Effects of S-312-d on cerebral microcirculation in ischemic penumbra in rat focal cerebral ischemia

Ischemic stroke is a leading cause of death and disability worldwide. Yet, the effective therapy of focal cerebral ischemia has been an unresolved challenge. We propose here that ischemic tissue acidosis, a sensitive metabolic indicator of injury progression in cerebral ischemia, can be harnessed for the targeted delivery of neuroprotective agents. Ischemic tissue acidosis, which represents the accumulation of lactic acid in malperfused brain tissue is significantly exacerbated by the recurrence of spreading depolarizations. Deepening acidosis itself activates specific ion channels to cause neurotoxic cellular Ca2+ accumulation and cytotoxic edema. These processes are thought to contribute to the loss of the ischemic penumbra. The unique metabolic status of the ischemic penumbra has been exploited to identify the penumbra zone with imaging tools. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Agents with neuroprotective promise are suggested here to be delivered selectively to the ischemic penumbra with pH-responsive smart nanosystems. The administered nanoparticels release their cargo in acidic tissue environment, which reliably delineates sites at risk of injury. Therefore, tissue pH-targeted drug delivery is expected to enrich sites of ongoing injury with the therapeutical agent, without the risk of unfavorable off-target effects.

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Enriched environment and spatial learning enhance hippocampal neurogenesis and salvages ischemic penumbra after focal cerebral ischemia

Neurobiology of Disease ◽

10.1016/j.nbd.2005.10.015 ◽

2006 ◽

Vol 22 (1) ◽

pp. 187-198 ◽

Cited By ~ 49

Author(s):

Yasuhiko Matsumori ◽

Shwuhuey M. Hong ◽

Yang Fan ◽

Takamasa Kayama ◽

Chung Y. Hsu ◽

...

Keyword(s):

Cerebral Ischemia ◽

Spatial Learning ◽

Focal Cerebral Ischemia ◽

Hippocampal Neurogenesis ◽

Enriched Environment ◽

Ischemic Penumbra

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Lidocaine attenuates apoptosis in the ischemic penumbra and reduces infarct size after transient focal cerebral ischemia in rats

Neuroscience ◽

10.1016/j.neuroscience.2004.02.034 ◽

2004 ◽

Vol 125 (3) ◽

pp. 691-701 ◽

Cited By ~ 73

Author(s):

B Lei ◽

S Popp ◽

C Capuano-Waters ◽

J.E Cottrell ◽

I.S Kass

Keyword(s):

Cerebral Ischemia ◽

Infarct Size ◽

Focal Cerebral Ischemia ◽

Ischemic Penumbra ◽

Transient Focal Cerebral Ischemia

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Abstract TP268: Induction Profile of Mesencephalic Astrocyte-derived Neurotrophic Factor by Cerebral Ischemia and its Implication for Neuroprotection

Stroke ◽

10.1161/str.48.suppl_1.tp268 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Ludmila Belayev ◽

Sung-Ha Hong ◽

Pranab K Mukherjee ◽

Hemant Menghani ◽

Larissa Khoutorova ◽

...

Keyword(s):

Cerebral Ischemia ◽

Dentate Gyrus ◽

Mrna Expression ◽

Neurotrophic Factor ◽

Focal Cerebral Ischemia ◽

Artery Occlusion ◽

Ischemic Penumbra ◽

Protein Levels

Introduction: Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been identified as a secretion protein, which biases immune cells toward an anti-inflammatory phenotype, thereby promoting tissue repair after various injuries to neurons in vivo or in vitro. However, the function of MANF during and after brain ischemia is still not known. The purpose of our study was to examine the characteristics and implication of MANF expression induced by focal cerebral ischemia. In addition we investigated if docosahexaenoic acid (DHA) potentiates MANF mRNA expression and provides additional neuroprotection. Methods: Male SD (280-320) rats were anesthetized with isoflurane and subjected to 2 h of middle cerebral artery occlusion (MCAo) by intraluminal suture. DHA (5 mg/kg; n=13) or vehicle (saline; n=8) was administered IV at 3 h after the onset of MCAo. Neurological function was evaluated during occlusion (60 min) and on days 1, 3 and 7 after MCAo. MANF mRNA expression, protein levels, and apoptosis were measured by immunohistochemistry and Western blotting. Results: Behavioral deficit was significantly improved by treatment with DHA compared to vehicle on days 1, 3 and 7. MANF was found to be extremely upregulated in the ischemic penumbra. The expression of MANF was neuronal in the cortex and dentate gyrus. DHA administration significantly increased the number of MANF + /NeuN + cells in the cortex (by 76.6 %) and dentate gyrus (by 20.5 %) compared to saline-treated animals. The number of MANF/NeuN-positive cells was not different in the subcortex, CA1 and CA3 regions between DHA- and saline-treated groups. Treatment with DHA increased MANF + /GFAP + cells in the subcortex (by 27.7 %) and dentate gyrus (by 38.0 %) compared to the vehicle-treated brains. Total and cortical infarct volumes were attenuated by DHA treatment by 48 % and by 73 % compared to vehicle treatment at 24 h after MCAo. Conclusion: MANF mRNA expression and protein levels are increased after focal cerebral ischemia. It was found to be extremely upregulated in the ischemic penumbra and dentate gyrus. The expression of MANF was mostly neuronal and astrocytic. DHA potentiates MANF expression and provides additional neuroprotection.

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Selective up-regulation of IκB-α in ischemic penumbra following focal cerebral ischemia

Neuroreport ◽

10.1097/00001756-200005150-00033 ◽

2000 ◽

Vol 11 (7) ◽

pp. 1529-1533 ◽

Cited By ~ 31

Author(s):

Jaroslaw Aronowski ◽

Roger Strong ◽

Hui Suk Kang ◽

James C. Grotta

Keyword(s):

Cerebral Ischemia ◽

Focal Cerebral Ischemia ◽

Ischemic Penumbra

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Spatial Assessment of the Dynamics of Lactate Formation in Focal Ischemic Rat Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199904000-00003 ◽

1999 ◽

Vol 19 (4) ◽

pp. 376-379 ◽

Cited By ~ 12

Author(s):

Rick M. Dijkhuizen ◽

Robin A. de Graaf ◽

Michael Garwood ◽

Kees A. F. Tulleken ◽

Klaas Nicolay

Keyword(s):

Cerebral Ischemia ◽

Magnetic Resonance ◽

Early Identification ◽

Focal Cerebral Ischemia ◽

Imaging Techniques ◽

Intervention Strategies ◽

Ischemic Penumbra ◽

The Core ◽

Lactate Formation

Early identification of the potentially salvageable penumbra is critical for the determination of therapeutic intervention strategies in acute focal cerebral ischemia. This study differentiates the ischemic penumbra from the core on the basis of the dynamics of lactate formation. This was tested in a rat model of focal cerebral ischemia by infusion of [1-13C]-glucose, using lactate-edited magnetic resonance spectroscopic imaging techniques. The authors detected essentially no enrichment of lactate with 13C-label from the infused 13C-glucose in the ischemic core. However, in borderzone areas, 13C was incorporated into lactate, which could point toward compromised but potentially viable tissue. The authors' findings suggest that this combination of 13C-glucose infusion with the proposed magnetic resonance methods may aid in differentiating the penumbra from the core in cerebral ischemia.

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