title: Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice.
abstract: Exendin-4 is now considered as a promising drug for the treatment of cerebral ischemia. To determine the neuroprotective effects of intranasal exendin-4, C57BL/6J mice were intranasally administered with exendin-4 daily for 7 days before middle cerebral artery occlusion (MCAO) surgery. Intranasally administered exendin-4 produced higher brain concentrations and lower plasma concentrations when compared to identical doses administered interperitoneally. Neurological deficits and volume of infarcted lesions were analyzed 24 h after ischemia. Intranasal administration of exendin-4 exhibited significant neuroprotection in C57BL/6 mice subjected to MCAO by reducing neurological deficit scores and infarct volume. The neuroprotective effects of exendin-4 were blocked by the knockdown of GLP-1R with shRNA. However, exendin-4 has no impact on glucose and insulin levels which indicated that the neuroprotective effect was mediated by the activation of GLP-1R in the brain. Exendin-4 intranasal administration restored the balance between pro- and anti-apoptotic proteins and decreased the expression of Caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. These findings provided evidence that exendin-4 intranasal administration exerted a neuroprotective effect mediated by an anti-apoptotic mechanism in MCAO mice and protected neurons against ischemic injury through the GLP-1R pathway in the brain. Intranasal delivery of exendin-4 might be a promising strategy for the treatment of ischemic stroke.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China.
authors.forename: Huinan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China.
authors.forename: Shimeng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: School of Nursing, The Fourth Military Medical University, Xi'an, China.
authors.forename: Yunhan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China.
authors.forename: Di
authors.initials: D
authors.lastname: Qu
authors.affiliation: Department of Health Statistics, Faculty of Preventative Medicine, The Fourth Military Medical University, Xi'an, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China.
authors.forename: Xubo
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China. zhanghuinanshen@126.com.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, 169 Changle West Rd., Xi'an, 710032, China. maxuel@fmmu.edu.cn.
authors.forename: Xue
authors.initials: X
authors.lastname: Ma
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D000077270:Exenatide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D016896:Treatment Outcome; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
keywords: cerebral ischemia; exendin-4; intranasal delivery; neuroprotection