Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice

Abstract

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.

Neuroprotective Mechanisms of Glucagon‐like Peptide‐1‐based Therapies in Ischaemic Stroke: A Systematic Review based on Pre‐Clinical Studies

“…The timing of drug administration varied between studies. Eight studies administered GLP‐1RAs pre‐ischaemia , eight post‐ischaemia and four both pre‐ and post‐ischaemia . For the seven studies involving DPP‐4Is, one study applied the drugs pre‐ischaemia , one post‐ischaemia and five studies both pre‐ and post‐ischaemia .…”

“…Mouse (C57BL/6), rat (Sprague Dawley/Wistar/Wistar albino) and gerbil (Mongolian) animal models were used (n = 1766). Fifteen studies tested non‐diabetic animals , six used diabetic/hyperglycaemic animals , and six studies included both non‐diabetic and diabetic . Diabetes was induced by streptozotocin , high‐fat diet or genetically modified animal strains including db/db mice , Goto‐Kakizaki rats and hyperglycaemia induced by infusion of 50% dextrose .…”

“…All studies but one used a non‐active vehicle as a control, and some studies also investigated sham‐operated animals , other kinds of GLP‐1‐based therapies , other administration routes or other drug classes . Five studies observed the effects of GLP‐1R suppression using knockout animals or specific short hairpin ribonucleic acid (RNA) sequences to target the GLP‐1R .…”

“… reported GLP‐1R expression on the cerebral endothelium. Administration of GLP‐1RAs in experimental stroke stimulated the molecules phosphoinositide 3‐kinase (PI3K), cyclic adenosine monophosphate (cAMP), protein kinase B (Akt), protein kinase A (PKA) and cAMP response element‐binding protein (CREB) , which were all inhibited by GLP‐1R suppression .…”

Cell‐Based Drug Delivery and Use of Nano‐and Microcarriers for Cell Functionalization

“…MCAO is widely used as an animal model to study drug delivery systems and pharmacokinetics. Different types of nanoparticles, such as poly( n ‐isopropylacrylamide)‐based, rutin‐encapsulated chitosan nanoparticles and PEGylated liposomal‐encapsulated drugs, have been tested (Figure ) via various routes of administration . Although the most common methods of novel drug administration remain intravenous, intraperitoneal, and intranasal, newer methods, such as administration via implanted subcutaneous osmotic minipumps and intra‐arterial route, have been recently introduced.…”