Reovirus infection and tissue injury in the mouse central nervous system are associated with apoptosis.

ABSTRACTThe tumor suppressor p53 plays a critical part in determining cell fate both as a regulator of the transcription of several proapoptotic genes and through its binding interactions with Bcl-2 family proteins at mitochondria. We now demonstrate that p53 protein levels are increased in infected brains during reovirus encephalitis. This increase occurs in the cytoplasm of reovirus-infected neurons and is associated with the activation of caspase 3. Increased levels of p53 in reovirus-infected brains are not associated with increased expression levels of p53 mRNA, suggesting that p53 regulation occurs at the protein level. Increased levels of p53 are also not associated with the increased expression levels of p53-regulated, proapoptotic genes. In contrast, upregulated p53 accumulates in mitochondria. Previous reports demonstrated that the binding of p53 to Bak at mitochondria causes Bak activation and results in apoptosis. We now show that Bak is activated and that activated Bak is bound to p53 during reovirus encephalitis. In addition, survival is enhanced in reovirus-infected Bak−/−mice compared to controls, demonstrating a role for Bak in reovirus pathogenesis. Inhibition of the mitochondrial translocation of p53 with pifithrin μ prevents the formation of p53/Bak complexes following reovirus infection ofex vivobrain slice cultures and results in decreased apoptosis and tissue injury. These results suggest that the mitochondrial localization of p53 regulates reovirus-induced pathogenesis in the central nervous system (CNS) through its interactions with Bak.IMPORTANCEThere are virtually no specific treatments of proven efficacy for virus-induced neuroinvasive diseases. A better understanding of the pathogenesis of virus-induced CNS injury is crucial for the rational development of novel therapies. Our studies demonstrate that p53 is activated in the brain following reovirus infection and may provide a therapeutic target for virus-induced CNS disease.

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CB1 and LPA1 Receptors Relationship in the Mouse Central Nervous System

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2019.00223 ◽

2019 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Estíbaliz González de San Román ◽

Iván Manuel ◽

Catherine Ledent ◽

Jerold Chun ◽

Fernando Rodríguez de Fonseca ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Mouse Central Nervous System

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Apoptotic Cells, Including Macrophages, Are Prominent in Theiler's Virus-Induced Inflammatory, Demyelinating Lesions

Journal of Virology ◽

10.1128/jvi.77.7.4383-4388.2003 ◽

2003 ◽

Vol 77 (7) ◽

pp. 4383-4388 ◽

Cited By ~ 41

Author(s):

Brian P. Schlitt ◽

Matthew Felrice ◽

Mary Lou Jelachich ◽

Howard L. Lipton

Keyword(s):

Central Nervous System ◽

T Cells ◽

Nervous System ◽

In Situ Hybridization ◽

Apoptotic Cells ◽

Theiler's Virus ◽

Demyelinating Lesions ◽

Encephalomyelitis Virus ◽

Mouse Central Nervous System

ABSTRACT Theiler's murine encephalomyelitis virus (TMEV) persists in the mouse central nervous system principally in macrophages, and infected macrophages in culture undergo apoptosis. We have detected abundant apoptotic cells in perivascular cuffs and inflammatory, demyelinating lesions of SJL mice chronically infected with TMEV. T cells comprised 74% of apoptotic cells, while 8% were macrophages, 0.6% were astrocytes, and ∼17% remained unidentified. In situ hybridization revealed viral RNA in ∼1% of apoptotic cells.

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Further studies on free-radical pathology in the major central nervous system disorders: effect of very high doses of methylprednisolone on the functional outcome, morphology, and chemistry of experimental spinal cord impact injury

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y82-210 ◽

1982 ◽

Vol 60 (11) ◽

pp. 1415-1424 ◽

Cited By ~ 150

Author(s):

H. B. Demopoulos ◽

E. S. Flamm ◽

M. L. Seligman ◽

D. D. Pietronigro ◽

J. Tomasula ◽

...

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Free Radical ◽

Tissue Injury ◽

Functional Restoration ◽

Radical Reactions ◽

Free Radical Reactions ◽

Cord Injury

The hypothesis that pathologic free-radical reactions are initiated and catalyzed in the major central nervous system (CNS) disorders has been further supported by the current acute spinal cord injury work that has demonstrated the appearance of specific, cholesterol free-radical oxidation products. The significance of these products is suggested by the fact that: (i) they increase with time after injury; (ii) their production is curtailed with a steroidal antioxidant; (iii) high antioxidant doses of the steroidal antioxidant which curtail the development of free-radical product prevent tissue degeneration and permit functional restoration. The role of pathologic free-radical reactions is also inferred from the loss of ascorbic acid, a principal CNS antioxidant, and of extractable cholesterol. These losses are also prevented by the steroidal antioxidant. This model system is among others in the CNS which offer distinctive opportunities to study, in vivo, the onset and progression of membrane damaging free-radical reactions within well-defined parameters of time, extent of tissue injury, correlation with changes in membrane enzymes, and correlation with readily measurable in vivo functions.

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