RGD Reference Report - Favorable effects of MMP-9 knockdown in murine herpes simplex encephalitis using small interfering RNA. - Rat Genome Database

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Favorable effects of MMP-9 knockdown in murine herpes simplex encephalitis using small interfering RNA.

Authors: Zhou, Y  Lu, ZN  Guo, YJ  Mei, YW 
Citation: Zhou Y, etal., Neurol Res. 2010 Oct;32(8):801-9. doi: 10.1179/016164110X12644252260556. Epub 2010 May 18.
RGD ID: 8547867
Pubmed: PMID:20483026   (View Abstract at PubMed)
DOI: DOI:10.1179/016164110X12644252260556   (Journal Full-text)

BACKGROUND AND PURPOSE: The prognosis of herpes simplex encephalitis (HSE) remains poor despite available antiviral treatment. Matrix metalloproteinase-9 (MMP-9) is currently considered to play a major role in promoting cerebrovascular complications which contribute to the high mortality and morbidity of HSE. We hypothesize that temporally knockdown MMP-9 expression in early phase of HSE might be an effective treatment strategy. METHODS: The animal models of herpes simplex encephalitis were established by intracerebrally inoculated herpes simplex virus type 1 (HSV-1) in mice. Mice were inoculated intracerebrally with MMP-9 targeting siRNA (MMP-9 siRNA). MMP-9 expression was assessed by RT-PCR and western blot analysis at 3 and 7 days after HSV-1 infected. The blood-brain barrier (BBB) permeability was quantitated by Evans blue dye extravasations and brain water content. Immunohistochemistry method was adopted to analyse the expression of AQP4 protein. Quantitative real-time PCR analysis was used to detect cytokines expression. Neurological score was quantified using an established neurological scale at 7 days after HSE. RESULTS: Using synthetic small interfering RNA, we found a single intracerebral injection of siRNA targeting murine MMP-9 mRNA (MMP-9 siRNA) silenced MMP-9 expression and reduced it to normal level at day 7 post-infection. The improvement in neurological function and increased cumulative survival reflected the functional consequence of this therapy. MMP-9 knockdown mice also displayed less uptake of Evans blue and reduced brain water content compared with control siRNA-treated group. Also the HSV-1-induced upregulation of proinflammatory cytokines was significantly diminished in MMP-9 siRNA-treated mice. In addition, aquaporin-4 expression in perivascular decreased in MMP-9 siRNA-treated mice and might contribute to the protection of blood-brain barrier. DISCUSSION: This compelling evidence suggests that MMP-9 is a key pathogenic factor within HSE, and local injection of synthetic siRNA in the brain could knock down MMP-9 expression in acute phase of HSE, reduce brain edema and improves mice neurological function and increase cumulative survival.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MMP9HumanHerpes Simplex Encephalitis treatmentISOMmp9 (Mus musculus) RGD 
Mmp9RatHerpes Simplex Encephalitis treatmentISOMmp9 (Mus musculus) RGD 
Mmp9MouseHerpes Simplex Encephalitis treatmentIMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mmp9  (matrix metallopeptidase 9)

Genes (Mus musculus)
Mmp9  (matrix metallopeptidase 9)

Genes (Homo sapiens)
MMP9  (matrix metallopeptidase 9)

Objects referenced in this article
Gene AQP4 aquaporin 4 Homo sapiens
Gene Aqp4 aquaporin 4 Mus musculus
Gene Aqp4 aquaporin 4 Rattus norvegicus

Additional Information