NPT520-34 improves neuropathology and motor deficits in a transgenic mouse model of Parkinson's disease.

Abstract

NPT520-34 is a clinical stage, small molecule being developed for the treatment of Parkinson's disease and other neurodegenerative disorders. The therapeutic potential of NPT520-34 was first suggested by findings from cell-based assays of alpha-synuclein clearance. As reported here, NPT520-34 was subsequently evaluated for therapeutically relevant actions in a transgenic animal model of Parkinson's disease that overexpresses human alpha-synuclein and in an acute lipopolysaccharide-challenge model using wild-type mice. Daily administration of NPT520-34 to mThy1-alpha-synuclein (Line 61) transgenic mice for 1 or 3 months resulted in reduced alpha-synuclein pathology, reduced expression of markers of neuroinflammation, and improvements in multiple indices of motor function. In a lipopolysaccharide-challenge model using wild-type mice, a single dose of NPT520-34 reduced lipopolysaccharide-evoked increases in the expression of several pro-inflammatory cytokines in plasma. These findings demonstrate the beneficial effects of NPT520-34 on both inflammation and protein-pathology end points, with consequent improvements in motor function in an animal model of Parkinson's disease. These findings further indicate that NPT520-34 may have two complementary actions: (i) to increase the clearance of neurotoxic protein aggregates; and (ii) to directly attenuate inflammation. NPT520-34 treatment may thereby address two of the predominate underlying pathophysiological aspects of neurodegenerative disorders such as Parkinson's disease.

• Authors: Asma Khan, Robert Johnson, Carrie Wittmer, Michelle Maile, Keith Tatsukawa, Julian L Wong, Martin B Gill, Emily M Stocking, Srinivasa R Natala, Amy D Paulino, Jon K Bowden-Verhoek, Wolfgang Wrasidlo, Eliezer Masliah, Douglas W Bonhaus, Diana L Price
• Journal: Brain : a journal of neurology (Brain) Vol. 144 Issue 12 Pg. 3692-3709 (12 31 2021) ISSN: 1460-2156 [Electronic] England
• PMID: 34117864 (Publication Type: Journal Article)
• Copyright: © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Neuroprotective Agents

Topics

• Animals
• Brain (drug effects, pathology)
• Humans
• Mice
• Mice, Transgenic
• Motor Activity (drug effects)
• Neuroprotective Agents (pharmacology)
• Parkinsonian Disorders (pathology)
• Synucleinopathies (pathology)