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

Abstract

The aim of this study was to evaluate the potential efficacy of SB-3CT, a matrix metallopeptidase 9 inhibitor, on behavioral and histological outcomes after traumatic brain injury (TBI) in rats. Adult male Sprague-Dawley rats were randomly divided into three groups (n = 15/group): TBI with SB-3CT treatment, TBI with saline, and sham injury. The TBI model was induced by a fluid percussion TBI device. SB-3CT (50 mg/kg in 10% dimethyl sulfoxide) was administered intraperitoneally at 30 min, 6 h, and 12 h after the TBI. Motor function (beam-balance/beam-walk tests) and spatial learning/memory (Morris water maze) were assessed on post-operative Days 1 -5 and 11-15, respectively. Fluoro-Jade staining, immunofluorescence, and cresyl violet-staining were carried out for histopathological evaluation at 24 h, 72 h, and 15 days after TBI, respectively. It was shown that TBI can result in significant behavioral deficit induced by acute neurodegeneration, increased expression of cleaved caspase-3, and long-term neuronal loss. SB-3CT intervention via the current regime provides robust behavioral protection and hippocampal neurons preservation from the deleterious effects of TBI. Hence, the efficacy of SB-3CT on TBI prognosis could be ascertained. It is believed that the current study adds to the growing literature in identifying SB-3CT as a potential therapy for human brain injury.

Endogenous and synthetic MMP inhibitors in CNS physiopathology

“…The SB-3CT inhibitor has been extensively studied and tested in several animal models of CNS diseases because of its ability to cross the BBB and to be used as a pharmacological modulator of MMP-2 and MMP-9 in several CNS diseases (Gooyit et al, 2012;Gu et al, 2005;Hadass et al, 2013;Jiang et al, 2014). Likewise, the TC scaffold could also be exploited to provide more hydrophobic features to the inhibitor while preserving its Zn 2+chelating ability.…”

Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury

“…2 In a rat model of TBI, SB-3CT attenuated behavioral impairments and hippocampal loss. 13 Significant elevation of MMP-9 has been observed in the cerebral spinal fluid of TBI patients. 14 As compound 2 is a metabolite of SB-3CT and prodrug 3 is metabolized to 2 , the underlying mechanism for the beneficial effects of prodrug 3 /compound 2 may be similar to SB-3CT.…”

Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity

“…Chronically increased MMP9 activity may promote excessive ECM damage and subsequent disruption of the satellite cell niche, ultimately inhibiting satellite cell return to PAX7 + quiescence by interrupting crucial cell-niche crosstalk. To test this, a MMP9 small molecule inhibitor, SB-3CT (Jia et al, 2014; Sassoli et al, 2014), was administered through IP injection to auf1 KO mice in conjunction with BaCl 2 -mediated TA injury. SB-3CT blocks MMP9 activity through an irreversible covalent interaction (Jia et al, 2014; Sassoli et al, 2014).…”

“…To test this, a MMP9 small molecule inhibitor, SB-3CT (Jia et al, 2014; Sassoli et al, 2014), was administered through IP injection to auf1 KO mice in conjunction with BaCl 2 -mediated TA injury. SB-3CT blocks MMP9 activity through an irreversible covalent interaction (Jia et al, 2014; Sassoli et al, 2014). Mice were treated with 10 mg/kg SB-3CT daily starting 24 hours prior to injury in combination with MMP9-specific collagen matrix injections (Cai et al, 2015).…”