Neuroprotective effect of secukinumab against rotenone induced Parkinson's disease in rat model: Involvement of IL-17, HMGB-1/TLR4 axis and BDNF/TrKB cascade.
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| Abstract |
Neuroinflammatory status produced via activation of toll like receptor-4 (TLR-4) and interleukin-17 receptor (IL-17R) is one of the principal mechanisms involved in dopaminergic neuronal loss in Parkinson's disease (PD). Activation of TLR-4 and IL-17R stimulates reactive oxygen species (ROS) and proinflammatory cytokines (IL-17, IL-1β, TNFα, IL-6) production that augments neurodegeneration and reduces neuro-survival axis (TrKB/Akt/CREB/BDNF). So, reducing IL-17-driven neuroinflammation via secukinumab, monoclonal antibody against IL-17A, may be one of therapeutic approach for PD. Moreover, the aim was extended to delineate the possible neuroprotective mechanism involved against neuronal loss in rotenone induced PD in rats. Rats received 11 subcutaneous injection of rotenone (1.5 mg/kg) every other day for 21 consecutive days and treated with 2 subcutaneous injections of secukinumab (15 mg/kg) on day 9 and 15, one hour after rotenone administration. Treatment with secukinumab improved motor impairment and muscle incoordination induced by rotenone, as verified by open field and rotarod tests. Moreover, secukinumab attenuated neuronal loss and improve histopathological profile. Noteworthy, secukinumab reduces neuro-inflammatory status by hindering the interaction between IL and 17A and IL-17RA together with inhibiting the activation of TLR-4 and its downstream cascade including pS536-NFκB p65, IL-1β and HMGB-1. Additionally, secukinumab stimulated neuro-survival signalling cascade via activation pY515-TrKB receptor and triggered upsurge in its downstream targets (pS473-Akt/pS133-CREB/BDNF). Furthermore, secukinumab increased striatal tyrosine hydroxylase immunoexpression, the rate limiting step in dopamine biosynthesis, to guard against dopaminergic neuronal loss. In conclusion, secukinumab exerts a neuroprotective effect against rotenone induced neuronal loss via inhibition IL17A/IL17RA interaction and HMGB-1/TLR-4/NF-κBp65/IL1β signalling cascade, together with activation of TrKB/ Akt/CREB/BDNF axis.
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| Authors | Yara T Mohamed, Abeer Salama, Mostafa A Rabie, Mai A Abd El Fattah |
| Journal | International immunopharmacology (Int Immunopharmacol) Vol. 114 Pg. 109571 (Jan 2023) ISSN: 1878-1705 [Electronic] Netherlands |
| PMID | 36527875 (Publication Type: Journal Article) |
| Copyright | Copyright © 2022 Elsevier B.V. All rights reserved. |
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