RGD Reference Report - Matrix metalloproteinases inhibition provides neuroprotection against hypoxia-ischemia in the developing brain. - Rat Genome Database

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Matrix metalloproteinases inhibition provides neuroprotection against hypoxia-ischemia in the developing brain.

Authors: Chen, W  Hartman, R  Ayer, R  Marcantonio, S  Kamper, J  Tang, J  Zhang, JH 
Citation: Chen W, etal., J Neurochem. 2009 Nov;111(3):726-36. Epub 2009 Aug 27.
RGD ID: 2325131
Pubmed: PMID:19712057   (View Abstract at PubMed)
DOI: DOI:10.1111/j.1471-4159.2009.06362.x   (Journal Full-text)

The present study was designed to investigate the role of matrix metalloproteinases (MMPs) in the immature brain and the long term effects of early MMPs inhibition after hypoxic-ischemic (HI) injury. HI was induced by unilateral ligation of the right carotid artery followed by hypoxia (8% O(2) for 2 h) in P7 rat pups. GM6001, a broad spectrum MMPs inhibitor, was injected (50 mg/kg or 100 mg/kg) intraperitoneally at 2 h and 24 h after HI injury. Blood-brain barrier (BBB) integrity, brain edema, MMP-2/-9 activity, TIMP-1/-2 and tight junction protein (TJP) level were evaluated using IgG staining, Evan's blue extravasation, brain water content, zymography and western blot. Doxycycline, another MMPs inhibitor, was injected (10 mg/kg or 30 mg/kg) intraperitoneally at 2 h after HI, then BBB integrity and brain edema were measured at 48 h post-HI using brain water content measurement and IgG staining. The long-term effects of early MMPs inhibition (GM6001, 100 mg/kg) were evaluated by neurobehavioral tests, body weight, and brain atrophy measurement. GM6001 attenuated brain edema and BBB disruption at the dosage of 100 mg/kg. MMP-2 activity increased at 24 h and peaked at 48 h after HI, whereas MMP-9 activity peaked at 24 h and tapered by 48 h after HI. MMP-9/-2 activities were significantly attenuated by GM6001 at 24 h and 48 h after HI. The degradation of TJPs (ZO-1 and occludin) at 48 h after HI was reversed by GM6001 treatment. Early MMPs inhibition had long-term effects that attenuated ipsilateral brain tissue loss, and improved neurobehavioral outcomes after HI. These results suggest that early MMPs inhibition with a broad-spectrum inhibitor provides both acute and long-term neuroprotection in the developing brain by reducing TJPs degradation, preserving BBB integrity, and ameliorating brain edema after neonatal HI injury.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
brain disease  ISOTjp1 (Rattus norvegicus)2325131; 2325131associate with Pancreatitis and Acute NecrotizingRGD 
brain disease  IEP 2325131associate with Pancreatitis and Acute NecrotizingRGD 
brain ischemia  ISOTjp1 (Rattus norvegicus)2325131; 2325131protein:decreased expression:brainRGD 
brain ischemia  IEP 2325131protein:decreased expression:brainRGD 

Objects Annotated

Genes (Rattus norvegicus)
Tjp1  (tight junction protein 1)

Genes (Mus musculus)
Tjp1  (tight junction protein 1)

Genes (Homo sapiens)
TJP1  (tight junction protein 1)


Additional Information