Ultrastructural studies of cerebral vascular spasm after cardiac arrest-related global cerebral ischemia in rats

Hm, Wiśniewski; Pluta, Ryszard; As, Lossinsky; Mj, Mossakowski

doi:10.1007/bf00294802

Cited by 42 publications

(42 citation statements)

References 27 publications

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“…The mechanisms involved in this blood brain barrier disruption are unknown. Additionally, intermittent cortical vasospasms have been observed after cardiac arrest and global brain ischemia 82,83 and the potential of striatal vasospasms was not evaluated in these studies. 3NPA produces bradycardia and systemic hypotension and vasodilation, 57,84 although regional striatal blood flow dynamics have not been studied.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

Gabrielson

Hogue

Bohr

et al. 2001

The American Journal of Pathology

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We investigated the effects of 3-nitropropionic acid (3NPA), a previously characterized neurotoxin, in four strains of mice to better understand the molecular basis of variable host responses to this agent. Unexpectedly, we found significant cardiac toxicity that always accompanied the neurotoxicity in all strains of mice in acute and subacute/chronic toxicity testing. Caudate putamen infarction never occurred without cardiac toxicity. All mouse strains tested are sensitive to 3NPA although the C57BL/6 and BALB/c mice require more exposure than 129SVEMS and FVB/n mice. Cardiac toxicity alone was found in 50% of symptomatic mice tested and morphologically, the cardiac toxicity is characterized by diffuse swelling of cardiomyocytes and multifocal coagulative contraction band necrosis. In subacute to chronic exposure, atrial thrombosis, cardiac mineralization, cell loss, and fibrosis are combined with cardiomyocyte swelling and necrosis. Ultrastructurally, mitochondrial swelling occurs initially, followed by disruption of myofilaments. Biochemically, isolated heart mitochondria from the highly sensitive 129SVEMS mice have a significant reduction of succinate dehydrogenase activity, succinate oxygen consumption rates, and heart adenosine triphosphate after 3NPA treatment. The severity of morphological changes parallels the biochemical alterations caused by 3NPA, consistent with cardiac toxicity being a consequence of the effects of 3NPA on succinate dehydrogenase. These experiments show, for the first time, that 3NPA has important cardiotoxic effects as well as neurotoxic effects, and that cardiac toxicity possibly resulting from inhibition of the succinate dehydrogenase in heart mitochondria, contributes to the cause of death in 3NPA poisoning in acute and subacute/chronic studies in mice.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Toxin 3-Nitropropionic Acid Induces Cardiac and Neurotoxicity Differentially in Mice

Gabrielson

Hogue

Bohr

et al. 2001

The American Journal of Pathology

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“…Along with astrocytes, microglia and neurons, these cells comprise the neuron vascular unit (NVU). During the disease progression, the TJ can be disrupted and BBB breached [51], BM degraded [30], immune cells migrate from blood to brain, microglia abnormally activated [32], pinocytosis and transcytosis intensified [52, 53], and inwardly and outwardly transporters of various substances modified.…”

Section: Figurementioning

confidence: 99%

Agile delivery of protein therapeutics to CNS

Xiang

Manickam

Brynskikh

et al. 2014

Journal of Controlled Release

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A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics.

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“…Ischemic brain injury provoked a number of vessel abnormalities, which are open tight junctions and blood-brain barrier, diffuse leakage through necrotic vessels and vasospasm (Petito et al, 1982;Mossakowski et al, 1993;Mossakowski et al, 1994;Pluta et al 1994a;Wisniewski et al, 1995;Gartshore et al, 1997;Shinnou et al, 1998;Lippoldt et al, 2000;Ueno et al, 2002;Pluta 2003;Pluta 2005;Pluta et al, 2006b). Till one year after ischemic brain injury brain white and gray regions contained many diffuse and focal sites of horseradish peroxidase and gadolinium extravasations (Mossakowski et al, 1994;Pluta et al, 1994a;Pluta 2003;Pluta 2005;Andjus 2010).…”

Section: Blood-brain Barrier After Ischemiamentioning

confidence: 99%