16 research outputs found
Influence of Organic Solvents on Secondary Brain Damage after Experimental Traumatic Brain Injury
Many compounds tested for a possible neuroprotective effect after traumatic brain injury (TBI) are not readily soluble and therefore organic solvents need to be used as a vehicle. It is, however, unclear whether these organic solvents have intrinsic pharmacological effects on secondary brain damage and may therefore interfere with experimental results. Thus, the aim of the current study was to evaluate the effect of four widely used organic solvents, dimethylsulfoxide (DMSO), Miglyol 812 (Miglyol(R)), polyethyleneglycol 40 (PEG 40), and N-2-methyl-pyrrolidone (NMP) on outcome after TBI in mice. A total of 143 male C57Bl/6 mice were subjected to controlled cortical impact (CCI). Contusion volume, brain edema formation, and neurological function were assessed 24 h after TBI. Test substances or saline were injected intraperitoneally (i.p.) 10 min before CCI. DMSO, Miglyol, and PEG 40 had no effect on post-traumatic contusion volume after CCI;NMP, however, significantly reduced contusion volume and brain edema formation at different concentrations. The use of DMSO, Miglyol, and PEG 40 is unproblematic for studies investigating neuroprotective treatment strategies as they do not influence post-traumatic brain damage. NMP seems to have an intrinsic neuroprotective effect that should be considered when using this agent in pharmacological experiments;further, a putative therapeutic effect of NMP needs to be elucidated in future studies
Central Application of Aliskiren, a Renin Inhibitor, Improves Outcome After Experimental Stroke Independent of Its Blood Pressure Lowering Effect
Epidemiological studies suggest that pharmacological reduction of systemic hypertension lowers incidence and severity of stroke. However, whether the reduction of blood pressure per se or the compounds used to reduce hypertension are responsible for this effect received little attention. In the current study we therefore aimed to investigate whether Aliskiren, a renin-inhibitor used to treat arterial hypertension, may improve outcome in a mouse model of ischemic stroke when applied centrally and in a dose not affecting blood pressure. Male C57BL/6 mice received 0.6, 2.0, or 6.0 mu g Aliskiren or vehicle by intracerebroventricular injection as a pre-treatment and were then subjected to 60 min of middle cerebral artery occlusion (MCAo). Infarct volume, brain edema formation, mortality, antioxidant effects, and functional outcome were assessed up to seven days after MCAo. Central administration of Aliskiren (0.6 or 2.0 mu g) had no effect on systemic blood pressure but significantly reduced infarct volume and brain edema formation, blunted mortality, and improved neurological outcome up to 1 week after MCAo. Due to the central and prophylactic administration of the compound, we cannot make any conclusions about the potency of Aliskiren for acute stroke treatment, however, our study clearly demonstrates, that in addition to lowering blood pressure Aliskiren seems to have a direct neuroprotective effect. Hence, renin-inhibitors may be an effective addition to prophylactic treatment regimens in stroke patients
Microvasospasms After Experimental Subarachnoid Hemorrhage Do Not Depend on Endothelin A Receptors
Background and Purpose-Perturbations in cerebral microcirculation (eg, microvasospasms) and reduced neurovascular communication determine outcome after subarachnoid hemorrhage (SAH). ET-1 (endothelin-1) and its receptors have been implicated in the pathophysiology of large artery spasms after SAH;however, their role in the development of microvascular dysfunction is currently unknown. Here, we investigated whether inhibiting ETA (endothelin A) receptors can reduce microvasospasms after experimentally induced SAH. Methods-SAH was induced in male C57BL/6 mice by filament perforation of the middle cerebral artery. Three hours after SAH, a cranial window was prepared and the pial and parenchymal cerebral microcirculation was measured in vivo using two-photon microscopy before, during, and after administration of the ETA receptor inhibitor clazosentan. In separate experiments, the effect of clazosentan treatment on neurological outcome was measured 3 days after SAH. Results: Clazosentan treatment had no effect on the number or severity of SAH-induced cerebral microvasospasms nor did it affect neurological outcome. Conclusions: Our results indicate that ETA receptors, which mediate large artery spasms after SAH, do not seem to play a role in the development of microarterial spasms, suggesting that posthemorrhagic spasms are mediated by distinct mechanisms in large and small cerebral vessels. Given that cerebral microvessel dysfunction is a key factor for outcome after SAH, further research into the mechanisms that underlie posthemorrhagic microvasospasms is urgently needed
Role of endothelial nitric oxide synthase for early brain injury after subarachnoid hemorrhage in mice
The first few hours and days after subarachnoid hemorrhage (SAH) are characterized by cerebral ischemia, spasms of pial arterioles, and a significant reduction of cerebral microperfusion, however, the mechanisms of this early microcirculatory dysfunction are still unknown. Endothelial nitric oxide production is reduced after SAH and exogenous application of NO reduces post-hemorrhagic microvasospasm. Therefore, we hypothesize that the endothelial NO-synthase (eNOS) may be involved in the formation of microvasospasms, microcirculatory dysfunction, and unfavorable outcome after SAH. SAH was induced in male eNOS deficient (eNOS(-/-)) mice by endovascular MCA perforation. Three hours later, the cerebral microcirculation was visualized using in vivo 2-photon-microscopy. eNOS(-/-) mice had more severe SAHs, more severe ischemia, three time more rebleedings, and a massively increased mortality (50 vs. 0%) as compared to wild type (WT) littermate controls. Three hours after SAH eNOS(-/-) mice had fewer perfused microvessels and 40% more microvasospasms than WT mice. The current study indicates that a proper function of eNOS plays a key role for a favorable outcome after SAH and helps to explain why patients suffering from hypertension or other conditions associated with impaired eNOS function, have a higher risk of unfavorable outcome after SAH
Long-term impairment of neurovascular coupling following experimental subarachnoid hemorrhage
CO2-reactivity and neurovascular coupling are sequentially lost within the first 24 h after subarachnoid hemorrhage (SAH). Whether and when these impairments recover is not known. Therefore, we investigated the reactivity of pial and intraparenchymal vessels by in vivo two-photon microscopy one month after experimental SAH. C57BL/6 mice were subjected to either sham surgery or SAH by filament perforation. One month later, cerebral blood flow following CO2-challenge and forepaw stimulation was assessed by laser Doppler fluxmetry. Diameters of pial and intraparenchymal arterioles were quantified by in vivo two-photon microscopy. One month after SAH, pial and parenchymal vessels dilated in response to CO2. Neurovascular coupling was almost completely absent after SAH: vessel diameter did not change upon forepaw stimulation compared to a 20% increase in sham-operated mice. The current results demonstrate that neurovascular function differentially recovers after SAH: while CO2-reactivity normalizes within one month after SAH, neurovascular coupling is still absent. These findings show an acute and persistent loss of neurovascular coupling after SAH that may serve as a link between early brain injury and delayed cerebral ischemia, two distinct pathophysiological phenomena after SAH that were so far believed not to be directly related
Temporal profile of MicroRNA expression in contused cortex after traumatic brain injury in mice
MicroRNAs (miRNAs) were recently identified as important regulators of gene expression under a wide range of physiological and pathophysiological conditions. Thus, they may represent a novel class of molecular targets for the management of traumatic brain injury (TBI). In this study, we investigated the temporal profile of miRNA expression during the development of secondary brain damage after experimental TBI. For this purpose, we used a controlled cortical impact model in C57Bl/6 mice (n = 6) to induce a cortical contusion and analyzed miRNA expression in the traumatized cortex by microarray analysis during the development of secondary contusion expansion-i.e., at 1, 6, and 12 h after TBI. Of a total 780 mature miRNA sequences analyzed, 410 were detected in all experimental groups. Of these, 158 miRNAs were significantly upregulated or downregulated in TBI compared with sham-operated animals, and 52 miRNAs increased more than twofold. We validated the upregulation of five of the most differentially expressed miRNAs (miR-21*, miR-144, miR-184, miR-451, miR-2137) and the downregulation of four of the most differentially expressed miRNAs (miR-107, miR-137, miR-190, miR-541) by quantitative polymerase chain reaction (qPCR). miR-2137, the most differentially expressed miRNA after TBI, was further investigated by in situ hybridization and was found to be upregulated in neurons within the traumatic penumbra. This study gives a comprehensive picture of miRNA expression levels during secondary contusion expansion after TBI and may pave the way for the identification of novel targets for the management of brain trauma
Minimally invasive third ventriculostomy with stereotactic internal shunt placement for the treatment of tumor-associated noncommunicating hydrocephalus
The formation of microthrombi in parenchymal microvessels after traumatic brain injury is independent of coagulation factor XI
Microthrombus formation and bleeding worsen the outcome after traumatic brain injury (TBI). The aim of the current study was to characterize these processes in the brain parenchyma after experimental TBI and to determine the involvement of coagulation factor XI (FXI). C57BL/6 mice (n = 101) and FXI-deficient mice (n = 15) were subjected to controlled cortical impact (CCI). Wild-type mice received an inhibitory antibody against FXI (14E11) or control immunoglobulin G 24 h before or 30 or 120 min after CCI. Cerebral microcirculation was visualized in vivo by 2-photon microscopy 2-3 h post-trauma and histopathological outcome was assessed after 24 h. TBI induced hemorrhage and microthrombus formation in the brain parenchyma (p < 0.001). Inhibition of FXI activation or FXI deficiency did not reduce cerebral thrombogenesis, lesion volume, or hemispheric swelling. However, it also did not increase intracranial hemorrhage. Formation of microthrombosis in the brain parenchyma after TBI is independent of the intrinsic coagulation cascade since it was not reduced by inhibition of FXI. However, since targeting FXI has well-established antithrombotic effects in humans and experimental animals, inhibition of FXI could represent a reasonable strategy for the prevention of deep venous thrombosis in immobilized patients with TBI
Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms.
Subarachnoid hemorrhage is a stroke subtype with particularly bad outcome. Recent findings suggest that constrictions of pial arterioles occurring early after hemorrhage may be responsible for cerebral ischemia and - subsequently - unfavorable outcome after subarachnoid hemorrhage. Since we recently hypothesized that the lack of nitric oxide may cause post-hemorrhagic microvasospasms, our aim was to investigate whether inhaled nitric oxide, a treatment paradigm selectively delivering nitric oxide to ischemic microvessels, is able to dilate post-hemorrhagic microvasospasms; thereby improving outcome after experimental subarachnoid hemorrhage. C57BL/6 mice were subjected to experimental SAH. Three hours after subarachnoid hemorrhage pial artery spasms were quantified by intravital microscopy, then mice received inhaled nitric oxide or vehicle. For induction of large artery spasms mice received an intracisternal injection of autologous blood. Inhaled nitric oxide significantly reduced number and severity of subarachnoid hemorrhage-induced post-hemorrhage microvasospasms while only having limited effect on large artery spasms. This resulted in less brain-edema-formation, less hippocampal neuronal loss, lack of mortality, and significantly improved neurological outcome after subarachnoid hemorrhage. This suggests that spasms of pial arterioles play a major role for the outcome after subarachnoid hemorrhage and that lack of nitric oxide is an important mechanism of post-hemorrhagic microvascular dysfunction. Reversing microvascular dysfunction by inhaled nitric oxide might be a promising treatment strategy for subarachnoid hemorrhage