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?-Linolenic Acid-Valproic Acid Conjugates: Toward Single-Molecule Polypharmacology for Multiple Sclerosis.

ABSTRACT: Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from reported beneficial effects of ?-linolenic acid (ALA) and valproic acid (VPA) in MS, and by applying a rational strategy, we developed a small set of codrugs obtained by conjugating VPA and ALA through proper linkers. A cellular profiling identified 1 as a polypharmacological tool able not only to modulate microglia polarization, but also to counteract neurodegeneration and demyelination and induce oligodendrocyte precursor cell differentiation, by acting on multiple biochemical and epigenetic pathways.

SUBMITTER: Rossi M

PROVIDER: S-EPMC7734798 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

α-Linolenic Acid-Valproic Acid Conjugates: Toward Single-Molecule Polypharmacology for Multiple Sclerosis.

Rossi Michele M Petralla Sabrina S Protti Michele M Baiula Monica M Kobrlova Tereza T Soukup Ondrej O Spampinato Santi Mario SM Mercolini Laura L Monti Barbara B Bolognesi Maria Laura ML

ACS medicinal chemistry letters 20201027 12

Multiple sclerosis (MS) is a complex inflammatory, degenerative, and demyelinating disease of the central nervous system. Although treatments exist, MS cannot be cured by available drugs, which primarily target neuroinflammation. Thus, it is feasible that a well concerted polypharmacological approach able to act at multiple points within the intricate network of inflammation, neurodegeneration, and demyelination/remyelination pathways would succeed where other drugs have failed. Starting from re ...[more]

PMID: 33329762

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Project description:Cisplatin is an antineoplastic agent used in the treatment of various types of solid tumors. Despite the dose-dependency of its antineoplastic effect, the high risk for nephrotoxicity frequently precludes the use of higher doses. ?-Linolenic acid (ALA), a carboxylic acid having three cis double bonds, is an essential fatty acid required for health and can be acquired via foods that contain ALA or supplementation of foods high in ALA. Previous studies have shown that ALA demonstrates anti-cancer, anti-inflammatory, and anti-oxidative effects. In this study, we show the protective effect of ALA on cisplatin-induced renal toxicity associated with oxidative stress in mice using biochemical parameters. The mice were randomly assigned into four experimental groups. Group 1 (control group) were administered physiological saline solution for 9 days; group 2 (ALA group) received 200 mg/kg alpha-linolenic acid via gavage for 9 days; group 3 (CIS group) received 100 mg/kg intraperitoneal (i.p.) CIS for 9 days; and group 4 (ALA?+?CIS group) received 100 mg/kg i.p. CIS and followed by ALA 200 mg/kg via gavage for 9 days. Alpha-linolenic acid significantly reduced the expression of myeloperoxidase (MPO), phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the ALA?+?CIS group compared to the CIS group. Furthermore, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) quantities were significantly elevated in the ALA?+?CIS group when compared to the CIS group. ALA significantly decreased the levels of Bax and cleaved caspase-3, while significantly increasing the level of bcl-2, an anti-apoptotic protein, in the ALA?+?CIS group than in the CIS group. Finally, histopathological examination in renal tissue showed that the significant edematous damage induced by CIS administration alone was reduced in ALA?+?CIS group. In conclusion, our findings show that ALA is beneficial to CIS-induced nephrotoxicity in mice via its anti-inflammatory and anti-oxidative effects.

Dataset Information

?-Linolenic Acid-Valproic Acid Conjugates: Toward Single-Molecule Polypharmacology for Multiple Sclerosis.

Publications

α-Linolenic Acid-Valproic Acid Conjugates: Toward Single-Molecule Polypharmacology for Multiple Sclerosis.

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