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AbstractThe formation of brain edema and subsequent intracranial hypertension are major predictors of unfavorable outcome following traumatic brain injury (TBI). Previously, we reported that arginine vasopressin (AVP) receptor antagonists reduce post-traumatic and post-ischemic brain edema in mice. The aim of the current study was to investigate further the contribution of arginine vasopressin V1areceptors to TBI-induced secondary brain damage in V1areceptor knock-out mice. V1areceptor knock-out (V1a-/-) and wild-type mice were subjected to controlled cortical impact (CCI), and edema (brain water content measured before and 24 h after CCI), primary and secondary contusion volume (15 min and 24 h after CCI), neurological function (one day before and seven days after CCI), body weight (before and seven days after CCI) and mortality were measured. Twenty-four h after CCI, V1a receptor knock-out mice had significantly less brain water content than wild-type mice (mean±standard error of the mean: 79.8%±0.3 vs. 80.6%±0.2, respectively), and secondary contusion volume was significantly smaller (38.2±1.7 mm3vs. 45.1±1.5 mm3in wild-type mice). Furthermore, the V1areceptor knock-out mice had less neurological dysfunction (3.2±0.8 vs. 7.0±1.4 in wild-type mice) and weight loss (1.0±1.0% vs. 4.9±1.8% in wild-type mice) seven days after CCI. Our data show that mice lacking V1a receptors have less secondary brain damage following experimental traumatic brain injury. We therefore conclude that V1areceptors may represent a novel drug target for preventing post-traumatic brain edema. [ABSTRACT FROM AUTHOR]

Inflammatory mechanisms are known to contribute to the pathophysiology of traumatic brain injury (TBI). Since bradykinin is one of the first mediators activated during inflammation, we investigated the role of bradykinin and its receptors in posttraumatic secondary brain damage. We subjected wild-type (WT), B1-, and B2-receptor-knockout mice to controlled cortical impact (CCI) and analyzed tissue bradykinin as well as kinin receptor mRNA and protein expression up to 48 h thereafter. Brain edema, contusion volume, and functional outcome were assessed 24 h and 7 days after CCI. Tissue bradykinin was maximally increased 2 h after trauma (P<0.01 versus sham). Kinin B1 receptor mRNA was upregulated up to four-fold 24 h after CCI. Immunohistochemistry showed that B1 and B2 receptors were expressed in the brain and were significantly upregulated in the traumatic penumbra 1 to 24 h after CCI. B2R−/− mice had significantly less brain edema (−51% versus WT, 24 h; P<0.001), smaller contusion volumes (∼50% versus WT 24 h and 7 d after CCI; P<0.05), and better functional outcome 7 days after TBI as compared with WT mice (P<0.05). The present results show that bradykinin and its B2 receptors play a causal role for brain edema formation and cell death after TBI. [ABSTRACT FROM AUTHOR]

Abstract: Perifocal depolarizations (PFD) have been observed after traumatic brain injury, are known to disturb cerebrovascular reactivity and thus may contribute to the morphological consequences of brain injury. In this investigation, the role of PFD was studied in focal brain lesions with/without induction of delayed hypotension. Cerebral freeze lesions were induced in anesthetized normotensive rats that underwent perfusion fixation of brains 5 min, 4 h or 24 h after lesioning, respectively, to obtain quantitative histopathology. In additional groups, a 45-min period of moderate hypobaric hypotension was applied 15 min post-trauma and brains were perfusion fixed after 4 h or 24 h. In a second series, the direct current (DC) potential and cortical laser-Doppler flow (LDF) were measured adjacent to lesions under normotensive or hypotensive conditions. Sham procedures were carried out in rats that underwent hypotension alone. Lesioning resulted in a significant LDF decrease to 50% of baseline, further decreased during hypotension to less than 40% of control (P < 0.05). Sham animals had LDF values between 60 and 70% of control when subjected to hypotension. Focal brain injury always induced a negative DC shift shortly after lesioning. In 6 of 8 rats that underwent cold lesion plus hypotension, a second PFD was observed approximately 2.5 min after onset of hypotension accompanied by a relative LDF increase by 25 ± 12%. Lesion expansion was significantly worsened by hypotension (8.19 ± 0.56 mm3 at 24 h) compared with normotensive rats (7.01 ± 0.3 mm3 at 24 h, P < 0.01). We conclude that hypotension triggers depolarizations by an ischemic mechanism that contributes to final tissue damage. [Copyright &y& Elsevier]

Brain edema formation contributes to secondary brain damage and unfavorable outcome after traumatic brain injury (TBI). Aquaporins (AQP), highly selective water channels, are involved in the formation of post-trauma brain edema; however, their regulation is largely unknown. Because vasopressin receptors are involved in AQP-mediated water transport in the kidney and inhibition of V 1a receptors reduces post-trauma brain edema formation, we hypothesize that cerebral AQPs may be regulated by V 1a receptors. Cerebral Aqp1 and Aqp4 messenger ribonucleic acid (mRNA) and AQP1 and AQP4 protein levels were quantified in wild-type and V 1a receptor knockout (V 1a -/- ) mice before and 15 min, 1, 3, 6, 12, or 24 h after experimental TBI by controlled cortical impact. In non-traumatized mice, we found AQP1 and AQP4 expression in cortical neurons and astrocytes, respectively. Experimental TBI had no effect on Aqp4 mRNA or AQP4 protein expression, but increased Aqp1 mRNA ( p  < 0.05) and AQP1 protein expression ( p  < 0.05) in both hemispheres. The Aqp1 mRNA and AQP1 protein regulation was blunted in V 1a receptor knockout mice. The V 1a receptors regulate cerebral AQP1 expression after experimental TBI, thereby unraveling the molecular mechanism by which these receptors may mediate brain edema formation after TBI.

Objective: After a subarachnoid hemorrhage (SAH), the primary cause of mortality is secondary brain injury occurring within the first 48 hours after the initial bleeding. Because of the unknown pathophysiology of these early events, therapeutic approaches are scarce. Because mild hypothermia (33 degrees C) is among the strongest neuroprotectants known so far, the aim of this study was to investigate acute and delayed effects of hypothermia if applied after SAH., Methods: Male Sprague-Dawley rats were subjected to SAH and randomly assigned to the following groups: 1) SAH under normothermia, 2) SAH followed by 2 hours of hypothermia starting 1 hour after the bleeding, and 3) SAH followed by 2 hours of hypothermia starting 3 hours after the bleeding. Cerebral blood flow and intracranial pressure were continuously measured up to 6 hours after SAH. Mortality, neurological deficits, and body weight were assessed from postoperative day 1 to day 7. Brain water content and morphological brain damage were quantified 24 hours and 7 days after SAH, respectively., Results: Mild hypothermia reduced intracranial pressure (P < 0.001) and posthemorrhagic neurological deficits (P < 0.05) and improved postoperative weight gain significantly (P < 0.05). Mortality, cerebral blood flow, and the formation of cerebral edema were not significantly influenced by mild hypothermia., Conclusion: The current results show that mild hypothermia (33 degrees C) exhibits sustained neuroprotection if applied up to 3 hours after SAH. Overall, mild hypothermia seems to be an effective neuroprotective strategy after SAH and should therefore be evaluated as a treatment option for SAH in patients.

Although changes of cerebral blood flow (CBF) in and around traumatic contusions are well documented, the role of CBF for the delayed death of neuronal cells in the traumatic penumbra ultimately resulting in secondary contusion expansion remains unclear. The aim of the current study was therefore to investigate the relationship between changes of CBF and progressive peri-contusional cell death following traumatic brain injury (TBI). CBF and contusion size were measured in C57Bl6 mice under continuous on-line monitoring of (ETp)CO2 before, and at 15 min and 24 h following controlled cortical impact by 14C-iodoantipyrine autoradiography (IAP-AR; n = 5-6 per group) and by Nissl staining, respectively. Contused and ischemic (CBF < 10%) tissue volumes were calculated and compared over time. Cortical CBF in not injured mice varied between 69 and 93 mL/100mg/min depending on the anatomical location. Fifteen minutes after trauma, CBF decreased in the whole brain by approximately 50% (39 +/- 18 mL/100mg/min; p < 0.05), except in contused tissue where it fell by more than 90% (3 +/- 2 mL/100mg/min; p < 0.001). Within 24 h after TBI, CBF recovered to normal values in all brain areas except the contusion where it remained reduced by more than 90% (p < 0.001). Contusion volume expanded from 24.9 to 35.5 mm3 (p < 0.01) from 15 min to 24 h after trauma (+43%), whereas the area of severe ischemia (CBF < 10%) showed only a minimal (+13%) and not significant increase (22.3 to 25.1 mm3). The current data therefore suggest that the delayed secondary expansion of a cortical contusion following traumatic brain injury may not be caused by a reduction of CBF alone.