Dataset Information

Focal Malonate Injection Into the Internal Capsule of Rats as a Model of Lacunar Stroke.

ABSTRACT: Background: Stroke is the first cause of disability in adults in western countries. Infarct of the internal capsule (IC) may be related to motor impairment and poor prognosis in stroke patients. Functional deficits due to medium-sized infarcts are difficult to predict, except if the specific site of the lesion is taken into account. None of the few pre-clinical models recapitulating this type of stroke has shown clear, reproducible, and long-lasting sensorimotor deficits. Here, we developed a rat model of lacunar infarction within the IC, key structure of the sensorimotor pathways, by precise injection of malonate. Methods: The mitochondrial toxin malonate was injected during stereotactic surgery into the IC of rat brains. Rats were divided in three groups: two groups received malonate solution at 1.5M (n = 12) or at 3M (n = 10) and a sham group (n = 5) received PBS. Three key motor functions usually evaluated following cerebral lesion in the clinic strength, target reaching, and fine dexterity were assessed in rats by a forelimb grip strength test, a skilled reaching task (staircase) for reaching and dexterity, and single pellet retrieval task. Sensorimotor functions were evaluated by a neurological scale. Live brain imaging, using magnetic resonance (MRI), and post-mortem immunohistochemistry in brain slices were performed to characterize the lesion site after malonate injection. Results: Intracerebral injection of malonate produced a 100% success rate in inducing a lesion in the IC. All rats receiving the toxin, regardless the dose injected, had similar deficits in strength and dexterity of the contralateral forepaw, and showed significant neurological impairment. Additionally, only partial recovery was observed with respect to strength, while no recovery was observed for dexterity and neurological deficit. MRI and immunostaining show volume size and precise location of the lesion in the IC, destruction of axonal structures and Wallerian degeneration of fibers in the area above the injection site. Conclusions: This pre-clinical model of lacunar stroke induces a lesion in the IC with measurable and reproducible sensorimotor deficits, and limited recovery with stabilization of performance 2 weeks post-injury. Future therapies in stroke may be successfully tested in this model.

SUBMITTER: Cirillo C

PROVIDER: S-EPMC6297868 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Focal Malonate Injection Into the Internal Capsule of Rats as a Model of Lacunar Stroke.

Cirillo Carla C Le Friec Alice A Frisach Isabelle I Darmana Robert R Robert Lorenne L Desmoulin Franck F Loubinoux Isabelle I

Frontiers in neurology 20181211

<b>Background:</b> Stroke is the first cause of disability in adults in western countries. Infarct of the internal capsule (IC) may be related to motor impairment and poor prognosis in stroke patients. Functional deficits due to medium-sized infarcts are difficult to predict, except if the specific site of the lesion is taken into account. None of the few pre-clinical models recapitulating this type of stroke has shown clear, reproducible, and long-lasting sensorimotor deficits. Here, we develop ...[more]

PMID: 30619036

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Project description:Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets. Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n = 12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05; n = 23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common). Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of differentially expressed genes) validated for this microarray did not reveal any sex differences.

Project description:Lacunar strokes are a common type of ischemic stroke. They are associated with long-term disability, but the factors affecting the dynamic of the infarcted lesion and the brain imaging features associated with them, reflective of small vessel disease (SVD) severity, are still largely unknown. We investigated whether the distribution, volume and 1-year evolution of white matter hyperintensities (WMH), one of these SVD features, relate to the extent and location of these infarcts, accounting for vascular risk factors. We used imaging and clinical data from all patients [n = 118, mean age 64.9 (SD 11.75) years old] who presented to a regional hospital with a lacunar stroke syndrome within the years 2010 and 2013 and consented to participate in a study of stroke mechanisms. All patients had a brain MRI scan at presentation, and 88 had another scan 12 months after. Acute lesions (i.e., recent small subcortical infarcts, RSSI) were identified in 79 patients and lacunes in 77. Number of lacunes was associated with baseline WMH volume (B = 0.370, SE = 0.0939, P = 0.000174). RSSI volume was not associated with baseline WMH volume (B = 3.250, SE = 2.117, P = 0.129), but predicted WMH volume change (B = 2.944, SE = 0.913, P = 0.00184). RSSI location was associated with the spatial distribution of WMH and the pattern of 1-year WMH evolution. Patients with the RSSI in the centrum semiovale (n = 33) had significantly higher baseline volumes of WMH, recent and old infarcts, than patients with the RSSI located elsewhere [median 33.69, IQR (14.37 50.87) ml, 0.001 ≤ P ≤ 0.044]. But patients with the RSSI in the internal/external capsule/lentiform nucleus experienced higher increase of WMH volume after a year [n = 21, median (IQR) from 18 (11.70 31.54) ml to 27.41 (15.84 40.45) ml]. Voxel-wise analyses of WMH distribution in patients grouped per RSSI location revealed group differences increased in the presence of vascular risk factors, especially hypertension and recent or current smoking habit. In our sample of patients presenting to the clinic with lacunar strokes, lacunar strokes extent influenced WMH volume fate; and RSSI location and WMH spatial distribution and dynamics were intertwined, with differential patterns emerging in the presence of vascular risk factors. These results, if confirmed in wider samples, open potential avenues in stroke rehabilitation to be explored further.

Project description:Background: Hemorrhagic transformation, neurotoxicity, short treatment time windows, and other defects are considered as the major limitations for the thrombolytic therapy. This study is devoted to figure out whether Danhong injection (DHI) combined with tissue-plasminogen activator (t-PA) could extend the treatment time windows and ameliorate brain injury, hemorrhagic complication and BBB disruption after focal embolic stroke. Methods:In vitro, the combined concentrations of DHI and t-PA were added to wells reacted with plasminogen and D-Val-Leu-Lys-AMC. The optimum ratio of the combination of DHI plus t-PA was explored by detecting relative fluorescent. In vivo experiments, we firstly investigated the optimal dose of t-PA and Danhong injection for focal embolic stroke. The neurological deficit score, infarct volume and brain edema were assessed. Secondly, we proved that the combination group extended the thrombolytic window for treatment of focal embolic stroke. The neurological deficit score, infarct volume, brain edema and hemorrhagic complication were assessed, while levels of BAX, Bcl-2 and caspase-3 in brain tissue were analyzed by real-time polymerase chain reaction. Finally, to ask whether combination therapy with DHI plus t-PA protected the blood-brain barrier in a rat model of focal embolic stroke, neurological deficit score, ELISA, RT-PCR, western blot and fluorescence were used to detect the indicators of blood-brain barrier, such as tight junction protein, blood-brain barrier permeability and related gene expression. Results:In vitro, plasmin activity assays showed that the combination of t-PA with DHI at about 1:1.6 w/v ratio increased by almost 1.4-fold the plasmin-generating capability of t-PA. In vivo experiments, the results showed that the combination of Danhong injection (4 mL/kg) and t-PA (2.5 mg/kg) could extend the t-PA treatment time windows to 4.5 h. And the combination t-PA (2.5 mg/kg) with DHI (4 mL/kg) ameliorated neurological score, cerebral infarction, brain edema, brain hemorrhage, and BBB disruption. Conclusion: Combination therapy with Danhong injection (4 mL/kg) plus t-PA (2.5 mg/kg) could extend the t-PA treatment time windows to 4.5 h, ameliorate BBB disruption, reduce infarction, brain swelling and hemorrhage after ischemic stroke.

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Focal Malonate Injection Into the Internal Capsule of Rats as a Model of Lacunar Stroke.

Publications

Focal Malonate Injection Into the Internal Capsule of Rats as a Model of Lacunar Stroke.

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