Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis (Artic

Fitoterapia

Volume 111, 1 June 2016, Pages 109-123

le)

Brown, D.P.^a, 

Rogers, D.T.^b , 

Pomerleau, F.^ahi, 

Siripurapu, K.B.^c, 

Kulshrestha, M.^d, 

Gerhardt, G.A.^aefghi, 

Littleton, J.M.^bc

 

^a  College of Medicine, Department of Anatomy and Neurobiology, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY, United States
^b  Naprogenix™, UK-AsTeCC, 145 Graham Avenue, Lexington, KY, United States
^c  College of Arts and Sciences, Department of Psychology, University of Kentucky, Kastle Hall, Lexington, KY, United States 

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Abstract

In screening a library of plant extracts from ∼ 1000 species native to the Southeastern United States, Lobelia cardinalis was identified as containing nicotinic acetylcholine receptor (nicAchR) binding activity which was relatively non-selective for the α₄β₂- and α₇-nicAchR subtypes. This nicAchR binding profile is atypical for plant-derived nicAchR ligands, the majority of which are highly selective for α₄β₂-nicAchRs. Its potential therapeutic relevance is noteworthy since agonism of α₄β₂- and α₇-nicAchRs is associated with anti-inflammatory and neuroprotective properties. Bioassay-guided fractionation of L. cardinalis extracts led to the identification of lobinaline, a complex binitrogenous alkaloid, as the main source of the unique nicAchR binding profile. Purified lobinaline was a potent free radical scavenger, displayed similar binding affinity at α₄β₂- and α₇-nicAchRs, exhibited agonist activity at nicAchRs in SH-SY5Y cells, and inhibited [³H]-dopamine (DA) uptake in rat striatal synaptosomes. Lobinaline significantly increased fractional [³H] release from superfused rat striatal slices preloaded with [³H]-DA, an effect that was inhibited by the non-selective nicAchR antagonist mecamylamine. In vivo electrochemical studies in urethane-anesthetized rats demonstrated that lobinaline locally applied in the striatum significantly prolonged clearance of exogenous DA by the dopamine transporter (DAT). In contrast, lobeline, the most thoroughly investigated Lobelia alkaloid, is an α₄β₂-nicAchR antagonist, a poor free radical scavenger, and is a less potent DAT inhibitor. These previously unreported multifunctional effects of lobinaline make it of interest as a lead to develop therapeutics for neuropathological disorders that involve free radical generation, cholinergic, and dopaminergic neurotransmission. These include neurodegenerative conditions, such as Parkinson's disease, and drug abuse. © 2016 Elsevier B.V. All rights reserved.

Author keywords

Dopamine transporter; Dopaminergic neurodegeneration; Free radical scavenger; Lobelia cardinalis; Multifunctional alkaloid; Nicotinic acetylcholine receptors

ISSN: 0367326X CODEN: FTRPASource Type: Journal Original language: English

DOI: 10.1016/j.fitote.2016.04.013Document Type: Article

Publisher: Elsevier

Funding Details

Number; Acronym; Sponsor: 2T32DA016176-11; NIDA; National Institute on Aging
Number; Acronym; Sponsor: 5T32AG000242-20; NIA; National Institute on Aging

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