Lobeline: A multifunctional alkaloid modulates cholinergic and glutamatergic activities

Abstract

Developing drugs for Alzheimer's disease (AD) is an extremely challenging task due to its devastating pathology. Previous studies have indicated that natural compounds play a crucial role as lead molecules in the development of drugs. Even though, there are remarkable technological advancements in the isolation and synthesis of natural compounds, the targets for many of them are still unknown. In the present study, lobeline, a piperidine alkaloid has been identified as a cholinesterase inhibitor through chemical similarity assisted target fishing method. The structural similarities between lobeline and donepezil, a known acetylcholinesterase (AChE) inhibitor encouraged us to hypothesize that lobeline may also exhibit AChE inhibitory properties. It was further confirmed by in silico, in vitro and biophysical studies that lobeline could inhibit cholinesterase. The binding profiles indicated that lobeline has a higher affinity for AChE than BChE. Since excitotoxicity is one of the major pathological events associated with AD progression, we also investigated the neuroprotective potential of lobeline against glutamate mediated excitotoxicity in rat primary cortical neurons. The cell based NMDA receptor (NMDAR) assay with lobeline suggested that neuroprotective potential of lobeline is mediated through the blockade of NMDAR activity.

Unveiling the molecular basis of lobeline's allosteric regulation of NMDAR: insights from molecular modeling

“…Our previous studies demonstrated lobeline’s neuroprotective activity against glutamate mediated excitotoxicity 26 . The cell-based studies provided a valid proof for the NMDAR channel blockade activity of lobeline 26 ; however, the atomic level interaction of lobeline with NMDAR is unknown.…”

“…Our previous studies demonstrated lobeline’s neuroprotective activity against glutamate mediated excitotoxicity 26 . The cell-based studies provided a valid proof for the NMDAR channel blockade activity of lobeline 26 ; however, the atomic level interaction of lobeline with NMDAR is unknown. Since lobeline was blocking the NMDAR channel activity, we hypothesized that lobeline may directly bind to the channel vestibule or bind to a site that can modulate the channel activity.…”

“…Previously, we demonstrated that lobeline, a plant-based alkaloid present in Lobelia inflata blocks NMDAR activity and protects neurons from glutamate mediated excitotoxicity 26 . Lobeline is known for its CNS directed anxiolytic, anti-depressant and neuroprotective activities 27 – 35 .…”

Targeting c‐Myc transactivation by LMNA inhibits tRNA processing essential for malate‐aspartate shuttle and tumour progression

“…In this study, we identified lobeline as a LMNA‐binding inhibitor of c‐Myc activity in NB cells. Lobeline is a natural alkaloid derived from Lobelia inflate , and has beneficial actions via affinities for nicotinic acetylcholine receptor, vesicular monoamine transporter, opioid receptor 36 or N‐methyl‐D‐aspartate receptor 37 . Thus, it is clinically applied as a therapeutic agent for psychostimulant abuse 38 or tobacco smoking cessation 39 .…”

“…Lobeline is a natural alkaloid derived from Lobelia inflate , and has beneficial actions via affinities for nicotinic acetylcholine receptor, vesicular monoamine transporter, opioid receptor 36 or N‐methyl‐D‐aspartate receptor. 37 Thus, it is clinically applied as a therapeutic agent for psychostimulant abuse 38 or tobacco smoking cessation. 39 Of note, lobeline is able to reverse multidrug resistance of tumour cells via inhibiting P‐glycoprotein activity.…”