Vortioxetine ameliorates experimental autoimmune encephalomyelitis model of multiple sclerosis in mice via activation of PI3K/Akt/CREB/BDNF cascade and modulation of serotonergic pathway signaling.

Autor: Shafiek MS; Department of Pharmacology and Toxicology, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, Egypt., Mekky RY; Department of Pharmacology and Toxicology, October University for Modern Science and Arts (MSA), Giza, 12622, Egypt., Nassar NN; Department of Pharmacology and Toxicology, October University for Modern Science and Arts (MSA), Giza, 12622, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt., El-Yamany MF; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt., Rabie MA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 11562, Cairo, Egypt. Electronic address: Mostafa.mohammed@pharma.cu.edu.eg.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2024 Nov 05; Vol. 982, pp. 176929. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1016/j.ejphar.2024.176929
Abstrakt: Multiple sclerosis (MS) is a chronic condition characterized by immune cell infiltration and cytokine overproduction that led to myelin sheath inflammatory assaults, thus causing axonal destruction. The former consequently provokes motor impairment and psychological disorders. Markedly, depression is one of the most prevalent lifelong comorbidities that negatively impacts the quality of life in MS patients. Vortioxetine (VTX), a multi-modal molecule prescribed to manage depression and anxiety disorder, additionally, it displays a promising neuroprotective properties against neurodegenerative diseases such as Alzheimer's and Parkinson's. To this end, the present study investigated the potential therapeutic efficacy of VTX against experimental autoimmune encephalomyelitis (EAE) model of MS in mice. Notably, treatment with VTX significantly ameliorated EAE-induced motor disability, as evident by enhanced performance in open field, rotarod and grip strength tests, alongside a reduction in immobility time during the forced swimming test, indicating a mitigation of the depressive-like behavior; outcomes that were corroborated with histological examinations and biochemical analyses. Mechanistically, VTX enhanced serotonin levels by inhibiting both serotonin transporter (SERT) and indoleamine 2,3-dioxygenase (IDO) enzyme, thereby promoting the activation of serotonin 1A (5-HT 1A ) receptor. The latter triggered the stimulation of phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) cascade that entailed activation/phosphorylation of cAMP response element-binding protein (CREB). This activation increased brain derived neurotrophic factor (BDNF) and myelin basic protein (MBP) contents that mitigated demyelination in the corpus callosum. Furthermore, VTX suppressed phospho serine 536 nuclear factor kappa B (pS536 NF-κB p65) activity and reduced tumor necrosis factor-alpha (TNF-α) production. The results underscore VTX's beneficial effects on disease severity in EAE model of MS in mice by amending both inflammatory and neurodegenerative components of MS progression.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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