Pelle Nilsson

Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats

The aim of this study was to measure extracellular chemical changes in the cerebral cortex in response to compression contusion trauma in rats. Energy-related metabolites (i.e., lactate, pyruvate, adenosine, inosine, and hypoxanthine) and amino acids were harvested from the extracellular fluid (ECF) using microdialysis and analyzed by high-performance liquid chromatography. The measurements were performed in cortical tissue, where neuronal injury occurs in this model. The severity of the trauma was varied by using different depths of impact: mild trauma, 1.5 mm; severe trauma, 2.5 mm. The trauma induced a dramatic increase in the ECF levels of energy-related metabolites that was conditioned by the severity of the insult. The ECF level of taurine, glutamate, aspartate, and γ-aminobutyric acid (GABA) also rose markedly, while other amino acids did not change significantly. The results suggest that the trauma induced a transient, profound focal disturbance of energy metabolism in the cortical tissue, probably as a result of mechanically induced disruption of ion homeostasis and reduced blood flow in combination. The data support the potential role of glutamate and aspartate as mediators of traumatic brain injury. However, the concomitantly released adenosine, GABA, and taurine may be protective and ameliorate excitotoxicity. In analogy with the reported cumulative damaging effects of repeated ischemic insults, the observed ECF changes may help explain the vulnerability of traumatized brain tissue to secondary ischemia.

Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats

Brain trauma is associated with acute functional impairment and neuronal injury. At present, it is unclear to what extent disturbances in ion homeostasis are involved in these changes. We used ion-selective microelectrodes to register interstitial potassium ([K+]e) and calcium ([Ca2+]e) concentrations in the brain cortex following cerebral compression contusion in the rat. The trauma was produced by dropping a 21 g weight from a height of 35 cm onto a piston that compressed the cortex 1.5 mm. Ion measurements were made in two different locations of the contused region: in the perimeter, i.e., the shear stress zone (region A), and in the center (region B). The trauma resulted in an immediate increase in [K+]e from a control level of 3 mM to a level >60 mM in both regions, and a concomitant negative shift in DC potential. In both regions, there was a simultaneous, dramatic decrease in [Ca2+]e from a baseline of 1.1 mM to 0.3–0.1 mM. Interstitial [K+] and the DC potential normalized within 3 min after trauma. In region B, [Ca2+]e recovered to near control levels within 5 min after ictus. In region A, however, recovery of [Ca2+]e was significantly slower, with a return to near baseline values within 50 min after trauma. The prolonged lowering of [Ca2+]e in region A was associated with an inability to propagate cortical spreading depression, suggesting a profound functional disturbance. Histologic evaluation 72 h after trauma revealed that neuronal injury was confined exclusively to region A. The results indicate that compression contusion trauma produces a transient membrane depolarization associated with a pronounced cellular release of K+ and a massive Ca2+ entry into the intracellular compartment. We suggest that the acute functional impairment and the subsequent neuronal injury in region A is caused by the prolonged disturbance of cellular calcium homeostasis mediated by leaky membranes exposed to shear stress.

Epileptic seizure activity in the acute phase following cortical impact trauma in rat

The aim of this investigation was to determine the incidence of seizure activity in the acute phase following traumatic brain injury. Compression contusion trauma was produced in the right parietal cortex in 19 artificially ventilated rats. Electroencephalographic recordings were carried out in 17 of the animals for 2 h following the impact. The extracellular levels of neuroactive amino acids were simultaneously monitored in 9 of the experiments using microdialysis. In 14 of the 17 animals a generalized seizure activity with an average duration of 59 s (range 30-101 s) was recorded. The mean time lag between trauma and seizure onset was 67 s (range 26-90 s). The seizure activity was consistently followed by post-ictal depression. The trauma was accompanied by a transient increase of aspartate, taurine, glutamate and glycine, in decreasing rank order. The seizure activity occurred when the levels of these neuroactive amino acids were elevated. It is concluded that the high incidence of seizure activity observed may be an important factor contributing to secondary ischemia after traumatic brain injury. Aspartate and glutamate, potentiated by glycine, may play a role in post-traumatic seizure activity.

Calcium movements in traumatic brain injury : the role of glutamate receptor-operated ion channels

Ion-selective microelectrodes were used to study acute effects of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor blockade on posttraumatic calcium disturbances. An autoradiographic technique with 45Ca2+ was used to study calcium disturbances at 8, 24, and 72 h. Compression contusion trauma of the cerebral cortex was produced by a 21-g weight dropped from a height of 35 cm onto a piston that compressed the brain 2 mm. Pre- and posttrauma interstitial [Ca2+] ([Ca2+]e) concentrations were measured in the perimeter, i.e., the shear stress zone (SSZ) and in the central region (CR) of the trauma site. For the [Ca2+]e studies the animals were divided into controls and groups pretreated with dizocilipine maleate (MK-801) or with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[F]quinoxaline (NBQX). In all groups, [Ca2+]e decreased from pretrauma-values of approximately 1 mM to posttraumatic values of 0.1 mM in both the CR and the SSZ. This was followed by a slow restitution toward pretraumatic levels during the 2-h observation period. There was no significant difference in recovery pattern between controls and pretreated animals. Accumulation of 45Ca2+ and serum proteins was seen in the entire SSZ, while neuronal necrosis was confined to a narrow band within the SSZ. The CR was unaffected apart from occasional eosinophilic neurons and showed no accumulation of 45Ca2+. Posttraumatic treatment with MK-801 or NBQX had no obvious effect on neuronal injury in the SSZ. We conclude that (a) acute [Ca2+]e disturbances in compression contusion brain trauma are not affected by blockade of NMDA or AMPA receptors, (b) 45Ca2+ accumulation in the SSZ reflects mainly protein accumulation due to blood–brain barrier breakdown rather than cell death, and (c) acute cellular Ca2+ overload per se does not seem to be a major determinant of cell death after cerebral trauma in our model.

Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis.

Purpose of reviewThis review highlights recent advances in cerebral microdialysis as a tool for neurochemical monitoring of patients with traumatic brain injury. Recent findingsProgress in microdialysis research has come from validation studies of microdialysis biomarkers and clinical outcome in large cohorts of traumatic brain injury patients and by combining microdialysis with other methods, such as positron emission tomography, magnetic resonance spectroscopy, brain tissue oximetry and electrophysiology. The combination of rapid-sampling microdialysis and electrocorticography has revealed complex, transient fluctuations of microdialysis glucose and lactate and depolarization-like events that may affect the secondary injury process. The use of microdialysis to monitor global cerebral metabolic events (related to intracranial hypertension or reduced cerebral perfusion pressure for example) as opposed to focal events in peri-lesional brain tissue need to be clearly distinguished and the microdialysis catheter location verified by neuroimaging to ensure proper data interpretation. Differences in microdialysis biomarker levels between grey and white matter following traumatic brain injury need clarification. SummaryMicrodialysis is established as a neurochemical research tool in neurointensive care, particularly in combination with other monitoring methods, and contributes to a growing knowledge of secondary injury mechanisms in traumatic brain injury. The value of microdialysis as a tool in routine neurointensive care decision-making remains unclear.

Traumatic brain injury in rat produces changes of β-amyloid precursor protein immunoreactivity

beta-Amyloid precursor protein immunoreactivity (APP) was studied after a mild compression contusion trauma to rat parietal cortex. Neurones in the periphery of the cortical lesion, i.e. tissue subjected to shear stress, showed markedly reduced immunoreactivity 1 and 3 days after injury. Numerous axons in the ipsilateral subcortical white matter and thalamus became immunoreactive. At 21 days, small rounded profiles appeared in the neuropil of the damaged cortex and in the thalamus. Thus, traumatic brain injury appears to induce several types of APP changes. The accumulation in neuronal processes is probably caused by disturbed axonal transport induced by trauma. Since APP is assumed to be excitoprotective, modulating intracellular Ca2+ responses, the decreased immunoreactivity noticed in the periphery of the lesion may render the neurones in this region more vulnerable to secondary injury mechanisms.

Cerebral glutamine and glutamate levels in relation to compromised energy metabolism : a microdialysis study in subarachnoid hemorrhage patients

Astrocytic glutamate (Glt) uptake keeps brain interstitial Glt levels low. Within the astrocytes Glt is converted to glutamine (Gln), which is released and reconverted to Glt in neurons. The Glt–Gln cycle is energy demanding and impaired energy metabolism has been suggested to cause low interstitial Gln/Glt ratios. Using microdialysis (MD) measurements from visually noninjured cortex in 33 neurointensive care patients with subarachnoid hemorrhage, we have determined how interstitial Glt and Gln, as a reflection of the Glt–Gln cycle turnover, relate to perturbed energy metabolism. A total of 3703 hourly samples were analyzed. The lactate/pyruvate (L/P) ratios correlated to the Gln/Glt ratios (r = −0.66), but this correlation was not stronger than the correlation between L/P and Glt (r = 0.68) or the correlation between lactate and Glt (r = 0.65). A novel observation was a linear relationship between interstitial pyruvate and Gln (r = 0.52). There were 13 periods (404 h) of ‘energy crisis’, defined by L/P ratios above 40. All were associated with high interstitial Glt levels. Periods with L/P ratios above 40 and low pyruvate levels were associated with decreased interstitial Gln levels, suggesting ischemia and failing astrocytic Gln synthesis. Periods with L/P ratios above 40 and normal or high pyruvate levels were associated with increased interstitial Gln levels, which may represent an astrocytic hyperglycolytic response to high interstitial Glt levels. The results imply that moderately elevated L/P ratios cannot always be interpreted as failing energy metabolism and that interstitial pyruvate levels may discriminate whether or not there is sufficient astrocytic capacity for Glt–Gln cycling in the brain.

Cerebral perfusion pressure between 50 and 60 mmHg may be beneficial in head-injured patients: a computerized secondary insult monitoring study.

OBJECTIVE To describe the occurrence of secondary insults using a computerized monitoring data collecting system and to investigate their relationship to outcome when the neurointensive care was dedicated to avoiding secondary insults. METHODS Patients 16 to 79 years old admitted to the neurointensive care unit between August 1998 and December 2002 with traumatic brain injury and 54 hours or more of valid monitoring within the first 120 hours after trauma (one value/min) were included. Monitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP), systolic blood pressure (BPs), and mean blood pressure (BPm) was required, and insult levels were defined (ICP >25/>35, BPs <100/<90/>160/>180, BPm <80/<70/>110/>120, and CPP <60/<50/>70/>80 mm Hg). Insults were quantified as proportion of valid monitoring time at the insult level. Logistic regression analyses were performed with admission and secondary insult variables as explanatory variables and favorable outcome as dependent variable. RESULTS Eighty-one patients, 63 men and 18 women, with a mean age of 43.0 years, fulfilled the inclusion criteria. Seventy-two patients (89%) had Glasgow Coma Scale scores of 8 or less. Thirty-one patients (38%) had diffuse injury, and 50 (62%) had mass lesions. Mean Injury Severity Score was 26.6. After 6 months, 54% of the patients had achieved a favorable outcome. Most patients spent 5% or less of the monitoring time at the insult level except for CPP greater than 70 mm Hg. Low age, high Glasgow Coma Scale motor score, low Injury Severity Score, and CPP less than 60 mm Hg insults were significant predictors of favorable outcome in the final multiple logistic regression model. CONCLUSION Overall, the secondary insults were rare, except for high CPP. The results suggest that patients with traumatic brain injury might benefit from a CPP slightly less than 60 mm Hg.

Trauma-induced increase of extracellular ascorbate in rat cerebral cortex

Extracellular (EC) ascorbate concentrations were measured in microdialysates from the cerebral cortex in rats subjected to cortical compression-contusion trauma. The trauma induced a transient, dramatic increase in EC ascorbate compared to the basal level before the insult and compared to control animals. The data support the presence of a releasable intracellular pool of ascorbate in the neocortex. The possibility that ascorbate may influence traumatic brain damage by its proposed neuromodulatory property and/or by its ability to induce lipid peroxidation is considered.

Early cerebral hyperglycolysis after subarachnoid haemorrhage correlates with favourable outcome

Summary. Background: Intracerebral microdialysis (MD) was applied in patients with severe subarachnoid haemorrhage treated in a neurosurgical intensive care unit in order to explore their cerebral energy metabolism. Method: Brain MD fluid levels of glucose, lactate and pyruvate were measured for 3 to 12 days in 20 patients and 2,635 hourly samples were analysed. The MD data were related to computerized tomography and clinical outcome, assessed by the Glasgow Outcome Scale. Findings: The study showed that most patients who made a good recovery had a specific curve pattern when plotting the studied metabolites over time, characterised by a distinct decrease in MD-glucose and a parallel increase in both MD-lactate and pyruvate. Patients who had an unfavourable outcome lacked this distinct curve pattern and exhibited more irregular changes, including increased levels of both MD-glucose and lactate and low MD-pyruvate levels. Interpretation: This exploratory study suggests that accumulation of interstitial lactate and pyruvate, together with decreasing levels of glucose is a favourable prognostic pattern presumably reflecting increased glucose metabolism. Such hyperglycolysis may be elicited in patients with recovery potential to cope with an extreme metabolic demand set in motion by a brain insult to restore brain cell homeostasis and integrity.