Inhibition of MMP-9 Activity following Hypoxic Ischemia in the Developing Brain Using a Highly Specific Inhibitor

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.

Title: role of matrix metalloproteinase −9 in progression of tuberculous meningitis: a pilot study in patients at different stages of the disease

“…Specific inhibitor of MMP-9, SB-3CT has come forth with desirable properties of crossing blood brain barrier and therapeutic effects for treating neurological diseases due to inflammation [10]. This inhibitor has been studied for ischemia of immature brain and found to work efficiently; showing its utility in pediatric cases [11]. In this study, role of MMP-9 has been evaluated in progression of TBM.…”

Inhibition of Matrix Metalloproteinases-2/-9 Transiently Reduces Pre-Oligodendrocyte Loss during Lipopolysaccharide- but Not Tumour Necrosis Factor-alpha-Induced Inflammation in Fetal Ovine Glial Culture

“…It is possible for example that detrimental effects of MMPs such as myelin disruption, processing of other death pathway molecules and alteration of the extracellular matrix [50,51] may not be observed in vitro. Nevertheless, we have previously reported that SB-3CT was not neuroprotective after hypoxia-ischaemia in postnatal day 21 rats, consistent with a limited role of gelatinases in secondary inflammatory damage of the developing brain [52]. …”

MMP-9 Inhibitor SB-3CT Attenuates Behavioral Impairments and Hippocampal Loss after Traumatic Brain Injury in Rat

“…18 This also was indicated by an investigation carried out by Ranasinghe and colleagues. 48 In their study, significant inhibition of brain pro-MMP-9 activity after hypoxic ischemia was observed by SB-3CT. Similar phenomena was observed in TBI models that increase in the pro-MMP-9 level was also observed in the lesioned cortex within 24 h after TBI in addition to the up-regulation of activated MMP-9.…”

“…However, it is interesting to find that significant loss of behavioral deficit caused by acute neuro-degeneration and neuronal loss also was lessened by SB-3CT post-treatment. Similar administration was shown to be effective in inhibiting MMP activity in adult rat models of spinal cord injury 52 and ischemia 17 without any confounding toxic effects. Moreover, it was also demonstrated that apoptotic cell death within the hippocampus was significantly reduced, and the presence of immature neurons was significantly increased if acute post-intervention was carried out after TBI.…”

“…An intraperitoneal route of delivery was chosen as effective delivery of this inhibitor to the brain had previously been reported in adult rats via the same route. 21 Further, similar dosages have been shown to be effective in inhibiting MMP activity in adult rat models of spinal cord injury 17 and ischemia 21 without any confounding toxic effects. After SB-3CT or saline treatment in the current study, the animals were returned to the normal rat housing rooms (22°C, 50% relative humidity, 12-h light/12-h dark cycle).…”