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Published on: July 2, 2020
Inhibition of MMP-9 activity following hypoxic ischemia in the developing brain using a highly specific inhibitor
Himani S Ranasinghe1, Arjan Scheepens, Ernest Sirimanne
1The Liggins Institute, University of Auckland, Auckland, New Zealand.
Insights
Matrix metalloproteinase-9 (MMP-9) inhibition did not protect against perinatal hypoxic ischemic brain injury in a rat model. Further research is needed to clarify MMP-9
Area of Science:
- Neuroscience
- Biochemistry
- Developmental Biology
Background:
- Perinatal hypoxic-ischemic (HI) brain injury causes significant neurological disability in newborns.
- Elevated matrix metalloproteinase-9 (MMP-9) activity is implicated in HI brain injury pathogenesis.
- MMP-9 inhibition is a potential therapeutic strategy for protecting the developing brain from HI injury.
Purpose of the Study:
- To investigate the therapeutic potential of MMP-9 inhibition in a rat model of perinatal HI brain injury.
- To determine if SB-3CT, an MMP-2 and MMP-9 inhibitor, can attenuate HI-induced brain injury.
Main Methods:
- Twenty-one-day-old Wistar rats underwent unilateral carotid artery occlusion followed by hypoxia.
- SB-3CT or vehicle was administered intraperitoneally at 2, 5, and 14 hours post-insult.
- Gelatin zymography assessed pro-MMP-9 levels; neuroprotection was evaluated 3 days after HI.
Main Results:
- SB-3CT significantly reduced pro-MMP-9 levels at 6 hours post-hypoxic-ischemia (p ≤ 0.05).
- Despite MMP-9 inhibition, SB-3CT did not provide significant neuroprotection in postnatal day 21 rats.
- The study highlights a potential disconnect between MMP-9 inhibition and neuroprotective outcomes in this model.
Conclusions:
- MMP-9 inhibition alone may not be sufficient for neuroprotection in perinatal HI brain injury.
- Further studies using selective MMP-9 inhibitors or modified SB-3CT are warranted.
- The precise role of MMP-9 in the delayed injury processes following HI in the developing brain requires further elucidation.
Abstract:
Perinatal hypoxic ischemic (HI) brain injury is a leading cause of long-term neurological handicap in newborn babies. Recently, excessive activity of matrix metalloproteinases (MMPs), and in particular MMP-9, has been implicated in the aetiology of HI injuries to the immature brain. Our previous study suggested that MMP-9 may be involved in the development of the delayed injury processes following HI injury to the developing brain. Given this, we therefore propose that MMP-9 may be a useful target for rescue therapies in the injured developing brain. To address this, we chose to use SB-3CT, a highly selective inhibitor that is known to target only MMP-2 and MMP-9, to attenuate the elevated MMP-9 activity seen following HI injury to the developing brain. Twenty-one-day-old postnatal Wistar rats were subjected to unilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 1 h). SB-3CT (50 mg/kg body weight in 25% dimethyl sulphoxide/75% polyethylene glycol) or an equal volume of vehicle or saline diluent was then administered intraperitoneally at 2, 5 and 14 h following the insult. Gelatin zymography revealed that pro-MMP-9 levels were significantly reduced at 6 h following hypoxic ischaemia (p ≤ 0.05). However, our results showed that despite significantly inhibiting brain pro-MMP-9 activity after hypoxic ischaemia, SB-3CT failed to confer significant neuroprotection in postnatal day 21 rats 3 days after an HI insult. Further investigations are warranted using a recently reported selective water-soluble version of SB-3CT or another MMP-9 selective inhibitor to resolve the role of MMP-9 in the aetiology of HI injury in the developing brain.
