PMID- 11136943
OWN - NLM
STAT- MEDLINE
DCOM- 20010125
LR  - 20190727
IS  - 1524-4628 (Electronic)
IS  - 0039-2499 (Linking)
VI  - 32
IP  - 1
DP  - 2001 Jan
TI  - Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha 
      expression is neuroprotective after intracerebral hemorrhage.
PG  - 240-8
AB  - BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) expression is 
      increased in brain after cerebral ischemia, although little is known about its 
      abundance and role in intracerebral hemorrhage (ICH). A TNF-alpha-specific 
      antisense oligodeoxynucleotide (ORF4-PE) was used to study the extent to which 
      TNF-alpha expression influenced neurobehavioral outcomes and brain damage in a 
      collagenase-induced ICH model in rat. METHODS: Male Sprague-Dawley rats were 
      anesthetized, and ICH was induced by intrastriatal administration of heparin and 
      collagenase. Immediately before or 3 hours after ICH induction, ORF4-PE was 
      administered directly into the site of ICH. TNF-alpha mRNA and protein levels 
      were measured by reverse transcriptase-polymerase chain reaction and immunoblot 
      analyses. Cell death was measured by terminal deoxynucleotidyl 
      transferase-mediated uridine 5'triphosphate-biotin nick end labeling (TUNEL). 
      Neurobehavioral deficits were measured for 4 weeks after ICH. RESULTS: ICH 
      induction (n=6) elevated TNF-alpha mRNA and protein levels (P:<0.01) at 24 hours 
      after the onset of injury compared with sham controls (n=6). Immunohistochemical 
      labeling indicated that ICH was accompanied by elevated expression of TNF-alpha 
      in neutrophils, macrophages, and microglia. Administration of ORF4-PE (2.0 nmol) 
      directly into striatal parenchyma, 15 minutes before (n=4) or 3 hours after (n=6) 
      ICH, decreased levels of TNF-alpha mRNA (P:<0.001) and protein (P:<0. 01) in the 
      brain tissue surrounding the hematoma compared with animals treated with saline 
      alone (n=6). Mean+/-SEM striatal cell death (cells per high-powered field) was 
      also reduced in animals receiving ORF4-PE (34.1+/-5.0) compared with the 
      saline-treated ICH group (80.3+/-7.50) (P:<0.001). ORF4-PE treatment improved 
      neurobehavioral deficits observed at 24 hours (P:<0.001) after induction of ICH 
      (n=6) compared with the untreated ICH group (n=6). This improvement was 
      maintained at 28 days after hemorrhage induction (P:<0.001). CONCLUSIONS: These 
      results indicate a pathogenic role for TNF-alpha during ICH and demonstrate that 
      reducing TNF-alpha expression using antisense oligodeoxynucleotides is 
      neuroprotective.
FAU - Mayne, M
AU  - Mayne M
AD  - Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, 
      Manitoba, Canada.
FAU - Ni, W
AU  - Ni W
FAU - Yan, H J
AU  - Yan HJ
FAU - Xue, M
AU  - Xue M
FAU - Johnston, J B
AU  - Johnston JB
FAU - Del Bigio, M R
AU  - Del Bigio MR
FAU - Peeling, J
AU  - Peeling J
FAU - Power, C
AU  - Power C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Stroke
JT  - Stroke
JID - 0235266
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9005-49-6 (Heparin)
RN  - EC 3.4.24.- (Collagenases)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Behavior, Animal/drug effects
MH  - Cerebral Hemorrhage/chemically induced/*drug therapy/pathology
MH  - Collagenases
MH  - Corpus Striatum/drug effects/pathology
MH  - Disease Models, Animal
MH  - Encephalitis/immunology/pathology
MH  - Heparin
MH  - Immunohistochemistry
MH  - In Situ Nick-End Labeling
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Microinjections
MH  - Neuroprotective Agents/*administration & dosage
MH  - Neutrophil Infiltration/drug effects/immunology
MH  - Oligonucleotides, Antisense/*administration & dosage
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Severity of Illness Index
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/biosynthesis/genetics
EDAT- 2001/01/04 11:00
MHDA- 2001/02/28 10:01
CRDT- 2001/01/04 11:00
PHST- 2001/01/04 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2001/01/04 11:00 [entrez]
AID - 10.1161/01.str.32.1.240 [doi]
PST - ppublish
SO  - Stroke. 2001 Jan;32(1):240-8. doi: 10.1161/01.str.32.1.240.