en Neurophysiology/Pharmacology Neurophysiology/Pharmacology Experimental research article Experimental research article <span style="font-size:12px;"><span style="font-family:Arial;"><strong>I<span style="line-height:2;">ntroduction:</span></strong><span style="line-height:1.5;"> Toll-like receptor (TLR) 4 is involved in neuroinflammatory processes in peripheral tissues and central nervous system. Pro-inflammatory cytokines production, due to over activation of TLR4, interfere with insulin signaling elements lead to insulin resistance. Regarding the critical roles of TLR4 and insulin in the pathogenesis of Parkinson&rsquo;s disease (PD), in the present study the TLR4/insulin receptor interaction was assessed in a neuroinflammation model of PD.<br /> <strong>Methods: </strong>LPS was injected into the right striatum of male Wistar rats (20&micro;g/rat). Insulin (2.5IU/ day), insulin receptor antagonist (S961; 6.5nM/kg), or TLR4 antibody (Resatorvid (TAK242); 0.01&micro;g/rat) were administered intracerebroventricularly (ICV) for 14 days. Insulin and TAK242 were also simultaneously injected in a distinct group. Behavioral assessments were performed using rotarod, apomorphine-induced rotation, and cylinder tests. The levels of &alpha;-synuclein, TLR4, and elements of the insulin signaling pathway were measured in the striatum.<br /> <strong>Results:</strong> LPS impaired motor performance of the animals and increased the levels of &alpha;-synuclein and TLR4. Furthermore, it reduced mRNA levels of IRS1 and IRS2 and enhanced GSK3&beta; mRNA and protein levels, indicating the development of insulin resistance. Treatment with insulin and TAK 242 improved motor deficits, restored insulin signaling pathway, and reduced &alpha;-synuclein and TLR4 levels.<br /> <strong>Conclusion:</strong> The findings indicate that LPS impaired motor function, at least in part, via &alpha;-synuclein and TLR4 overexpression, leading to insulin resistance. Suppression of TLR4 and activation of insulin receptors attenuated motor deficits, suggesting that TLR4 and insulin receptors are promising the</span>rapeutic targets for PD modification.</span></span> Parkinson’s disease, Insulin, Lipopolysaccharide,TLR4,TAK242 128 140 http://ppj.phypha.ir/browse.php?a_code=A-10-2217-1&slc_lang=en&sid=1 Fatemeh Hemmati lhemmati7@gmail.com 3200319475328460035726 0000000331252027 No Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Neda Valian mn.valian281@yahoo.com 3200319475328460035727 0000000238804325 No Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Abolhassan Ahmadiani aahmadiani@yahoo.com 3200319475328460035728 0000000266682302 No Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran Zahurin Mohamed zahurin@ummc.edu.my 3200319475328460035729 0000000243960517 No Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia Raymond Azman Ali raymond@ppukm.ukm.my 3200319475328460035730 0000000160665168 No Department of Medicine, University Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia Norlinah Mohamed Ibrahim norlinah@ppukm.ukm.edu.my 3200319475328460035731 0000000266847488 No Department of Medicine, University Kebangsaan Malaysia Medical Centre, Cheras, Kuala Lumpur, Malaysia Seyed Farshad Hosseini Shirazi farshadshirazisbmu7@gmail.com 3200319475328460035732 000000031356385X Yes Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran