can be designed to interrupt the processes that result in delayed cellular dysfunction and, thus, can decrease the amount of traumatic brain damage. Thus, for the first time, treatments specific for brain damage are envisioned. These can provide a fundamentally different approach to the treatment of the damaged brain than currently used treatments that deal with epiphenomena of traumatic injury, such as increased intracranial pressure or secondary ischemia. The processes that result in delayed cellular damage may be initiated by transient ionic fluxes induced by traumatic, temporary holes in the cell membrane lipid bilayer (mechanoporation). Resulting changes in intracellular ionic composition, if uncorrected, result in 1) traumatic depolarization with resultant neurotransmitter release, postsynaptic receptor dysfunction, and excitability changes; 2) calcium-mediated activation of proteases and phospholipases, with resultant cytoskeletal protein dissolution and free radical-induced lipid peroxidation; 3) inflammatory processes that elicit tissue-damaging cytokines; and 4) immediate and delayed activation of numerous genes with a resultant production of a panoply of new proteins. The future challenge to neurotrauma investigators is to better understand these processes and to develop interventions that will halt them before permanent brain damage occurs.

The Neurobiology of Central Nervous System Trauma

edited by S.K. Salzman and A.I. Faden, 347 pp., ill., New York, Oxford University Press, 1994. This reference work concerns the new field of neurotrauma. It came of age in 1990 when high doses of IV methylprednisolone were shown to control some of the pathobiology of human spinal cord injury. Methylprednisolone also controls brain edema, a common feature of poor outcomes from head trauma. Five chapters address the pathobiology and treatment of the three known types of brain edema (cytotoxic, vasogenic, ionic): Chapter 10 (\``The Pathobiology of Traumatic Brain Injury''), Chapter 11 (\`\`Ionic and Water Shifts in Injured Central Nervous Tissues''), Chapter 19 (\``Astrocytic …

Are the pathobiological changes evoked by traumatic brain injury immediate and irreversible?

Traumatic brain injury has long been thought to evoke immediate and irreversible damage to the brain parenchyma and its intrinsic vasculature. In this review, we call into question the correctness of this assumption by citing two traumatically related brain parenchymal abnormalities that are the result of a progressive, traumatically induced perturbation. In this context, we first consider the pathogenesis of traumatically induced axonal damage to show that it is not the immediate consequence of traumatic tissue tearing. Rather, we illustrate that it is a delayed consequence of complex axolemmal and/or cytoskeletal changes evoked by the traumatic episode which then lead to cytoskeletal collapse and impairment of axoplasmic transport, ultimately progressing to axonal swelling and disconnection. Second, we consider the traumatized brain's increased neuronal sensitivity to secondary ischemic insult by showing that even after mild traumatic brain injury, CA1 neuronal cell loss can be precipitated by the induction of sublethal ischemic insult within 24 hrs of injury. In demonstrating this increased sensitivity to secondary insult, evidence is provided that it is triggered by the neurotransmitter storm evoked by traumatic brain injury, allowing for sublethal neuro-excitation. In relation to this phenomenon, the protective effect of receptor antagonists are discussed, as well as the concept that this relatively prolonged posttraumatic brain hypersensitivity offers a potential window for therapeutic intervention. Collectively, it is felt that both examples of the brain parenchyma's response to traumatic brain injury show that the resulting pathobiology is much more complex and progressive than previously envisioned, and as such, rejects many of the previous beliefs regarding the pathobiology of traumatic brain injury.