The cerebrovascular effects of adrenaline, noradrenaline and dopamine infusions under propofol and isoflurane anaesthesia in sheep

Publisher's copy made available with the permission of the publisher © Australian Society of AnaesthetistsInfusions of catecholamines are frequently administered to patients receiving propofol or isoflurane anaesthesia. Interactions between these drugs may affect regional circulations, such as the brain. The aim of this animal (sheep) study was to determine the effects of ramped infusions of adrenaline, noradrenaline (10, 20, 40 µg/min) and dopamine (10, 20, 40 µg/kg/min) on cerebral blood flow (CBF), intracranial pressure (ICP), cerebrovascular resistance (CVR) and cerebral metabolic rate for oxygen (CMRO₂). These measurements were made under awake physiological conditions, and during continuous propofol (15 mg/min) or 2% isoflurane anaesthesia. All three catecholamines significantly and equivalently increased mean arterial pressure from baseline in a dose-dependent manner in the three cohorts (P0.05). Under propofol (n=6) and isoflurane (n=6), all three catecholamines significantly increased CBF (P<0.001). Dopamine caused the greatest increase in CBF, and was associated with significant increases in ICP (awake: P<0.001; propofol P<0.05; isoflurane P<0.001) and CVR (isoflurane P<0.05). No significant changes in CMRO₂ were demonstrated. Under propofol and isoflurane anaesthesia, the cerebrovascular effects of catecholamines were significantly different from the awake, physiological state, with dopamine demonstrating the most pronounced effects, particularly under propofol. Dopamine-induced hyperaemia was associated with other cerebrovascular changes. In the presence of an equivalent effect on mean arterial pressure, the exaggerated cerebrovascular effects under anaesthesia appear to be centrally mediated, possibly induced by propofol- or isoflurane-dependent changes in blood-brain barrier permeability, thereby causing a direct influence on the cerebral vasculature.http://www.aaic.net.au/Article.asp?D=200205

Quantitative MRI reveals the elderly ischemic brain is susceptible to increased early blood-brain barrier permeability following tissue plasminogen activator related to claudin 5 and occludin disassembly

Great uncertainty exists as to whether aging enhances the detrimental effects of tissue plasminogen activator (tPA) on vascular integrity of the ischemic brain. We hypothesized that tPA treatment would augment ischemic injury by causing increased blood-brain barrier (BBB) breakdown as determined by quantitative serial T 1 and T 2 magnetic resonance imaging (MRI), and the transfer constant for gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) from blood to brain in aged (18 to 20 months) compared with young (3 to 4 months) Wistar rats after middle cerebral artery occlusion, mediated through the acute disassembly of claudin 5 and occludin. Increased T 2 values over the first hour of postreperfusion were independently augmented following treatment with tPA (P<0.001) and aging (P<0.01), supporting a synergistic effect of tPA on the aged ischemic brain. Blood-brain barrier permeability for Gd-DTPA (K Gd) was substantial following reperfusion in all animal groups and was exacerbated by tPA treatment in the elderly rat (P<0.001). The frequency of hematoma formation was proportionately increased in the elderly ischemic brain (P<0.05). Both tPA and age independently increased claudin 5 and occludin phosphorylation during ischemia. Early BBB permeability detected by quantitative MRI following ischemic stroke is enhanced by increased age and tPA and is related to claudin 5 and occludin phosphorylation. \ua9 2011 ISCBFM All rights reserved.Peer reviewed: YesNRC publication: Ye

Imaging Corticospinal Degeneration in Neonatal Rats with Unilateral Cerebral Infarction

Recent human studies indicate that magnetic resonance (MR) imaging, particularly diffusion weighted imaging, detects abnormalities within the descending cortico-spinal tract following stroke. Whether these changes are directly related to processes of axonal degeneration and how MR changes (e.g. apparent diffusion coefficient of water (ADC) and T 2) vary in their diagnostic utility over time is not known. The present study demonstrates that a commonly used rat model of neonatal transient unilateral hypoxia-ischemia provides similar diffusion weighted and ADC changes in the cerebral peduncle as those observed in human neonates clinically. Imaging the descending cortico-spinal tract in this model at defined acute (1-3days) and chronic (1 and 4weeks) time points demonstrates increased T 2 and progressive changes in ADC within the descending cortico-spinal tract in the first days to weeks following hypoxia-ischemia with a normalization by 1week and further increases in ispilateral cerebral cortex by 4weeks. These imaging changes are associated with reduced axonal neurofilament staining both at the subacute and more chronic time points. This demonstrates directly the utility of ADC and T 2 MRI to detect acute changes in axons associated with early Wallerian degeneration. \ua9 2011.Peer reviewed: YesNRC publication: Ye

Targeted MRI and optical molecular imaging using gadolinium loaded small unilamellar vesicles

Noninvasive investigation of cellular and molecular processes becomes possible through the novel techniques, one of which is molecular imaging, where enhanced sensitivity is a key component for clinic translation of the technique. In this presentation, spontaneously forming, small unilamellar vesicles (ULVs) (30 nm in diameter) were used as a platform to build a bi-modal [i.e., optical and Magnetic Resonance Imaging (MRI)] targeted contrast agent for the molecular imaging of brain tumors. Small ULVs were loaded with a gadolinium (Gd) chelated lipid (Gd-DPTA-BOA), functionalized with targeting antibodies (anti-EGFR monoclonal and anti-IGFBP7 single domain), and incorporated a near infrared dye (Cy5.5). The resultant ULVs were characterized in vitro using small angle neutron scattering (SANS), in phantom MRI and dynamic light scattering (DLS). Targeted (with antibodies) and nontargeted-Gd loaded sULVs labeled with Cy5.5 were assessed in vivo in a mice brain tumor model using both optical imaging and MRI. The results demonstrated that a spontaneously forming, nanosized ULV loaded with a high payload of Gd can selectively target and image, using MR and optical imaging, brain tumor vessels when functionalized with antibodies. The unique features of these targeting ULVs make them promising molecular MRI contrast agents.Peer reviewed: YesNRC publication: Ye