4-07-19 E-selectin appears in non-ischemic tissue during experimental 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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Requisite ischemia for spreading depolarization occurrence after subarachnoid hemorrhage in rodents

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16659303 ◽

2016 ◽

Vol 37 (5) ◽

pp. 1829-1840 ◽

Cited By ~ 13

Author(s):

Fumiaki Oka ◽

Ulrike Hoffmann ◽

Jeong Hyun Lee ◽

Hwa Kyoung Shin ◽

David Y Chung ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Focal Cerebral Ischemia ◽

Delayed Cerebral Ischemia ◽

Laser Speckle ◽

Neurological Outcomes ◽

Spreading Depolarization ◽

Arterial Blood ◽

Electrophysiological Recordings ◽

Ischemic Tissue

Spontaneous spreading depolarizations are frequent after various forms of human brain injury such as ischemic or hemorrhagic stroke and trauma, and worsen the outcome. We have recently shown that supply-demand mismatch transients trigger spreading depolarizations in ischemic stroke. Here, we examined the mechanisms triggering recurrent spreading depolarization events for many days after subarachnoid hemorrhage. Despite large volumes of subarachnoid hemorrhage induced by cisternal injection of fresh arterial blood in rodents, electrophysiological recordings did not detect a single spreading depolarization for up to 72 h after subarachnoid hemorrhage. Cortical susceptibility to spreading depolarization, measured by direct electrical stimulation or topical KCl application, was suppressed after subarachnoid hemorrhage. Focal cerebral ischemia experimentally induced after subarachnoid hemorrhage revealed a biphasic change in the propensity to develop peri-infarct spreading depolarizations. Frequency of peri-infarct spreading depolarizations decreased at 12 h, increased at 72 h and normalized at 7 days after subarachnoid hemorrhage compared with sham controls. However, ischemic tissue and neurological outcomes were significantly worse after subarachnoid hemorrhage even when peri-infarct spreading depolarization frequency was reduced. Laser speckle flowmetry implicated cerebrovascular hemodynamic mechanisms worsening the outcome. Altogether, our data suggest that cerebral ischemia is required for spreading depolarizations to be triggered after subarachnoid hemorrhage, which then creates a vicious cycle leading to the delayed cerebral ischemia syndrome.

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Effects of Central Inhibition of Nitric Oxide Synthase on Focal Cerebral Ischemia in Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1995.98 ◽

1995 ◽

Vol 15 (5) ◽

pp. 779-786 ◽

Cited By ~ 26

Author(s):

Junichi Hamada ◽

Joel H. Greenberg ◽

Sid Croul ◽

Ted M. Dawson ◽

Martin Reivich

Keyword(s):

Nitric Oxide ◽

Cerebral Ischemia ◽

Nitric Oxide Synthase ◽

Focal Cerebral Ischemia ◽

High Dose ◽

Dose Administration ◽

Mca Occlusion ◽

Ischemic Tissue ◽

Central Inhibition ◽

Oxide Synthase

We have investigated whether central inhibition of nitric oxide synthase (NOS) could modify the tissue damage of focal cerebral ischemia produced by occlusion of the middle cerebral artery (MCA) in rats. NG-Nitro-l-arginine methyl ester (l-NAME) was administered intracerebroventricularly at two doses 15 min prior to occlusion of the MCA, as well as 4 and 24 h following occlusion. After the injection of l-NAME, the catalytic activity of the constitutive NOS, considered to be mainly neuronal, was effectively suppressed in the subcortical gray matter bilaterally, but not in the ischemic territory. Seven days after the MCA occlusion, the brains were evaluated for histopathologic damage. High-dose administration of l-NAME (120 μg/kg 15 min prior to MCA occlusion, followed by, 150 μg/kg 4 and 24 h after occlusion) produced an enlargement of the infarct area and increased the volume of ischemic damage. These results indicate that extensive inhibition of NOS by a central route can increase the cerebral infarct size in focal ischemia even if NOS is not inhibited in the ischemic tissue and suggest that NO may also play a potentially beneficial role as well as a neurodestructive role in the pathophysiological mechanisms of focal cerebral ischemia.

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Reduction in Focal Cerebral Ischemia by Agents Acting at Imidazole Receptors

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1992.7 ◽

1992 ◽

Vol 12 (1) ◽

pp. 53-63 ◽

Cited By ~ 81

Author(s):

Kenneth Maiese ◽

Laszlo Pek ◽

Scott B. Berger ◽

Donald J. Reis

Keyword(s):

Cerebral Ischemia ◽

Adrenergic Receptors ◽

Focal Cerebral Ischemia ◽

Optimal Dose ◽

Global Cerebral Ischemia ◽

Neuroprotective Effects ◽

Ischemic Infarction ◽

Ischemic Tissue ◽

Adrenergic Antagonist ◽

Dose Dependent

Treatment with the α2-adrenergic antagonist idazoxan (IDA) can provide protection from global cerebral ischemia. However, IDA also recognizes another class of receptors, termed imidazole (IM) receptors, which differ from α2-adrenergic receptors and are responsible for the hypotensive actions of some centrally acting agents such as the oxazole rilmenidine (RIL). We therefore sought to determine whether RIL, an agent highly selective for IM receptors, offered protection from focal cerebral ischemia elicited in rat by ligation of the middle cerebral artery (MCA). We compared the effects of RIL with the effects of IDA and the selective non-IM α2-antagonist SKF 86466 (SKF). In addition, we examined whether the neuroprotective effects of RIL and IDA could be attributed to changes in local CBF (LCBF). The MCA was occluded and animals either received immediate administration of drug while arterial pressure was maintained for 1 h or had local CBF increased to 200% of control for 1 h by hypercapnia or hypertension. RIL elicited a significant dose-dependent preservation of tissue to 33% of control at optimal dose (0.75 mg/kg). IDA (3 mg/kg) significantly reduced the size of ischemic infarction by 22%. In contrast, SKF (15 mg/kg) as well as doubling of LCBF did not preserve ischemic tissue. We conclude that both RIL and IDA can reduce focal ischemic infarction but that the mechanism does not appear secondary to antagonism of α2-adrenergic receptors or elevation of LCBF. Occupation of IM receptors, either in the ischemic zone or at remote brain sites, may be responsible for neuroprotection of RIL and IDA.

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In vivo Binding of Nimodipine in the Brain: II. Binding Kinetics in Focal Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1991.134 ◽

1991 ◽

Vol 11 (5) ◽

pp. 771-778 ◽

Cited By ~ 18

Author(s):

Matthew J. Hogan ◽

Albert Gjedde ◽

Antoine M. Hakim

Keyword(s):

Cerebral Ischemia ◽

Calcium Channel ◽

Focal Cerebral Ischemia ◽

Binding Capacity ◽

Affinity Constant ◽

Binding Characteristics ◽

In Vivo Binding ◽

Ischemic Tissue ◽

The Brain

We report the binding characteristics of [3H]nimodipine to normal and ischemic brain in vivo. We used the 1,4-dihydropyridine, nimodipine, to label the L-type voltage-sensitive calcium channel in focal cerebral ischemia after occlusion of both the middle cerebral and ipsilateral common carotid arteries in rats. Varying concentrations of [3H]nimodipine were infused 3.5 h after the onset of ischemia and circulated for 30 min before the brain was obtained for autoradiography and determination of regional nimodipine content. In separate sets of experiments, the metabolites of nimodipine were determined and the conditions for equilibrium of nimodipine distribution were established. Increased nimodipine uptake was observed in ischemic regions. This increased binding was saturable and specific with an affinity constant, KD, of 0.45 n M and a maximal regional binding capacity, Bmax, ranging from 3.1 to 10.9 pmol/g. Only binding to ischemic tissue was specific and saturable whereas that in nonischemic tissue was nonspecific. In vivo binding of nimodipine may be used to identify cell membrane depolarization and calcium channel activation in focal cerebral ischemia.

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