title: New isatin derivative inhibits neurodegeneration by restoring insulin signaling in brain.
abstract: Diabetes is associated with neurodegeneration. Glycation ensues in diabetes and glycated proteins cause insulin resistance in brain resulting in amyloid plaques and NFTs. Also glycation enhances gliosis by promoting neuroinflammation. Currently there is no therapy available to target neurodegenration in brain therefore, development of new therapy that offers neuroprotection is critical. The objective of this study was to evaluate mechanistic effect of isatin derivative URM-II-81, an anti-glycation agent for improvement of insulin action in brain and inhibition of neurodegenration. Methylglyoxal induced stress was inhibited by treatment with URM-II-81. Also, Ser473 and Ser9 phosphorylation of Akt and GSK-3β respectively were restored by URM-II-81. Effect of URM-II-81 on axonal integrity was studied by differentiating Neuro2A using retinoic acid. URM-II-81 restored axonal length in MGO treated cells. Its effects were also studied in high fat and low dose streptozotocin induced diabetic mice where it reduced RBG levels and inhibited glycative stress by reducing HbA1c. URM-II-81 treatment also showed inhibition of gliosis in hippocampus. Histological analysis showed reduced NFTs in CA3 hippocampal region and restoration of insulin signaling in hippocampii of diabetic mice. Our findings suggest that URM-II-81 can be developed as a new therapeutic agent for treatment of neurodegenration.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Meha Fatima
authors.initials: MF
authors.lastname: Aftab
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Shabbir Khan
authors.initials: SK
authors.lastname: Afridi
authors.affiliation: H.E.J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Uzma Rasool
authors.initials: UR
authors.lastname: Mughal
authors.affiliation: H.E.J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Aneela
authors.initials: A
authors.lastname: Karim
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Darakhshan Jabeen
authors.initials: DJ
authors.lastname: Haleem
authors.affiliation: University of Malaya, Institute of Biological Sciences, Kuala Lumpur 50603, Malaysia.
authors.forename: Nurul
authors.initials: N
authors.lastname: Kabir
authors.affiliation: H.E.J Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Khan
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan.
authors.forename: Rahman M
authors.initials: RM
authors.lastname: Hafizur
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270 Pakistan. Electronic address: rizwanas.waraich@gmail.com.
authors.forename: Rizwana S
authors.initials: RS
authors.lastname: Waraich
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007510:Isatin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; D007328:Insulin; D008996:Monoamine Oxidase Inhibitors; D007510:Isatin
keywords: Gliosis; Neurodegenration; Neurofibrillary tangles; Schiff base; Tau