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Endogenous and synthetic MMP inhibitors in CNS physiopathology
Kévin Baranger1, Santiago Rivera2, Fabian D Liechti3
1Aix Marseille Université, CNRS, UMR 7259, NICN, 13344, Marseille, France; Neurology and Neuropsychology Department, AP-HM, Marseille, France.
Abstract:
Matrix metalloproteinases (MMPs, including the membrane-type MMPs (MT-MMPs)), a disintegrin and metalloproteinase (ADAM), and ADAM with thrombospondin motifs belong to the metzincins, a subclass of metalloproteinases that contain a Met residue and a Zn(2+) ion at the catalytic site necessary for enzymatic reaction. MMP proteolytic activity is mainly controlled by their natural tissue inhibitors of metalloproteinase (TIMP). A number of synthetic inhibitors have been developed to control deleterious MMP activity. The roles of MMPs and some of their ECM substrates in CNS physiology and pathology are covered by other chapters of the present volume and will thus not be addressed in depth. This chapter will focus (i) on the endogenous MMP inhibitors in the CNS, (ii) on MMP and TIMP regulations in three large classes of neuropathologic processes (inflammatory, neurodegenerative, and infectious), and (iii) on synthetic inhibitors of MMPs and the perspective of their use in different brain diseases.
Insights
Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are crucial in brain health and disease. This review explores their regulation in neuropathologies and the potential of synthetic MMP inhibitors for treating brain disorders.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Matrix metalloproteinases (MMPs) are enzymes critical for extracellular matrix remodeling.
- MMP activity is tightly regulated by tissue inhibitors of metalloproteinase (TIMPs).
- Dysregulated MMPs are implicated in various central nervous system (CNS) pathologies.
Purpose of the Study:
- To review endogenous MMP inhibitors within the CNS.
- To examine MMP and TIMP regulation in inflammatory, neurodegenerative, and infectious neuropathologies.
- To discuss synthetic MMP inhibitors and their therapeutic potential in brain diseases.
Main Methods:
- Literature review focusing on MMPs, TIMPs, and neuropathology.
- Analysis of regulatory mechanisms of MMPs and TIMPs in the CNS.
- Evaluation of synthetic MMP inhibitors and their clinical perspectives.
Main Results:
- Endogenous MMP inhibitors play a significant role in CNS homeostasis.
- MMP and TIMP expression and activity are altered in diverse neuropathologic conditions.
- Synthetic MMP inhibitors show promise for treating various brain disorders.
Conclusions:
- Understanding MMP/TIMP regulation is key to developing CNS disease therapies.
- Targeting MMPs offers a potential therapeutic strategy for neuropathologies.
- Further research into synthetic MMP inhibitors is warranted for clinical application.
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