In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases.

Abstract

The purpose of this study was to investigate the induction of inducible nitric oxide synthase (iNOS) mRNA in the brain tissue of rats and mice under the following experimental conditions: in rats infected with borna disease virus and rabies virus, in mice infected with herpes simplex virus, and in rats after the induction of experimental allergic encephalitis. The results showed that iNOS mRNA, normally nondetectable in the brain, was present in animals after viral infection or after induction of experimental allergic encephalitis. The induction of iNOS mRNA coincided with the severity of clinical signs and in some cases with the presence of inflammatory cells in the brain. The results indicate that nitric oxide produced by cells induced by iNOS may be the toxic factor accounting for cell damage and this may open the door to approaches to the study of the pathogenesis of neurological diseases.The mechanisms involved in the development of central nervous system (CNS) lesions are readily understood only in those pathological conditions in which there is evidence that a virus destroys its target cell as a direct cytopathic consequence of viral replication (e.g., polio virus or other neurotrophic viruses; refs. 1 and 2). However, the effector mechanisms involved in tissue damage associated with a far wider variety of viral infections of the CNS, involving such viruses as the measles and rubella viruses as well as human immunodeficiency virus 1, are unclear. Likewise, the mediators responsible for the CNS damage associated with chronic neurologic diseases such as multiple sclerosis remain the subject of speculation. Interestingly, morphologic analyses have revealed that lesions in affected brain tissues are frequently surrounded by infiltrating inflammatory cell populations. Although the precise role that these cells play in CNS pathology is the subject of ongoing investigation, previous studies have focused on the ability of leukocyte populations to generate proinflammatory cytokines (e.g., interleukin 1, tumor necrosis factor, etc.), neurotoxins (e.g., quinolinic acid), or reactive oxygen intermediates (3). Recently, increased attention has focused on the possibility that reactive nitrogen intermediates (NOI) generated by a family of cytochrome P-450 reductase-like enzymes, the nitric oxide synthases (NOS), directly damage host tissues in a diverse array of pathogenic states (4).To date, at least three NOS genes have been cloned and characterized, and these have been provisionally categorized on the basis of their sensitivity to regulation by Ca2+ transients (4). In this schema, NOS forms that bind calmodulin in a reversible Ca2+-dependent manner are termed the constitutive forms of NOS, and those forms of the enzyme that bind calmodulin tightly at resting [Ca2+] are termed inducible NOSs (iNOSs). After the addition of rapid-acting agonists, the constitutive NOS system generates only low levels of the NOI, nitric oxide (NO), whereas the iNOS system begins to generate NO several hours after exposure to cyto...

Molecular detection of rabies encephalitis and correlation with cytokine expression

“…It is possible that cytokine expression may modulate rabies viral production in the central nervous system as suggested by others in animalbased studies, as well as contributing directly to the neuropathogenesis of the infectious process. [7][8][9][10] It follows that inhibition of cytokine expression may have some therapeutic potential in this otherwise fatal disease, as has been demonstrated in a murine model; 9 this clearly awaits further study in humans. To our knowledge, this study is the first to document the histologic relationship of direct infection of rabies virus with expression of TNFa and iNOS in people using an in situ-based assay.…”

“…However, despite the relatively paucicellular response in the central nervous system to the infection, there was massive upregulation of both TNFa and iNOS, each of which can damage neurons and supporting tissue. 7,[10][11][12] This suggests a multifactorial pathogenic process for rabies encephalitis that includes widespread viral infection and concomitant increased expression of a variety of cellular factors as well as downregulation of SOCS expression. It is possible that cytokine expression may modulate rabies viral production in the central nervous system as suggested by others in animalbased studies, as well as contributing directly to the neuropathogenesis of the infectious process.…”

“…Rabies-induced synthesis of inducible nitric oxide (iNOS) in the central nervous system has been suggested as a pathogenetic step in neuronal cell damage in rabies infections. 6,7 Tumor necrosis factor a (TNFa) expression has also been suggested as an important factor in rabies encephalitis, both in terms of direct toxicity and as modulating viral production. [8][9][10] However, the studies on TNFa and iNOS expression have been done on animal models, and it is not clear if these data can be extrapolated to human rabies.…”

The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

“…In addition to MBP-specific lymphocytes, activated monocytes expressing iNOS have been implicated in the development of EAE in conventional models (eg., 3,5,8,11) where disease pathogenesis has been associated with CNS inflammation and nitrotyrosine formation (eg., 3, 5). Therefore, we have assessed the effects of UA treatment on the distribution of iNOS-positive cells in PLSJL mice immunized with MBP.…”

Perspectives in Diagnosis and Treatment of Rabies Viral Encephalitis: Insights from Pathogenesis

“…Others have demonstrated dysfunction of ion channels in infected cell culture [97], and defective cholinergic neurotransmission [98]. Induction of inducible nitric oxide synthase mRNA and increased levels of nitric oxide have been demonstrated in rodents inoculated with the virus [96,97,99,100]. The role of these in natural rabies infection in humans is uncertain.…”