Squalamine Restores the Function of the Enteric Nervous System in Mouse Models of Parkinson’s Disease

Article type: Research Article

Authors: West, Christine L.^{a; b; *} | Mao, Yu-Kang^a | Delungahawatta, Thilini^a | Amin, Jessica Y.^a | Farhin, Sohana^a | McQuade, Rachel M.^c | Diwakarla, Shanti^c | Pustovit, Ruslan^c | Stanisz, Andrew M.^a | Bienenstock, John^{a; e; f} | Barbut, Denise^g | Zasloff, Michael^{g; h} | Furness, John B.^c | Kunze, Wolfgang A.^{a; b; d}

Affiliations: [a] Brain-Body Institute, St. Joseph’s Healthcare, Hamilton, ON, Canada | [b] Department of Biology, McMaster University, Hamilton, ON, Canada | [c] Department of Anatomy and Neuroscience, University of Melbourne, and the Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia | [d] Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada | [e] Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada | [f] Department of Medicine, McMaster University, Hamilton, ON, Canada | [g] Enterin, Inc., Philadelphia, PA, USA | [h] MedStar–Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC, USA

Correspondence: [*] Correspondence to: Christine L. West, Brain-Body Institute, St. Joseph’s Healthcare, Hamilton, ON, Canada. Tel.: +1 905 522 1155, Office: x35994, Lab: x32277; E-mail: [email protected].

Abstract: Background:Parkinson’s disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. Objective:Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. Methods:GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results:Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion:These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD.

Keywords: Parkinson’s disease, squalamine, intestinal motility, intrinsic primary afferent neuron, electrophysiology, gut-brain axis, vagus

DOI: 10.3233/JPD-202076

Journal: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1477-1491, 2020