Intranasal delivery of low-dose insulin ameliorates motor dysfunction and dopaminergic cell death in a 6-OHDA rat model of Parkinson's Disease. (1st January 2020)

• Record Type: Journal Article
• Authors: Fine, Jared M.; Stroebel, Benjamin M.; Faltesek, Katherine A.; Terai, Kaoru; Haase, Lucas; Knutzen, Kristin E.; Kosyakovsky, Jacob; Bowe, Tate J.; Fuller, Austin K.; Frey, William H.; Hanson, Leah R.
• Is Part Of: Neuroscience letters. Volume 714(2020)
• Publication Date: 2020-01-01
• Subjects: IRBS insulin-resistant brain state -- ROS reactive oxygen species -- PD Parkinson's Disease -- GLP-1 glucagon-like peptide-1 -- IN intranasal -- 6-OHDA 6-hydroxydopamine -- POD pressurized olfactory delivery device -- TH+ tyrosine hydroxylase positive' -- SNPc substantia nigra pars compacta -- A/P anterior/posterior -- M/L medial/lateral -- IU international units -- PBS phosphate buffered saline -- DAPI 4′6-diamidino-2-phenylindole -- MAO monoamine oxidase; Insulin -- Humulin -- Intranasal -- 6-hydroxydopamine -- Parkinson's Disease -- Tyrosine hydroxylase -- Drug-induced rotational test -- Horizontal ladder test; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2019.134567
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: We determined whether intranasal insulin would mitigate the behavioral and neuropathological effects of 6-OHDA in a rat model of PD. Insulin decreased the turns in a drug induced rotational test and walking errors on a ladder test. Insulin increased dopaminergic cell survival in the brain. The use of an olfactory delivery device with a low dose of insulin can help with translation to clinical trials. Abstract: Emerging evidence continues to demonstrate that disrupted insulin signaling and altered energy metabolism may play a key role underpinning pathology in neurodegenerative conditions. Intranasally administered insulin has already shown promise as a memory-enhancing therapy in patients with Alzheimer's and animal models of the disease. Intranasal drug delivery allows for direct targeting of insulin to the brain, bypassing the blood brain barrier and minimizing systemic adverse effects. In this study, we sought to expand upon previous results that show intranasal insulin may also have promise as a Parkinson's therapy. We treated 6-OHDA parkinsonian rats with a low dose (3 IU/day) of insulin and assessed apomorphine induced rotational turns, motor deficits via a horizontal ladder test, and dopaminergic cell survival via stereological counting. We found that insulin therapy substantially reduced motor dysfunction and dopaminergic cell death induced by unilateral injection of 6-OHDA. These results confirm insulin's efficacy within this model, and do so over a longer period after model induction which more closely resembles Parkinson's disease. This study also employed a lower dose than previous studies and utilizes a delivery device, which could lead to an easier transition into human clinical trials as a therapeutic for Parkinson's disease.