Metalloproteinases and their inhibitors as therapeutic targets for multiple sclerosis: current evidence and future perspectives

Figures & data

Table 1 MMP inhibitors in MS clinical development*

Type	Class	Agent	Specificity	Experimental model	Sample analyzed	Remarks	Reference
Synthetic MMP inhibitors	Hydroxamate MMP inhibitors	BB101	MMP-7, MMP-26	Acute EAE in Lewis rats	Spinal cord, CSF		79
		Ro31-9790	Broad spectrum	Acute EAE in Lewis rats	CNS tissue		81
		GM6001	MMP-2, MMP-9	EAE in SJL/J mice	CSF		82
Anti inflammatory drugs	Modified tetracyclines	Minocycline	MMP-9	EAE in C57BL/6 mice	Spinal cord		93
			MMP-2 MMP-9	EAE in DA rats Pilot study in RR-MS patients	CNS tissue Serum		94 96
	Antibiotics	Doxycycline	MMP-9	Open-label trial in RR-MS patients	Serum	Used in combination with IFNP	97
Anti-MS drugs	Corticosteroids	Methylprednisolone	MMP-9	MS patients	CSF		6l
	Immunomodulant drugs	IFNβ	MMP-9	RR-MS patients	Serum		6
			MMP-9 MMP-2, MMP-9	RR-MS patients RR-MS patients	Serum CSF, serum		87 88
	Immunosuppressive drugs	Mitoxantrone	MMP-9	RR-and SP-MS patients	PBMC		7
		Fingolimod (FTY720)	MMP-9	EAE in DA rats	Spinal cord		8
	Antibodies	Natalizumab	MMP-9	Open-label trial in RR-MS patients	CSF		9
Compounds from natural sources	Fatty acids	ω3 PUFA	MMP-9	Open-label trial in RR-MS patients	PBMC, serum		49
	Flavonoids	Quercetin	MMP-9	RR-MS patients	PBMC	Used in vitro in combination with IFNβ	41
	Thiol compounds	α-Lipoic acid	MMP-9 MMP-9	EAE in SJL mice MS patients	Serum		101 102
		Combination of antioxidants (ω3, α-lipoic acid, resveratrol), multivitamin complex, and vitamin D	MMP-9	Pilot study in RR- and PP-MS patients	Serum	Used in combination with IFNP	12

Note: *The list of MMP inhibitors is not exhaustive; it refers to drugs and compounds used for the treatment of MS in clinical trials and in human and animal studies and to those cited in the paper.

Abbreviations: PUFA, polyunsaturated fatty acid; PBMC, peripheral blood mononuclear cells; CSF, cerebrospinal fluid; DA, dark agouti; EAE, experimental allergic encephalomyelitis; RR-MS, relapsing–remitting multiple sclerosis; PP-MS, primary progressive MS; SP-MS, secondary progressive MS; SJL, Swiss/Jackson Laboratory.

Table

Treatment in multiple sclerosis Numerous challenges affect the medical community for the treatment of multiple sclerosis (MS), since there are no drugs able to cure this disease. MS treatment typically focuses on slowing the progression of the disease and minimizing MS-related disability. The choice of therapy will depend on the phase and clinical activity of the disease. Generally, therapies aim at regulating the immune system with different mechanisms: inhibition of T and B lymphocytes, monocyte and macrophage replication, or inhibition of cell migration by using immunomodulatory and immunosuppressive agents or antibodies against the antigens expressed on the cell surface. Currently, the drugs approved by the US Food and Drug Administration and the European Medicines Agency consist of corticosteroids, such as methylprednisolone, immunomodulatory drugs, such as IFNβ–1a or -1b, glatiramer acetate and dimethyl fumarate, immunosuppressive drugs, such as mitoxantrone and fingolimod, or monoclonal antibodies, such as natalizumab and alemtuzumab. Other therapies, not officially approved, consist in the use of azathioprine and cyclophosphamide, two immunosuppressive drugs, and methotrexate, an antimetabolite that limits cellular replication by acting as an antagonist of folic acid. Ocrelizumab, a second-generation humanized anti-CD20 antibody, was explored in a large Phase II trial in patients with relapsing–remitting MS, as well as in primary progressive MS. In a multicenter, randomized, Phase III study, patients with progressive MS treated with ocrelizumab showed less disability than placebos.^Citation103 These results indicate that ocrelizumab is a promising drug for the treatment of the progressive forms of MS for which the most used therapies are ineffective. The complexity and heterogeneity of MS pathogenesis makes for often-ineffective therapies. Therefore, a combination of drugs that act by different mechanisms of action may be a therapeutic strategy that is more effective. Indeed, unlike a single drug, the use of combination therapy would target the different mechanisms and pathways that occur concomitantly in MS pathogenesis. Combination therapy has thus become attractive, since it aims not only to reduce inflammatory processes but also to preserve neuroprotective functions. In this respect, in vitro experiments, animal studies, and clinical trials have achieved favorable results.^Citation104,Citation105 Currently, many people with MS explore complementary and alternative medicine treatments. In this respect, a low-fat diet and supplementation of pharmacological therapy with antioxidant and anti-inflammatory natural compounds has proved to be highly promising in the treatment of MS patients.^Citation12

Figure 1 Schematic representation of MMP structure based on domain arrangement.

Abbreviations: MT-MMP, membrane-type MMP; GPI, glycosylphosphatidylinositol.

Figure 2 Schematic representation of the involvement of MMPs in MS pathology.

Notes: MMPs, and in particular MMP-9, are involved in the mechanisms of BBB disruption through degradation of TJ proteins. This allows extravasation of autoreactive CD4⁺ T cells into the CNS. Within the brain parenchyma, activated T lymphocytes release inflammatory cytokines and MMPs. Moreover, T cells activate microglia cells/macrophages and astrocytes to the release of proinflammatory cytokines and MMPs, which contribute to myelin degradation and axonal loss.

Abbreviations: MS, multiple sclerosis; BBB, blood–brain barrier.

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