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Neuroprotection from tissue inhibitor of metalloproteinase-1 and its nanoparticles
Mayank Chaturvedi1, Izabela Figiel, Bojja Sreedhar
1Department of Molecular & Cellular Neurobiology, Nencki Institute, Warsaw, Poland.
Abstract:
Matrix metalloproteinases (MMPs) are family of zinc dependent endopeptidases, which cleave extracellular matrix proteins, and play an important role in tissue remodelling in physiological and pathological processes. There is enhanced expression of MMPs, in particular MMP-9, during numerous pathological conditions, including epilepsy and ischemic stroke. Therefore, inhibition of MMP-9 is considered as a potential therapeutic target. Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) is a 28kDa endogenous inhibitor of MMP-9. In this study we examined recombinant mouse TIMP-1 for its in-vitro neuroprotective effects, against Kainic Acid (KA) induced excitotoxicity in organotypic hippocampal slice culture (OHC) model. We also studied, sustained release effects of TIMP-1 in OHC by using poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). TIMP-1 and TIMP-1 PLGA NPs were added to the slice cultures at different time points, i.e., 30min before treatment with KA and 6h after KA treatment. Propidium iodide staining was used to reveal cell toxicity in the cultures. In addition, neurotoxicity was assessed using standard lactate dehydrogenase (LDH) release assay. Gelatinolytic activity in conditioned cultured medium of OHC was accessed by a fluorescent substrate assay. Briefly, our result show that TIMP-1 provided significant level of neuroprotection, especially when given before 30min of KA and released from the NPs. Since gelatinolytic activity assay showed a decrease in MMP-9 activity, it can be suggested that this neuroprotection might be mediated by the gelatinase inhibition.
Insights
Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) offers neuroprotection against excitotoxicity. Sustained release of TIMP-1 via nanoparticles enhanced its protective effects, suggesting a therapeutic strategy for neurological conditions like epilepsy and stroke.
Area of Science:
- Neuroscience
- Biochemistry
- Biomaterials Science
Background:
- Matrix metalloproteinases (MMPs), particularly MMP-9, are implicated in neurological disorders like epilepsy and ischemic stroke.
- MMP-9 inhibition is a potential therapeutic strategy for these conditions.
- Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) is a natural inhibitor of MMP-9.
Purpose of the Study:
- To investigate the in-vitro neuroprotective effects of recombinant mouse TIMP-1.
- To evaluate the sustained release of TIMP-1 using poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs).
- To assess the impact of TIMP-1 on Kainic Acid (KA)-induced excitotoxicity in organotypic hippocampal slice cultures (OHCs).
Main Methods:
- Organotypic hippocampal slice culture (OHC) model exposed to Kainic Acid (KA).
- Treatment with TIMP-1 and TIMP-1 PLGA NPs at various time points (pre- and post-KA).
- Assessment of cell toxicity using propidium iodide staining and lactate dehydrogenase (LDH) release assay.
- Measurement of gelatinolytic activity (MMP-9) using a fluorescent substrate assay.
Main Results:
- TIMP-1 demonstrated significant neuroprotection against KA-induced excitotoxicity.
- Sustained release of TIMP-1 from PLGA NPs further enhanced neuroprotective effects.
- TIMP-1 administration, especially pre-treatment and nanoparticle-mediated release, reduced MMP-9 activity.
Conclusions:
- Recombinant mouse TIMP-1 exhibits potent in-vitro neuroprotective properties.
- PLGA nanoparticle formulation enables sustained release and improved efficacy of TIMP-1.
- Neuroprotection by TIMP-1 is likely mediated through the inhibition of MMP-9 gelatinase activity, offering a potential therapeutic avenue for neurological injuries.
