An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat

Windle, Victoria; Szymanska, A; Granter‐Button, Shirley; White, C.H.; Buist, Richard; Peeling, James; Corbett, Dale

doi:10.1016/j.expneurol.2006.04.012

Cited by 166 publications

(164 citation statements)

References 39 publications

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“…In accordance with earlier studies, 5,22 ET-1 applied to the forelimb motor cortex and dorsolateral striatum produced profound impairments in sensorimotor function as demonstrated with the NDS assessments (Figure 1). Although the NDS was used to confirm ischemic injury and persisting sensorimotor deficits over the short time course of this study, these assessments are generally not sensitive to detecting rehabilitative changes in the long term because of the robust spontaneous recovery as observed in the current study.…”

Section: Discussionsupporting

confidence: 91%

“…A midline incision was made in the scalp and three burr holes drilled above the forelimb motor cortex and dorsolateral striatum. Focal ischemia was induced using injections of 400 pmol/mL ET-1 (CalBiochem, Hornby, ON, Canada): 2 mL at each of the forelimb cortical sites and 1 mL at the striatal site: 22 (1) forelimb sensorimotor cortexanteroposterior 0.0 mm/mediolateral þ / À 2.5 mm/dorsoventral À 2.3 mm; (2) forelimb sensorimotor cortex-anteroposterior þ 2.3 mm/mediolateral þ / À 2.5 mm/dorsoventral À 2.3 mm; and (3) dorsolateral -striatum anteroposterior þ 0.7 mm/mediolateral þ / À 3.8 mm/dorsoventral À 7.0 mm. The ischemic hemisphere was determined for each animal based on paw preferences observed during preexposure to the reaching apparatus (see below).…”

Section: Surgerymentioning

confidence: 99%

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Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Clarke

Langdon

Corbett

2014

J Cereb Blood Flow Metab

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Early poststroke rehabilitation effectively improves recovery of function, likely by engaging multiple plasticity processes through use-dependent activation of neural circuits. The loci of such neuroplastic reorganization have not been examined during the initial phase of behavioral recovery. In the current study, we sought to evaluate sub-components of rehabilitation and to identify brain sites first engaged by early rehabilitation. Rats were subjected to endothelin-1 ischemia and placed in either enriched environment (EE), daily reach training (RT), combination of enriched environment and reach training (ER), or standard housing (ST) starting 7 days post ischemia. Functional and histopathological assessments were made after 2, 5, and 10 days of treatment. Animals exposed to 10 days of ER treatment exhibited significantly more use-dependent neuronal activity (FosB/DFosB expression) in perilesional cortex than those exposed to EE, RT, or ST treatments. Similar trends were observed in both perilesional striatum and contralesional forelimb motor cortex. This use-dependent plasticity was not explained by differences in neuronal death, inflammation, or lesion volume. The increased activity likely contributes to the neuroplastic changes and functional recovery observed after extended periods of rehabilitation. Importantly, EE or RT alone did not lead to enhanced activity suggesting that combination therapy is necessary to promote maximum recovery.

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Section: Discussionsupporting

confidence: 91%

Section: Surgerymentioning

confidence: 99%

Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Clarke

Langdon

Corbett

2014

J Cereb Blood Flow Metab

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“…Endothelin-1 is a potent vasoconstrictor that has been used to produce ischemic infarcts [31] . Previously, it has been determined that reduction of blood flow to 20% of normal flow results in ischemic injury [32] .…”

Section: Neuronal Hent1 Expression Is Associated With Larger Endothelmentioning

confidence: 99%

Regulation of adenosine levels during cerebral ischemia

et al. 2012

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Adenosine is a neuromodulator with its level increasing up to 100-fold during ischemic events, and attenuates the excitotoxic neuronal injury. Adenosine is produced both intracellularly and extracellularly, and nucleoside transport proteins transfer adenosine across plasma membranes. Adenosine levels and receptor-mediated effects of adenosine are regulated by intracellular ATP consumption, cellular release of ATP, metabolism of extracellular ATP (and other adenine nucleotides), adenosine influx, adenosine efflux and adenosine metabolism. Recent studies have used genetically modified mice to investigate the relative contributions of intra-and extracellular pathways for adenosine formation. The importance of cortical or hippocampal neurons as a source or a sink of adenosine under basal and hypoxic/ischemic conditions was addressed through the use of transgenic mice expressing human equilibrative nucleoside transporter 1 (hENT1) under the control of a promoter for neuron-specific enolase. From these studies, we conclude that ATP consumption within neurons is the primary source of adenosine in neuronal cultures, but not in hippocampal slices or in vivo mice exposed to ischemic conditions.

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“…Our results demonstrated that the ET-1 multi-injection protocol employed produced reproducible lesions to brain areas that control forelimb function (Figure 1), specifically, the forelimb sensorimotor cortex and lateral striatum. Resulting infarcts were highly reproducible, were notably smaller than those previously reported using similar methods [22] while still producing reasonably long-lasting functional deficits (Figure 2), thereby preserving more neural tissue to support potential neuroplastic changes. It is possible that a larger stroke injury would have produced longer-lasting deficits that would improve opportunities for detecting accelerated recovery, but on the other hand a larger infarct could compromise rehabilitation by destroying excess neural substrate.…”

Section: Discussionmentioning

confidence: 71%

“…Endothelin-1 reduces local blood flow to produce ischemic injury, either when injected proximal to the MCA [19] , applied topically to the cortical surface [20] , injected intracerebrally [15] , or when used as a combination of intracerebral and topical application [21] . Intracerebral injection of ET-1 permits the induction of ischemic injury to the forelimb sensorimotor cortex as well as subcortical regions [15,17,22] allows for gradual reperfusion of circulation over the course of several hours [20,22,23] , and is characterized by a low mortality rate compared to MCAo [22,24] , making this method an attractive option for studying post-ischemic rehabilitation.…”

Section: Introductionmentioning

confidence: 99%

A novel approach to induction and rehabilitation of deficits in forelimb function in a rat model of ischemic stroke

et al. 2012

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Aim: Constraint-induced movement therapy (CIMt), which forces use of the impaired arm following unilateral stroke, promotes functional recovery in the clinic but animal models of CIMT have yielded mixed results. The aim of this study is to develop a refined endothelin-1 (ET-1) model of focal ischemic injury in rats that resulted in reproducible, well-defined lesions and reliable upper extremity impairments, and to determine if an appetitively motivated form of rehabilitation (voluntary forced use movement therapy; FuMt) would accelerate post-ischemic motor recovery. Methods: Male Sprague Dawley rats (3 months old) were given multiple intracerebral microinjections of et-1 into the sensorimotor cortex and dorsolateral striatum. Sham-operated rats received the same surgical procedure up to but not including the drill holes on the skull. Functional deficits were assessed using two tests of forelimb placing, a forelimb postural reflex test, a forelimb asymmetry test, and a horizontal ladder test. In a separate experiment et-1 stroke rats were subjected to daily rehabilitation with FuMt or with a control therapy beginning on post-surgery d 5. Performance and post-mortem analysis of lesion volume and regional BDnF expression were measured. Results: Following microinjections of ET-1 animals exhibited significant deficits in contralateral forelimb function on a variety of tests compared with the sham group. These deficits persisted for up to 20 d with no mortality and were associated with consistent lesion volumes. FUMT therapy resulted in a modest but significantly accelerated recovery in the forelimb function as compared with the control therapy, but did not affect lesion size or BDnF expression in the ipsilesional hemisphere. Conclusion: We conclude that refined ET-1 microinjection protocols and forcing use of the impaired forelimb in an appetitively motivated paradigm may prove useful in developing strategies to study post-ischemic rehabilitation and neuroplasticity.

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An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat

Cited by 166 publications

References 39 publications

Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Early Poststroke Experience Differentially Alters Periinfarct Layer II and III Cortex

Regulation of adenosine levels during cerebral ischemia

A novel approach to induction and rehabilitation of deficits in forelimb function in a rat model of ischemic stroke

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