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Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.

ABSTRACT: Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5' diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y(1)R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP(3))-dependent Ca(2+) release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries.

SUBMITTER: Zheng W

PROVIDER: S-EPMC3008710 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.

Zheng Wei W Zheng Wei W Watts Lora Talley LT Holstein Deborah M DM Prajapati Suresh I SI Keller Charles C Grass Eileen H EH Walter Christi A CA Lechleiter James D JD

PloS one 20101222 12

Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescenc ...[more]

PMID: 21203502

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Project description:Cytotoxic edema (CE) is an important form of perihematomal edema (PHE), which is a surrogate marker of secondary injury after intracerebral hemorrhage (ICH). However, knowledge about CE after ICH is insufficient. Whether CE has adverse effects on clinical outcomes of patients with ICH remains unknown. Therefore, we aimed to investigate the temporal pattern of CE and its association with clinical outcomes in patients with ICH. Data were derived from a randomized controlled study (comparing the deproteinized calf blood extract with placebo in patients with ICH). Intervention in this original study did not show any impact on hematoma and PHE volume, presence of CE, or clinical outcomes. We conducted our analysis in 20 patients who underwent magnetic resonance imaging with diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) images at day 3 and within 7-12 days after symptom onset. CE was defined as an elevated DWI b1000 signal and an ADC value reduced by > 10% compared with the mirror area of interest in the perihematomal region. The modified Rankin Scale (mRS), National Institutes of Health Stroke Scale (NIHSS), and Barthel Index (BI) were performed face to face at 30-day and 90-day follow-ups after ICH onset to assess the clinical outcomes of the patients. CE was detected in nearly two thirds of patients with ICH in our study and seemed to be reversible. CE within 7-12 days, rather than at day 3 after symptom onset, was associated with poor clinical outcome (mRS 3-6) at the 30-day follow-up (P = 0.020). In addition, compared with those without CE, patients with CE within 7-12 days had more severe neurological impairment measured by NIHSS score (P = 0.024) and worse daily life quality measured by BI (P = 0.004) at both the 30- and 90-day follow-ups. CE appears in the acute phase of ICH and might be reversible. CE within 7-12 days post ICH was related to poor outcomes, which provides a novel therapeutic target for ICH intervention.

Dataset Information

Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.

Publications

Purinergic receptor stimulation reduces cytotoxic edema and brain infarcts in mouse induced by photothrombosis by energizing glial mitochondria.

Similar Datasets

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