scholarly journals Peri-Infarct Hot-Zones Have Higher Susceptibility to Optogenetic Functional Activation-Induced Spreading Depolarizations

Stroke ◽  
2020 ◽  
Vol 51 (8) ◽  
pp. 2526-2535
Author(s):  
Kazutaka Sugimoto ◽  
David Y. Chung ◽  
Maximilian Böhm ◽  
Paul Fischer ◽  
Tsubasa Takizawa ◽  
...  
Keyword(s):  
Artery Occlusion ◽  
Laser Speckle ◽  
High Rate ◽  
Activation Threshold ◽  
Optogenetic Stimulation ◽  
Residual Blood Flow ◽  
Residual Blood ◽  
Cerebral Artery Occlusion ◽  
Distal Middle Cerebral Artery ◽  
Distinct Increase

Background and Purpose: Spreading depolarizations (SDs) are recurrent and ostensibly spontaneous depolarization waves that may contribute to infarct progression after stroke. Somatosensory activation of the metastable peri-infarct tissue triggers peri-infarct SDs at a high rate. Methods: We directly measured the functional activation threshold to trigger SDs in peri-infarct hot zones using optogenetic stimulation after distal middle cerebral artery occlusion in Thy1-ChR2-YFP mice. Results: Optogenetic activation of peri-infarct tissue triggered SDs at a strikingly high rate (64%) compared with contralateral homotopic cortex (8%; P =0.004). Laser speckle perfusion imaging identified a residual blood flow of 31±2% of baseline marking the metastable tissue with a propensity to develop SDs. Conclusions: Our data reveal a spatially distinct increase in SD susceptibility in peri-infarct tissue where physiological levels of functional activation are capable of triggering SDs. Given the potentially deleterious effects of peri-infarct SDs, the effect of sensory overstimulation in hyperacute stroke should be examined more carefully.

Abstract W MP91: Supply-demand Mismatch Transients Trigger Peri-infarct Depolarizations In Ischemic Penumbra

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Daniel von Bornstädt ◽  
Jessica Seidel ◽  
Mathias Bernard Houben ◽  
Ergin Dilekoz ◽  
Tao Qin ◽  
...  
Keyword(s):  
Tactile Stimulation ◽  
Focal Cerebral Ischemia ◽  
Sensory Stimulation ◽  
Artery Occlusion ◽  
Cortical Activation ◽  
Normobaric Hyperoxia ◽  
Critical Range ◽  
O2 Supply ◽  
Cerebral Artery Occlusion ◽  
Distal Middle Cerebral Artery

Background: Peri-infarct depolarizations (PIDs) worsen the outcome of ischemic stroke. Unlike their impact on metabolism and perfusion, triggering factors are virtually unknown. We hypothesized that transient worsening of O2 supply-demand mismatch precipitates a PID in critically hypoperfused penumbra. Methods: We optically imaged cortical blood flow and oxygenation during distal middle cerebral artery occlusion in mice under full systemic physiological monitoring, and tested whether a transient (5 min) drop in O2 supply (hypotension or hypoxia) or increase in O2 demand (somatosensory cortical activation) can trigger PIDs during acute focal cerebral ischemia. Results: Transient hypotension (<70 mmHg) or hypoxia (<90 mmHg) triggered a PID 90% of the time (p<0.01). Increasing the O2 demand by functional activation (tactile stimulation) of moderately ischemic cortex (contralesional forepaw or shoulder S1) increased the 5-min incidence of PIDs by approximately five-fold (p=0.001). Cortical oxyhemoglobin levels dropped by 35-40% in the activated S1 immediately before a PID (p=0.004) confirming increased O2 demand. Cortical foci from which PIDs originated during tactile stimulation had 27-32% residual CBF, indicating the presence of a critical range of ischemia vulnerable to PID initiation upon increased demand. Consistently, activation of non-ischemic cortex (hindpaw S1) or severely ischemic cortex (whisker S1) did not significantly increase the PID rate. Both tetrodotoxin (1 μM topical) and normobaric hyperoxia prevented somatosensory triggering of PIDs. Conclusion: PIDs are triggered upon O2 supply-demand mismatch transients in metastable peri-infarct hot zones due to increased demand or reduced supply. We propose that minimizing sensory stimulation and hypoxic or hypotensive transients in the early stages of stroke and brain injury would reduce PID incidence and their adverse impact on outcome.

scholarly journals Repeated administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) attenuates the chronic inflammatory response to experimental stroke

2021 ◽  
Author(s):  
Danielle A Becktel ◽  
Jacob C Zbesko ◽  
Jennifer B Frye ◽  
Amanda G Chung ◽  
Megan Hayes ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Plasma Cells ◽  
Spatial Working Memory ◽  
Repeated Administration ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Innate And Adaptive Immunity ◽  
Chronic Inflammatory Response ◽  
Cerebral Artery Occlusion ◽  
Distal Middle Cerebral Artery

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that contributes to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-hydroxypropyl-β-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide developed to solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPβCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion + hypoxia (DH) mouse model of stroke. We subcutaneously injected young adult and aged mice with vehicle or HPβCD three times per week for up to 7 weeks following stroke and evaluated them using immunostaining, RNA sequencing, lipidomics, and behavioral analyses. Chronic stroke infarct and peri-infarct regions of HPβCD-treated mice were characterized by an upregulation of genes involved in lipid metabolism and a downregulation of genes involved in innate and adaptive immunity, reactive astrogliosis, and chemotaxis. Correspondingly, HPβCD reduced the accumulation of lipid droplets, T lymphocytes, B lymphocytes, and plasma cells in stroke infarcts. Repeated administration of HPβCD also improved recovery through the preservation of neurons in the striatum and thalamus, induction of c-Fos in hippocampal regions, protection of hippocampal-dependent spatial working memory, and reduction in impulsivity at 7 weeks after stroke. These results indicate that systemic HPβCD treatment following stroke attenuates chronic inflammation and secondary neurodegeneration and prevents post-stroke cognitive decline.

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