ORCID Profile
0000-0002-9430-3314
Current Organisation
University of Adelaide
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Publisher: Springer Science and Business Media LLC
Date: 11-10-2016
Publisher: Public Library of Science (PLoS)
Date: 23-05-2014
Publisher: SAGE Publications
Date: 26-05-2021
DOI: 10.1177/0271678X211018901
Abstract: Hypertension is a leading risk factor for death and dependency after ischaemic stroke. However, administering anti-hypertensive medications post-stroke remains contentious with concerns regarding deleterious effects on cerebral blood flow and infarct expansion. This study sought to determine the effect of glyceryl trinitrate (GTN) treatment in both lissencephalic and gyrencephalic pre-clinical stroke models. Merino sheep underwent middle cerebral artery occlusion (MCAO) followed by GTN or control patch administration (0.2 mg/h). Monitoring of numerous physiologically relevant measures over 24 h showed that GTN administration was associated with decreased intracranial pressure, infarct volume, cerebral oedema and midline shift compared to vehicle treatment (p 0.05). No significant changes in blood pressure or cerebral perfusion pressure were observed. Using optical imaging spectroscopy and laser speckle imaging, the effect of varying doses of GTN (0.69–50 µg/h) on cerebral blood flow and tissue oxygenation was examined in mice. No consistent effect was found. Additional mice undergoing MCAO followed by GTN administration (doses varying from 0–60 µg/h) also showed no improvement in infarct volume or neurological score within 24 h post-stroke. GTN administration significantly improved numerous stroke-related physiological outcomes in sheep but was ineffective in mice. This suggests that, whilst GTN administration could potentially benefit patients, further research into mechanisms of action are required.
Publisher: Mary Ann Liebert Inc
Date: 11-2013
Abstract: Although clinical spinal cord injury (SCI) occurs within a closed environment, most experimental models of SCI create an open injury. Such an open environment precludes the measurement of intrathecal pressure (ITP), whose increase after SCI has been linked to the development of greater tissue damage and functional deficits. Raised ITP may be potentiated by edema, which we have recently shown to be associated with substance P (SP) induced neurogenic inflammation in both traumatic brain injury and stroke. The present study investigates whether SP plays a similar role as a mediator of neurogenic inflammation after SCI. A closed balloon compression injury was induced at T10 in New Zealand white rabbits. Animals were thereafter assessed for blood spinal cord barrier (BSCB) permeability, edema, ITP, histological outcome, and functional outcome from 5 h to 2 weeks post-SCI. The balloon compression model produced significant increases in BSCB permeability, edema, and ITP along with significant functional deficits that persisted for 2 weeks. Histological assessment demonstrated decreased SP immunoreactivity in the injured spinal cord while NK1 receptor immunoreactivity initially increased before returning to sham levels. In addition, aquaporin 4 immunoreactivity increased early post-SCI, implicating this water channel in the development of edema after SCI. The changes described in the present study support a role for SP as a mediator of neurogenic inflammation after SCI.
Publisher: MDPI AG
Date: 20-09-2010
Publisher: Wiley
Date: 15-02-2016
Abstract: Adult male Sprague Dawley rats were euthanized and placed in a horizontal or vertical (head-down) position at room temperature, after which brain fluid content was measured by a moisture analysis technique at variable time points. No significant difference in brain fluid content was observed between horizontal and vertical postmortem positions. A significant increase in brain fluid content was demonstrated 3, 6, and 24 h after death, with maximal fluid content observed at 24 h. Specifically, the brain fluid content of control animals was 77.79 ± 0.36%, increasing to 80.05 ± 0.22% at 24 h (p < 0.0001). This study has demonstrated no significant differences in brain fluid content related to postmortem position, suggesting that a head-down position is not associated with increased brain fluid content or swelling. However, significant temporal increases in brain fluid content after death, most likely related to cerebral liquefaction, occur.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
Publisher: Springer Vienna
Date: 2013
DOI: 10.1007/978-3-7091-1434-6_59
Abstract: The blood spinal cord barrier (BSCB) is disrupted following spinal cord injury (SCI) resulting in vasogenic edema and increased intrathecal pressure (ITP). The neuropeptide substance P (SP) has been implicated in the development of blood-brain barrier (BBB) disruption, edema, and increased intracranial pressure following brain injury, although it has not been investigated in SCI. The balloon compression model of experimental SCI has many advantages in that it replicates the "closed" environment observed clinically. Accordingly, this study characterized whether this model produces an increase in BSCB permeability and edema, and whether a SP, NK1 tachykinin receptor antagonist, N-acetyl-L-tryptophan (NAT) reduces such BSCB disruption and edema formation. At 30 min post-injury, animals were administered 2.5 mg/kg NAT or saline. Subgroups of animals were assessed for BSCB permeability (Evan's Blue) and spinal cord edema (wet weight/dry weight). BSCB permeability and edema were significantly increased in injured groups compared with sham (p < 0.001). There was no significant difference between vehicle and NAT treatment. We conclude that the balloon compression model of SCI produces significant BSCB disruption although NAT treatment did not attenuate BSCB permeability or edema. Further studies are required to fully elucidate the role of SP following SCI.
Publisher: Springer Vienna
Date: 2013
DOI: 10.1007/978-3-7091-1434-6_37
Abstract: Increased intracranial pressure (ICP) following acute brain injury requires the accumulation of additional water in the intracranial vault. One source of such water is the vasculature, although the mechanisms associated with control of blood-brain barrier permeability are unclear. We have recently shown that acute brain injury, such as neurotrauma and stroke, results in perivascular accumulation of the neuropeptide, substance P. This accumulation is associated with increased blood-brain barrier permeability and formation of vasogenic edema. Administration of a substance P antagonist targeting the tachykinin NK1 receptor profoundly reduced the increased blood-brain barrier permeability and edema formation, and in small animal models of acute brain injury, improved functional outcome. In a large, ovine model of experimental traumatic brain injury, trauma resulted in a significant increase in ICP. Administration of an NK1 antagonist caused a profound reduction in post--traumatic ICP, with levels returning to normal within 4 h of drug administration. Substance P NK1 antagonists offer a novel therapeutic approach to the treatment of acute brain injury.
Publisher: Wiley
Date: 06-2012
Publisher: Frontiers Media SA
Date: 05-07-2019
Publisher: Mary Ann Liebert Inc
Date: 03-2020
Publisher: Mary Ann Liebert Inc
Date: 15-03-2015
Abstract: Raised intrathecal pressure (ITP) after traumatic spinal cord injury (SCI) is a critically important aspect of injury development that may result in significantly greater tissue damage and worsened functional outcome. Raised ITP is caused by the accumulation of blood and/or water (edema), and while their occurrence after traumatic SCI has been well established, the relative contribution of both processes to the development of ITP after SCI has not yet been determined. Accordingly, the current study investigates the temporal profile of raised ITP after traumatic SCI in relation to both hemorrhage and edema development. A closed balloon compression injury was induced at T10 in New Zealand White rabbits. Animals were thereafter assessed for spinal water content (edema), ITP, lesion and hemorrhage volume, and albumin immunoreactivity from 5 h to 1 week post-SCI. Early increases in ITP at 5 h post-injury were associated with significant increases in blood volume. ITP, however, was maximal at 3 days post-SCI, at which time there was an associated significant increase in edema that persisted for 1 week. We conclude that raised ITP after traumatic SCI is initially driven by volumetric increases in hemorrhage, while edema becomes the primary driver of ITP at 3 days post-injury.
Publisher: Frontiers Media SA
Date: 09-07-2019
Publisher: Elsevier BV
Date: 10-2023
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.NEULET.2017.03.020
Abstract: Spinal cord injury (SCI) researchers have predominately utilized rodents for SCI modeling and experimentation. Unfortunately, a large number of novel therapies developed in rodent models have failed to demonstrate efficacy in human clinical trials which suggests that improved animal models are an important translational tool. Recently, porcine models of SCI have been identified as a valuable intermediary model for preclinical evaluation of promising therapies to aid clinical translation. However, the localization of the major spinal tracts in pigs has not yet been described. Given that significant differences exist in the location of the corticospinal tract (CST) between rodents and humans, determining its location in pigs will provide important information related to the translational potential of the porcine pre-clinical model of SCI. Thus, the goal of this study is to investigate the localization of the CST within the porcine spinal cord. Mature female domestic pigs (n=4, 60kg) received microinjections of fluorescent dextran tracers (Alexa Fluor, 10,000MW) into the primary motor cortex, using image-guided navigation (StealthStation
Publisher: Wiley
Date: 28-08-2014
DOI: 10.1111/JNC.12391
Abstract: We have previously shown that following traumatic brain injury (TBI) the presence of the amyloid precursor protein (APP) may be neuroprotective. APP knockout mice have increased neuronal death and worse cognitive and motor outcomes following TBI, which is rescued by treatment with exogenous sAPPα (the secreted ectodomain of APP generated by α-secretase cleavage). Two neuroprotective regions were identified in sAPPα, the N and C-terminal domains D1 and D6a/E2 respectively. As both D1 and D6a/E2 contain heparin binding activity it was hypothesized that this is responsible for the neuroprotective activity. In this study, we focused on the heparin binding site, encompassed by residues 96-110 in D1, which has previously been shown to have neurotrophic properties. We found that treatment with APP96-110 rescued motor and cognitive deficits in APP-/- mice following focal TBI. APP96-110 also provided neuroprotection in Sprague-Dawley rats following diffuse TBI. Treatment with APP96-110 significantly improved functional outcome as well as preserve histological cellular morphology in APP-/- mice following focal controlled cortical impact injury. Furthermore, following administration of APP96-110 in rats after diffuse impact acceleration TBI, motor and cognitive outcomes were significantly improved and axonal injury reduced. These data define the heparin binding site in the D1 domain of sAPPα, represented by the sequence APP96-110, as the neuroprotective site to confer neuroprotection following TBI. The product of α-secretase cleavage of the amyloid precursor protein, sAPPα is neuroprotective following traumatic brain injury (TBI). Of interest was whether this neuroprotective activity could be further delineated to a heparin binding region within sAPPα, corresponding to the region APP96-110 (see diagram demonstrating the domain structure of sAPPα). Indeed treatment with APP96-110 improved functional outcome following TBI, an effect that was not seen with a mutated version of the peptide that had reduced heparin binding affinity.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2013
DOI: 10.1038/SC.2013.136
Abstract: An immunohistological assessment of substance P (SP), its NK1 receptor and claudin-5 in human spinal cord injury (SCI) tissue. To determine whether SP and NK1 receptor immunoreactivity are altered following human traumatic SCI. Australia. SP has been implicated in the development of neurogenic inflammation and subsequent edema development following both traumatic brain injury and ischemic stroke. In these conditions, inhibition of its NK1 receptor has been shown to be neuroprotective as reflected in a reduction of edema and improved functional outcome. However, the role of SP following human SCI has not yet been assessed. Archived human SCI tissue was grouped according to survival times: control (no injury n=5) immediate (death within an hour of the incident n=6) 2-5 h (n=3) 3 days (n=5) 1 week (n=3) and 3-4 weeks (n=6). Sections were assessed for SP, its NK1 receptor and claudin-5 using immunohistochemical techniques. Following SCI, dorsal horn SP immunoreactivity demonstrated a profound decrease compared with control tissue, indicating the loss of SP with SCI. A marked increase in perivascular NK1 staining was demonstrated after SCI compared with control levels. No obvious change in claudin-5 immunoreactivity was present immediately following injury, however, by 1 week post-SCI, decreased levels were noted. This study demonstrates that severe acute traumatic human SCI results in decreased SP and an immediate increase in NK1 receptor immunoreactivity, suggesting that there is a neurogenic inflammatory component following human SCI.
Publisher: Medknow
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 18-01-2023
DOI: 10.1186/S12987-022-00401-4
Abstract: Detecting changes in pulsatile cerebrospinal fluid (CSF) flow may assist clinical management decisions, but spinal CSF flow is relatively understudied. Traumatic spinal cord injuries (SCI) often cause spinal cord swelling and subarachnoid space (SAS) obstruction, potentially causing pulsatile CSF flow changes. Pigs are emerging as a favoured large animal SCI model therefore, the aim of this study was to characterise CSF flow along the healthy pig spine. Phase-contrast magnetic resonance images (PC-MRI), retrospectively cardiac gated, were acquired for fourteen laterally recumbent, anaesthetised and ventilated, female domestic pigs (22–29 kg). Axial images were obtained at C2/C3, T8/T9, T11/T12 and L1/L2. Dorsal and ventral SAS regions of interest (ROI) were manually segmented. CSF flow and velocity were determined throughout a cardiac cycle. Linear mixed-effects models, with post-hoc comparisons, were used to identify differences in peak systolic/diastolic flow, and maximum velocity (cranial/caudal), across spinal levels and dorsal/ventral SAS. Velocity wave speed from C2/C3 to L1/L2 was calculated. PC-MRI data were obtained for 11/14 animals. Pulsatile CSF flow was observed at all spinal levels. Peak systolic flow was greater at C2/C3 (dorsal: − 0.32 ± 0.14 mL/s, ventral: − 0.15 ± 0.13 mL/s) than T8/T9 dorsally (− 0.04 ± 0.03 mL/s p 0.001), but not different ventrally (− 0.08 ± 0.08 mL/s p = 0.275), and no difference between thoracolumbar levels (p 0.05). Peak diastolic flow was greater at C2/C3 (0.29 ± 0.08 mL/s) compared to T8/T9 (0.03 ± 0.03 mL/s, p 0.001) dorsally, but not different ventrally (p = 1.000). Cranial and caudal maximum velocity at C2/C3 were greater than thoracolumbar levels dorsally (p 0.001), and T8/T9 and L1/L2 ventrally (p = 0.022). Diastolic velocity wave speed was 1.41 ± 0.39 m/s dorsally and 1.22 ± 0.21 m/s ventrally, and systolic velocity wave speed was 1.02 ± 0.25 m/s dorsally and 0.91 ± 0.22 m/s ventrally. In anaesthetised and ventilated domestic pigs, spinal CSF has lower pulsatile flow and slower velocity wave propagation, compared to humans. This study provides baseline CSF flow at spinal levels relevant for future SCI research in this animal model.
No related grants have been discovered for Anna Leonard.