Recurrent mild cerebral ischemia: enhanced brain injury following acute compared to subacute recurrence in the rat

Additional file 3. Histological assessments for Figure 3. Shown are the data for each animal at either 1d or 3d post a single mild ischemic insult. The H&E scores, the ED1 counts and the GFAP scores are presented

Retraction notice to "Differential impact of diabetes and hypertension in the brain: Adverse effects in grey matter" [Neurobiol. Dis., 44 (2011) 161–173, http://dx.doi.org/10.1016/j.nbd.2011.06.005]

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Advanced experimental magnetic resonance imaging

Magnetic resonance imaging (MRI) is a noninvasive imaging technique with an extensive range of applications in biomedical diagnostic imaging. This chapter reviews selected aspects of advanced experimental MRI with a focus on brain imaging using animal MRI systems and their application to improving understanding of the pathophysiology of the brain. Anatomical MRI is advancing diagnostic applications through the increased use of quantitative morphology and MR relaxation times. Microscopic imaging is progressing with improvements in spatial resolution. Diffusion MRI imaging continues to enhance the information it provides on tissue and cellular or axonal structure using diffusion tensor imaging and diffusion tensor tractography. Magnetization transfer imaging is also providing supplementary information on pathophysiological changes in tissue, particularly white matter. Functional MRI in animals in conjunction with other invasive methods has improved our understanding of the fMRI response. Molecular MRI is a rapidly growing field that holds promise for the noninvasive imaging of molecular cellular processes using targeted or responsive contrast agents.Peer reviewed: YesNRC publication: Ye

Chronic treatment with Losartan and cerebral ischemic tolerance.

Clinical trials have suggested that Losartan has beneficial effects on preventing stroke beyond its antihypertensive properties. Although there is evidence for Losartan reducing ischemic damage following a highly localized type of stroke, its role in larger focal and global ischemic insults and the importance of blood pressure change are not known. We hypothesized that pre-treatment with Losartan would enhance the tolerance of the brain to both global and focal ischemia. Two weeks prior to ischemia, rats were administered either Losartan 50 mg/day in their drinking water or vehicle (water) alone. The neuroprotective effects of Losartan were assessed by either global ischemia using 10 minutes of four-vessel occlusion (4-VO) or 90 minutes of focal ischemia by distal middle cerebral artery occlusion. Seven days after 4-VO, histological assessment of cellular injury in the hippocampal CA1 region was performed. In addition, brain injury following transient MCAO was assessed by magnetic resonance imaging and histology. Losartan pretreatment reduced neuronal damage following global ischemia, as detected by 92 percent versus 46 percent neuronal cell death in CA1 region for Control and Losartan groups, respectively (p<0.001). Following transient ischemia, pre-treatment with Losartan resulted in a reduced infarct volume: measured as 41 percent \ub1 10 percent versus 26 percent \ub1 12 percent of the hemisphere in control and Losartan groups, respectively (p<0.04). These protective effects were observed in spite of 12\u201315 percent reductions in blood pressure in the Losartan treated group. Our results demonstrate that pre-treatment with Losartan enhances the tolerance of the brain to either global or focal ischemia and provides further evidence for Losartan as a treatment for stroke prevention.Peer reviewed: YesNRC publication: Ye

Mild cerebral hypoxia-ischemia produces a sub-acute transient inflammatory response that is less selective and prolonged after a substantial insult

Cerebral ischemia initiates various injurious processes including neuroinflammatory responses such as activation of microglia and increases in cytokine and nitric oxide release. Evidence primarily from in vitro studies, indicates that neuroinflammatory effects can be either beneficial or harmful, possibly related to stimulus strength. We investigated using in vivo models, the effect of a mild or substantial cerebral hypoxia-ischemia on: cerebral microglial/macrophage activation (ED1), pro-inflammatory cytokines (tumor necrosis factor-alpha), nitrosative stress (nitrotyrosine) and permanent brain damage. A mild insult produced a transient (1-2 days post) increase in activated microglia/macrophages within subcortical white and not gray matter but transiently increased cytokine or nitrotyrosine expression in cortex and not white matter. There was also prolonged scattered cell death in cortex and white matter over weeks along with loss of myelin/axons and cortical atrophy at 4 weeks post-insult. In contrast, a substantial insult produced white and gray matter necrosis, cyst formation and atrophy, along with increases in tumor necrosis factor and nitrotyrosine staining within both white and gray matter starting at 1-2 days post-insult. Microglial/macrophage staining was increased starting at 1-week post a substantial insult and remained elevated for weeks thereafter. Thus, a transient neuroinflammatory response occurs following a mild insult whereas prolonged scattered cell death occurs for weeks, particularly in white matter. Insult severity also affects the progression of the neuroinflammatory response, which is prolonged after a substantial insult. Effective therapy will need to be customized for insult severity and timing; and, monitoring the injury processes with imaging or biomarkers may help guide treatment.Peer reviewed: YesNRC publication: Ye

Infrared optical imaging of matrix metalloproteinases (MMPs) up regulation following ischemia reperfusion is ameliorated by hypothermia

Abstract Background We investigated the use of a new MMP activatable probe MMPSense™ 750 FAST (MMPSense750) for in-vivo visualization of early MMP activity in ischemic stroke. Following middle cerebral artery occlusion (MCAO) optical imaging was performed. Near-infrared (NIR) fluorescent images of MMPSense activation were acquired using an Olympus fluorescent microscope, 1.25x objective, a CCD camera and an appropriate filter cube for detecting the activated probe with peak excitation and emission at 749 and 775 nm, respectively. Images were acquired starting at 2 or 24 hours after reperfusion over the ipsilateral and contralateral cortex before and for 3 hours after, MMPSense750 was injected. Results Increased intensities ipsilaterally were observed following MMPSense750 injection with ischemic injury but not in sham animals. There were significant ipsilateral and contralateral differences at 15 minutes (P Conclusions Matrix-metalloproteinase upregulation in ischemia reperfusion can be imaged acutely in-vivo with NIRF using MMPSense750. Hypothermia attenuated both the optical increase in intensity after MMPSense750 and the increase in MMP-9 protein expression supporting the proof of concept that NIRF imaging using MMPSense can be used to assess potential therapeutic strategies for stroke treatment.</p

Infrared optical imaging of matrix metalloproteinases (MMPs) up regulation following ischemia reperfusion is ameliorated by hypothermia

Background: We investigated the use of a new MMP activatable probe MMPSense\u2122 750 FAST (MMPSense750) for in-vivo visualization of early MMP activity in ischemic stroke. Following middle cerebral artery occlusion (MCAO) optical imaging was performed. Near-infrared (NIR) fluorescent images of MMPSense activation were acquired using an Olympus fluorescent microscope, 1.25x objective, a CCD camera and an appropriate filter cube for detecting the activated probe with peak excitation and emission at 749 and 775 nm, respectively. Images were acquired starting at 2 or 24 hours after reperfusion over the ipsilateral and contralateral cortex before and for 3 hours after, MMPSense750 was injected.Results: Increased intensities ipsilaterally were observed following MMPSense750 injection with ischemic injury but not in sham animals. There were significant ipsilateral and contralateral differences at 15 minutes (P <0.05) in early ischemic reperfusion and at time 0 in 24 hours post ischemia (P <0.05) which persisted at 180 minutes in both these groups (P <0.01), but not following sham surgery. The increase in ipsilateral signal intensity was attenuated by hypothermia. These observations corresponded with a significant increase in the total MMP-9 protein levels, 5 and 24 hours following ischemia reperfusion (P <0.05) and their reduction by hypothermia.Conclusions: Matrix-metalloproteinase upregulation in ischemia reperfusion can be imaged acutely in-vivo with NIRF using MMPSense750. Hypothermia attenuated both the optical increase in intensity after MMPSense750 and the increase in MMP-9 protein expression supporting the proof of concept that NIRF imaging using MMPSense can be used to assess potential therapeutic strategies for stroke treatment.Peer reviewed: YesNRC publication: Ye