Hemmati, Fatemeh and Valian, Neda and Ahmadiani, Abolhassan and Mohamed, Zahurin and Ali, Raymond Azman and Ibrahim, Norlinah Mohamed and Shirazi, Seyed Farshad Hosseini (2024) Insulin and TLR4 inhibitor improve motor impairments in a rat model of parkinson's disease. Iranian Journal of Pharmaceutical Research, 23 (1). ISSN 1735-0328, DOI https://doi.org/10.5812/ijpr-144200.
Full text not available from this repository.Abstract
Background: Insulin resistance is an important pathological hallmark of Parkinson's disease (PD). Proinflammatory cytokinesduring neuroinflammation decrease insulin sensitivity by suppressing insulin signaling elements. Toll-like receptor 4 (TLR4),the main receptor involved in neuroinflammation, is also associated with the pathogenesis of PD. Objectives: The present study evaluated the effect of insulin, an insulin receptor antagonist, and a TLR4 inhibitor on behavioraldeficits and insulin resistance induced by 6-hydroxydopamine (6-OHDA). Methods: Male Wistar rats were divided into nine groups: (1) sham (normal saline NS] in the medial forebrain bundle MFB]);(2) 6-OHDA (20 mu g in the MFB); (3) 6-OHDA + NS; (4) 6-OHDA + dimethyl sulfoxide (DMSO); (5) 6-OHDA + insulin (2.5 IU/day,intracerebroventricular (ICV]); (6) 6-OHDA + insulin (5 IU/day, intranasal IN]); (7) 6-OHDA + insulin receptor antagonist (S961;6.5 nM/kg, ICV); (8) 6-OHDA + TLR4 inhibitor (TAK242; 0.01 mu g/rat, ICV); (9) 6-OHDA + insulin + TLR4 inhibitor. All treatments wereadministered for seven consecutive days. Motor performance was evaluated using apomorphine-induced rotation and cylindertests. Gene expression and protein levels of alpha-synuclein, TLR4, insulin receptor substrate (IRS) 1, IRS2, and glycogen synthasekinase 3 beta (GSK3 beta) were measured by real-time PCR and western blotting, respectively, in the striatum. Results: Insulin, alone and with TAK242, improved motor deficits induced by 6-OHDA. Administration of the insulin receptorantagonist had no effect on motor deficits. The increased expression of alpha-synuclein and TLR4 following 6-OHDA was attenuatedby insulin and TAK242. GSK3 beta levels, both mRNA and protein, were significantly increased by 6-OHDA and attenuated withinsulin and TAK242. Conclusions: The findings suggest that 6-OHDA induces neurodegeneration via activation of TLR4 and GSK3 beta, indicatinginsulin resistance, and that insulin can improve these impairments. Moreover, TLR4 inhibition prevents insulin signalingdysfunction and improves behavioral and molecular impairments, highlighting the critical role of TLR4 in the development ofinsulin resistance in PD pathology.
| Item Type: | Article |
|---|---|
| Funders: | None |
| Uncontrolled Keywords: | Parkinson's Disease,Insulin; Insulin Resistance; TLR4; Intranasal Administration; S961; TAK242 |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Faculty of Pharmacy |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 03 Nov 2025 12:18 |
| Last Modified: | 03 Nov 2025 12:18 |
| URI: | http://eprints.um.edu.my/id/eprint/46330 |
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