Sustained sensorimotor impairments after endothelin-1 induced focal cerebral ischemia (stroke) in aged rats

Soleman, Sara; Yip, Ping K.; Leasure, J. Leigh; Moon, Lawrence

doi:10.1016/j.expneurol.2009.11.007

Cited by 59 publications

(59 citation statements)

References 63 publications

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“…One possibility is that the same aging mechanism may affect both brain and kidneys in some aged animals. For instance, overactivation of the endothelin system may damage both brain and kidneys by impairing microvascular function in these organs (Zhang et al 1994;Kuiper et al 2008;Seccia et al 2008;Soleman et al 2010). On the other hand, the impaired kidney function results in accumulation of metabolic toxic products which could impair brain function (e.g., cognition).…”

Section: Discussionmentioning

confidence: 99%

Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production

Zuo

Wang

et al. 2010

AGE

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The purpose of this study was to determine changes in klotho, endothelin (ET) receptors, and superoxide production in kidneys of aged rats and whether these changes are exacerbated in aged rats with cognitive impairment. Twenty aged rats (male, 27 months) were divided into an Old Impaired group (n=9) and an Old Intact group (n=11) according to a cognitive function test. A group of 12-month-old rats (n=10) was used as a Young Intact group. Serum creatinine was increased significantly in the Old Impaired group, suggesting impaired renal function. Aged rats showed glomerulosclerosis and tubulointerstitialfibrosis. These pathological changes were markedly aggravated in the old cognitively impaired than in the old cognitively intact animals. Notably, aged rats demonstrated a significant decrease in klotho protein expression in renal cortex and medulla. Protein expression of IL-6, Nox2, ETa receptors and superoxide production were increased whereas mitochondrial SOD (MnSOD) and ETb receptors expression were decreased in kidneys of the aged rats. Interestingly, these changes were more pronounced in the old impaired than in the old intact rats. In conclusion, the aging-related kidney damage was exacerbated in aged rats with cognitive impairment. Klotho, ETB, and MnSOD were downregulated but ETa, IL-6, Nox2, and superoxide production were upregulated in the aging-related kidney damage. These changes were more pronounced in rats with cognitive impairment.

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Section: Discussionmentioning

confidence: 99%

Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production

Zuo

Wang

et al. 2010

AGE

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“…7 ET-1 was injected at 0.5 μL/min by an infusion pump, and the needle was left in situ for 3 minutes after injection before being slowly removed. The dose of ET-1 for each injection site was 2 μL.…”

Section: Et-1 Stroke Modelmentioning

confidence: 99%

Constraint-Induced Movement Therapy Overcomes the Intrinsic Axonal Growth–Inhibitory Signals in Stroke Rats

Zhao

Xiao

et al. 2013

Stroke

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Forty-two male Wistar rats (200-250 g) were randomly assigned as sham-operated rats (SHAM; n=12), rats subjected to cerebral ischemia (ISC; n=15), and rats with cerebral ischemia that were later treated with CIMT (ISC+CIMT; n=15). All rats were housed under controlled temperature in a 12-hour light/dark cycle with easy access to food and water and assigned to groups with a minimum of 4 animals per enclosure. Protocols and procedures were approved by the Institutional Animal Care and Use Committee of China Medical University (permit No. SCXK [Liao] 2008-0005).Background and Purpose-Constraint-induced movement therapy (CIMT) improves functional outcome in patients with stroke possibly through structural plasticity. We hypothesized that CIMT could enhance axonal growth by overcoming the intrinsic growth-inhibitory signals, leading eventually to improved behavioral performance in stroke rats. Methods-Focal cerebral ischemia was induced by intracerebral injection of endothelin-1. Adult Wistar rats were divided into a sham-operated group, an ischemic group, and an ischemic group treated with CIMT. CIMT started at postoperative day 7 and continued for 3 weeks. Biotinylated dextran amine was injected into the contralateral sensorimotor cortex at postoperative day 14 to trace crossing axons at the cervical spinal cord. The expressions of Nogo-A, Nogo receptor, RhoA, and Rho-associated kinase in the peri-infarct cortex, and the expressions of biotinylated dextran amine, growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated spinal cord were measured by immunohistochemistry and Western blots. Behavioral recovery was analyzed at postoperative days 29 to 32. Results-Infarct volumes were not different between groups after stroke. CIMT significantly increased the length and the number of midline crossings of contralateral corticospinal axons to the denervated cervical spinal cord. CIMT significantly decreased the expressions of Nogo-A/Nogo receptor and RhoA/Rho-associated kinase in the peri-infarct cortex, and increased the expressions of growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated cervical spinal cord. Behavioral performances assessed by the beam-walking test and the water maze test were improved significantly by CIMT. Conclusions-CIMT promoted poststroke synaptic plasticity and axonal growth at least partially by overcoming the intrinsic growth-inhibitory signaling, leading to improved behavioral outcome. (Stroke. 2013;44:1698-1705.)

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“…ET-1 can also be applied onto the cortical surface of the rat brain [12] , where it causes a critical reduction in CBF resulting in infarcts involving all layers of the neocortex. Variability of infarct size and greater accuracy of their location can be achieved by stereotactic intracortical injections of ET-1 into specific regions of the sensorimotor cortex, which produce impairment of the forelimb function [13] or sustained and robust sensorimotor deficits resembling functional impairments after stroke in humans [14] . In a comparative study of various ET-1 applications, the intracerebral injection into the forelimb motor region of the cortex and especially the combination of intracortical and intrastriatal injections produced more consistent injuries resulting in more consistent behavioral deficits than applications near the MCA or on the cortex.…”

Section: Introductionmentioning

confidence: 99%

Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1

et al. 2016

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Background: Cortical injections of the vasoconstrictor endothelin-1 (ET1) have widely been used to induce focal circumscribed ischemic lesions in the motor cortex of rodents in the context of stroke recovery studies. In order to apply this model correctly, it is essential to understand the time course of regional flow changes and of the development of penumbra and infarction. Methods: Multitracer micro-PET of ET1 focal ischemia in rats was performed using [¹¹C]-flumazenil ([¹¹C]FMZ) as a flow- and viability tracer and [¹⁸F]-fluoromisonidazole ([¹⁸F]FMISO) as hypoxia marker in order to characterize the physiological time-course of this model. Nine adult Sprague-Dawley rats received stereotaxic injections of ET1 into the right primary motor cortex, 3 served as controls. PET imaging was started 2, 3 and 20 h after the last ET1 injection. Histology was obtained at the end of the scans. Standardized uptake value ratios reflecting cerebral blood flow (CBF), [¹¹C]FMZ-binding and [¹⁸F]FMISO-retention were calculated for the region of hypoperfusion and the normoperfused cortex. Results: CBF in the hypoperfused cortex was significantly reduced (p < 0.01) at 5 h (0.58 ± 0.025), 6 h (0.54 ± 0.043) and 23 h (0.66 ± 0.024) compared to controls (1.00 ± 0.011) and moderately reduced (p < 0.05) in the remainder of the affected hemisphere at 5 h (0.93 ± 0.036). [¹¹C]FMZ-binding was within the control range at all time points. Significant [¹⁸F]FMISO-retention (1.16 ± 0.091, p < 0.05) was observed only after 6 h in the ischemic core that later turned into infarct. Conclusion: ET1 injections yield reproducible, slowly developing ischemic lesions with constant levels of hypoperfusion. This multitracer micro-PET study suggests that the ET1 model is appropriate for inducing chronic circumscribed ischemic lesions but seems to be less suited for studying acute stroke pathophysiology.

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Sustained sensorimotor impairments after endothelin-1 induced focal cerebral ischemia (stroke) in aged rats

Cited by 59 publications

References 63 publications

Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production

Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production

Constraint-Induced Movement Therapy Overcomes the Intrinsic Axonal Growth–Inhibitory Signals in Stroke Rats

Which Aspects of Stroke Do Animal Models Capture? A Multitracer Micro-PET Study of Focal Ischemia with Endothelin-1

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