title: Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression.
abstract: Diabetes and Alzheimer's disease share pathologic links toward cognitive deficits. Pharmacologic agonist of the nuclear receptor, peroxisomal proliferator-activating receptor gamma (PPARγ), that is, rosiglitazone (rosi), are insulin sensitizing agents that improve memory in Alzheimer's disease. However, direct molecular signaling targets that improve memory by PPARγ in the hippocampus have not been investigated. We compared outcomes from oral versus intracerebroventricular (ICV) administration of rosi on memory and changes in synaptic plasticity in type 2 diabetic (db/db) mice. Db/db mice treated with rosi (ICV) showed significant improvement in memory, long-term potentiation, and post-tetanic potentiation but did not improve peripheral insulin sensitivity. Gene and protein analysis revealed increased brain-derived neurotrophic factor (BDNF) in db/db mice treated with rosi (ICV). Transcriptional activation of exon IX as determined by luciferase assays confirmed PPARγ regulation of BDNF promoter activity. Transient transfection of constitutively active PPARγ plasmid in hippocampal neuronal cells induced increased BDNF, AMPA, and NMDA receptors expression and spine formation. Findings from the present study implicate a novel PPARγ-BDNF molecular signaling mechanism as a potential therapeutic target for cognitive impairment.
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Thiruchelvam
authors.initials: T
authors.lastname: Kariharan
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Gayani
authors.initials: G
authors.lastname: Nanayakkara
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Kodeeswaran
authors.initials: K
authors.lastname: Parameshwaran
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Inseyah
authors.initials: I
authors.lastname: Bagasrawala
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Manuj
authors.initials: M
authors.lastname: Ahuja
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Engy
authors.initials: E
authors.lastname: Abdel-Rahman
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Arin T
authors.initials: AT
authors.lastname: Amin
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Dhanasekaran
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA.
authors.forename: Vishnu
authors.initials: V
authors.lastname: Suppiramaniam
authors.affiliation: Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA. Electronic address: rha0003@auburn.edu.
authors.forename: Rajesh H
authors.initials: RH
authors.lastname: Amin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics / Q000523:psychology / Q000628:therapy*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects*; D006624:Hippocampus / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007333:Insulin Resistance; D008297:Male; D008568:Memory / Q000187:drug effects; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Cognitive deficits; Diabetes; Insulin resistance; Peroxisomal proliferator activating receptor; Synaptic plasticity