Cerebral microdialysis in acutely brain-injured patients with spreading depolarizations.

Multimodal cerebral monitoring was utilized to examine the relationship between pathological changes in microdialysis parameters and the occurrence of spreading depolarizations (SD) in brain-injured patients. SD are a relatively newly discovered phenomenon in man found to be linked to secondary insults and infarct growth and they can be detected via electrocorticography (ECoG). A total of 24 brain-injured patients (mean age: 52±11 years) requiring craniotomy took part in this prospective observational study. Each patient was monitored with a linear strip electrode for ECoG data and a cerebral microdialysis probe. SD were detected in 13 of the 24 patients. Pathological concentrations of glucose and lactate in brain parenchyma were significantly correlated with various time points prior to and/or immediately following the SD. Severe systemic hyperglycemia and systemic hypoglycemia were also found to be correlated with the occurrence of SD. The present study shows a clear relationship between SD and pathological changes in cerebral metabolism; further studies are needed to elucidate these complex interactions with the ultimate goal of developing therapeutic strategies for improving outcome in brain-injured patients.

Distribution of inositol-1,4,5-trisphosphate receptor isotypes and ryanodine receptor isotypes during maturation of the rat hippocampus.

Activation of inositol-1,4,5-trisphosphate receptors (InsP(3)Rs) and ryanodine receptors (RyRs) can lead to the release of Ca(2+) from intracellular stores and propagating Ca(2+) waves. Previous studies of these proteins in neurons have focused on their distribution in adult tissue, whereas, recent functional studies have examined neural tissue extracted from prenatal and young postnatal animals. In this study we examined the distribution of InsP(3)R isotypes 1-3 and RyR isotypes 1-3 in rat hippocampus during postnatal maturation, with a focus on InsP(3)R1 because it is most prominent in the hippocampus. InsP(3)R1 was observed in pyramidal cells and granule cells, InsP(3)R2 immunoreactivity was observed in perivascular astrocytes and endothelial cells, and InsP(3)R3 immunoreactivity was detected in axon terminals located in stratum pyramidale of CA1 and microvessels in stratum radiatum. RyR1 immunolabeling was enriched in CA1, RyR2 was most intense in CA3 and the dentate gyrus, and RyR3 immunolabeling was detected in all subfields of the hippocampus, but was most intense in stratum lacunosum-moleculare. During maturation from 2 to 10 weeks of age there was a shift in InsP(3)R1 immunoreactivity from a high density in the proximal apical dendrites to a uniform distribution along the dendrites. Independent of age, InsP(3)R1 immunoreactivity was observed to form clusters within the primary apical dendrite and at dendritic bifurcations of pyramidal neurons. As CA1 pyramidal neurons matured, InsP(3)R1 was often co-localized with the Ca(2+) binding protein calbindin D-28k. In contrast, InsP(3)R1 immunolabel was never co-localized with calbindin D-28k immunopositive interneurons located outside of stratum pyramidale or with parvalbumin, typically found in hippocampal basket cells, suggesting that InsP(3)R1s do not play a role in internal Ca(2+) release in these interneurons. These findings should help to interpret past functional studies and inform future studies examining the characteristics and consequences of InsP(3)R-mediated internal Ca(2+) release and Ca(2+) waves in hippocampal neurons.

Glibenclamide reduces secondary brain damage after experimental traumatic brain injury.

Following traumatic brain injury (TBI) SUR1-regulated NCCa-ATP (SUR1/TRPM4) channels are transcriptionally up-regulated in ischemic astrocytes, neurons, and capillaries. ATP depletion results in depolarization and opening of the channel leading to cytotoxic edema. Glibenclamide is an inhibitor of SUR-1 and, thus, might prevent cytotoxic edema and secondary brain damage following TBI. Anesthetized adult Sprague-Dawley rats underwent parietal craniotomy and were subjected to controlled cortical impact injury (CCI). Glibenclamide was administered as a bolus injection 15min after CCI injury and continuously via osmotic pumps throughout 7days. In an acute trial (180min) mean arterial blood pressure, heart rate, intracranial pressure, encephalographic activity, and cerebral metabolism were monitored. Brain water content was assessed gravimetrically 24h after CCI injury and contusion volumes were measured by MRI scanning technique at 8h, 24h, 72h, and 7d post injury. Throughout the entire time of observation neurological function was quantified using the "beam-walking" test. Glibenclamide-treated animals showed a significant reduction in the development of brain tissue water content(80.47%±0.37% (glibenclamide) vs. 80.83%±0.44% (control); p<0.05; n=14). Contusion sizes increased continuously within 72h following CCI injury, but glibenclamide-treated animals had significantly smaller volumes at any time-points, like 172.53±38.74mm(3) (glibenclamide) vs. 299.20±64.02mm(3) (control) (p<0.01; n=10; 24h) or 211.10±41.03mm(3) (glibenclamide) vs. 309.76±19.45mm(3) (control) (p<0.05; n=10; 72h), respectively. An effect on acute parameters, however, could not be detected, most likely because of the up-regulation of the channel within 3-6h after injury. Furthermore, there was no significant effect on motor function assessed by the beam-walking test throughout 7days. In accordance to these results and the available literature, glibenclamide seems to have promising potency in the treatment of TBI.