Abstract
Objective: To investigate the effects of chronic FTY720 drug treatment on myelination and anti-oxidant mechanisms in the brain.
Background: FTY720 is widely used for management of relapsing-remitting multiple sclerosis (MS), principally due to its anti-inflammatory properties. Loss of proteins involved in myelination and weekend cellular anti-oxidant defence systems have been implicated in MS pathology. FTY720 is increasingly suggested to play an important role in promoting neuroprotection. This study aimed to investigate the effects of chronic FTY720 treatment on the myelination and anti-oxidant associated pathways in the brain cortex.
Design/Methods: CBA/CaHArc mice were treated with the FTY720 drug (7.5 mg/kg i.p weekly) or vehicle control for 2 months. The prefrontal cortex of the brain was harvested and examined from drug-treated and control mice (n=10). The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on brain tissue followed by functional pathway and protein network interaction analysis using Ingenuity pathway analysis, STRING and Panther computational tools.
Results: Over 6500 proteins were identified in the treated and control mice brain cortices. Cellular pathway enrichment and functional protein network analyses of 2633 differentially expressed proteins using computational tools revealed 38 upregulated proteins associated with various aspects of myelination and oligodendrocyte development (fold changes; p<0.05) such as myelin basic protein (3.4), myelin-associated glycoprotein (2.4) and FOXO3 (2.6). In addition, anti-oxidant response proteins (21) including superoxide dismutase 1 and 2 (2.7, 1.8), catalase (1.8) and glutathione synthetase (1.5) were identified to be upregulated in the FTY720 drug treatment group.
Conclusions: FTY720 in addition to its known immunosuppressive roles brings about significant changes in the proteins involved in myelination and enhances the anti-oxidant system in the cortex. These effects may play a synchronous role in protecting the brain in MS pathology in addition to anti-inflammatory actions of the drug.
Disclosure: Dr. Mirzaei has nothing to disclose. Dr Gupta has nothing to disclose. Dr. Klistorner has nothing to disclose. Dr. Graham has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis. Dr. Graham has received personal compensation in an editorial capacity for Novartis.
Background: FTY720 is widely used for management of relapsing-remitting multiple sclerosis (MS), principally due to its anti-inflammatory properties. Loss of proteins involved in myelination and weekend cellular anti-oxidant defence systems have been implicated in MS pathology. FTY720 is increasingly suggested to play an important role in promoting neuroprotection. This study aimed to investigate the effects of chronic FTY720 treatment on the myelination and anti-oxidant associated pathways in the brain cortex.
Design/Methods: CBA/CaHArc mice were treated with the FTY720 drug (7.5 mg/kg i.p weekly) or vehicle control for 2 months. The prefrontal cortex of the brain was harvested and examined from drug-treated and control mice (n=10). The multiplexed Tandem Mass Tag based proteomics (TMT-MS3) was carried out on brain tissue followed by functional pathway and protein network interaction analysis using Ingenuity pathway analysis, STRING and Panther computational tools.
Results: Over 6500 proteins were identified in the treated and control mice brain cortices. Cellular pathway enrichment and functional protein network analyses of 2633 differentially expressed proteins using computational tools revealed 38 upregulated proteins associated with various aspects of myelination and oligodendrocyte development (fold changes; p<0.05) such as myelin basic protein (3.4), myelin-associated glycoprotein (2.4) and FOXO3 (2.6). In addition, anti-oxidant response proteins (21) including superoxide dismutase 1 and 2 (2.7, 1.8), catalase (1.8) and glutathione synthetase (1.5) were identified to be upregulated in the FTY720 drug treatment group.
Conclusions: FTY720 in addition to its known immunosuppressive roles brings about significant changes in the proteins involved in myelination and enhances the anti-oxidant system in the cortex. These effects may play a synchronous role in protecting the brain in MS pathology in addition to anti-inflammatory actions of the drug.
Disclosure: Dr. Mirzaei has nothing to disclose. Dr Gupta has nothing to disclose. Dr. Klistorner has nothing to disclose. Dr. Graham has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis. Dr. Graham has received personal compensation in an editorial capacity for Novartis.
| Original language | English |
|---|---|
| Article number | P1.411 |
| Journal | Neurology |
| Volume | 90 |
| Issue number | 15 Supplement |
| Publication status | Published - 10 Apr 2018 |
| Event | AAN 70th Annual Meeting (2018) - Los Angeles, United States Duration: 21 Apr 2018 → 27 Apr 2018 Conference number: 70th |