Novel multifunctional pharmacology of lobinaline, the major alkaloid from Lobelia cardinalis.
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 [(3)H]-dopamine (DA) uptake in rat striatal synaptosomes. Lobinaline significantly increased fractional [(3)H] release from superfused rat striatal slices preloaded with [(3)H]-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.
College of Medicine, Department of Anatomy & Neurobiology, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA.
Dustin P
DP
Brown
Naprogenix™, UK-AsTeCC, 145 Graham Avenue, Lexington, KY 40506-0286, USA. Electronic address: dennistrogers@gmail.com.
Dennis T
DT
Rogers
College of Medicine, Department of Anatomy & Neurobiology, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA; College of Medicine, Parkinson's Disease Translational Research Center for Excellence, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA; College of Medicine, Center for Microelectrode Technology, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA.
Francois
F
Pomerleau
College of Arts and Sciences, Department of Psychology, University of Kentucky, Kastle Hall, Lexington, KY 40506-0044, USA.
Kirin B
KB
Siripurapu
College of Agriculture, Department of Biosystems & Agricultural Engineering, University of Kentucky, 1100 S. Limestone, Lexington, KY 40546-0091, USA.
Manish
M
Kulshrestha
College of Medicine, Department of Anatomy & Neurobiology, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA; College of Medicine, Department of Neurology, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA; College of Medicine, Department of Psychiatry, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA; College of Medicine, Department of Neurosurgery, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA; College of Medicine, Parkinson's Disease Translational Research Center for Excellence, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA; College of Medicine, Center for Microelectrode Technology, University of Kentucky Chandler Medical Center, 138 Leader Avenue, Lexington, KY 40536-9983, USA.
Greg A
GA
Gerhardt
Naprogenix™, UK-AsTeCC, 145 Graham Avenue, Lexington, KY 40506-0286, USA; College of Arts and Sciences, Department of Psychology, University of Kentucky, Kastle Hall, Lexington, KY 40506-0044, USA.
John M
JM
Littleton
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D057166:High-Throughput Screening Assays; D029746:Lobelia / Q000737:chemistry*; D008297:Male; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
D000470:Alkaloids; D018733:Nicotinic Antagonists; D011804:Quinolines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C000613425:lobinaline; C403531:nicotinic receptor alpha4beta2; D004298:Dopamine
Dopamine transporter; Dopaminergic neurodegeneration; Free radical scavenger; Lobelia cardinalis; Lobinaline (PubChem CID: 419029); Multifunctional alkaloid; Nicotinic acetylcholine receptors