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NSAID treatment suppresses VSV propagation in mouse CNS
N Chen1, J L Warner, C S Reiss
1Department of Biology, New York University, New York, New York 10003, USA.
Abstract:
Cyclooxygenase (COX) is the key enzyme in the conversion of arachidonic acid to prostaglandins. COX has two isoforms: COX-1, the constitutively expressed form, and COX-2, the inducible form. Prostaglandins are mediators of many critical physiological and inflammatory responses, but little is known about their roles during a viral infection in the central nervous system (CNS). We used non-selective inhibitors of COX, aspirin and indomethacin, and a selective antagonist of COX-2, celecoxib, to study the role of prostaglandins in Vesicular Stomatitis Virus (VSV) induced encephalitis. We found that the inhibition of COX antagonizes VSV propagation both in vitro and in vivo. In addition, aspirin and celecoxib both prevented the disruption of the blood brain barrier in VSV-infected mice. In vitro experiments showed that the effect of COX inhibition was at least partially mediated by increased production of Nitric Oxide (NO), a molecule known to inhibit VSV replication. When NO production was inhibited by N(omega)-nitro-L-methyl-arginine-ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, the difference in viral titer between aspirin (or celecoxib)-treated and the control cells was abolished. VSV-infected mice treated with celecoxib expressed more NOS-1 and produced more NO in their CNS compared to the controls. Our data suggest that the product(s) of COX have antagonistic effect(s) on NO production in the mouse CNS.
Insights
Inhibition of cyclooxygenase (COX) enzymes reduces viral encephalitis and protects the blood-brain barrier. This effect is linked to increased nitric oxide (NO) production, which inhibits viral replication.
Area of Science:
- Neurovirology
- Immunology
- Biochemistry
Background:
- Cyclooxygenase (COX) enzymes regulate prostaglandin synthesis, crucial for physiological and inflammatory responses.
- The role of prostaglandins in viral central nervous system (CNS) infections remains largely unexplored.
- Vesicular Stomatitis Virus (VSV) serves as a model for studying viral encephalitis.
Purpose of the Study:
- To investigate the role of prostaglandins, mediated by COX enzymes, in VSV-induced encephalitis.
- To determine the impact of COX inhibition on viral propagation and blood-brain barrier integrity.
- To elucidate the relationship between COX activity, nitric oxide (NO) production, and viral replication in the CNS.
Main Methods:
- Utilized non-selective COX inhibitors (aspirin, indomethacin) and a selective COX-2 inhibitor (celecoxib).
- Assessed VSV propagation in vitro and in vivo.
- Evaluated blood-brain barrier disruption in infected mice.
- Measured nitric oxide synthase (NOS) activity and NO production in response to COX inhibition.
Main Results:
- COX inhibition significantly antagonized VSV propagation both in vitro and in vivo.
- Aspirin and celecoxib treatment prevented blood-brain barrier disruption in VSV-infected mice.
- COX inhibition led to increased nitric oxide (NO) production, which was found to inhibit VSV replication.
- Inhibition of NO production abolished the antiviral effects of COX inhibitors.
Conclusions:
- COX enzyme products appear to antagonize NO production in the mouse CNS.
- Targeting COX pathways may offer a therapeutic strategy against viral encephalitis by modulating NO levels.
- Prostaglandin-NO interactions play a critical role in the host response to viral CNS infections.
