Deconstructing the Iboga Alkaloid Skeleton: Potentiation of FGF2-induced Glial Cell Line-Derived Neurotrophic Factor Release by a Novel Compound.
Madalee M Gassaway, Teresa L Jacques, Andrew C Kruegel, Richard J Karpowicz, Xiaoguang Li, Shu Li, Yves Myer, Dalibor Sames
ACS Chemical Biology January 15, 2016 DOI: 10.1021/acschembio.5b00678 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study Peer reviewed |
|---|---|
| Population | C6 glioma cells |
| Interventions | XL-008 FGF2 |
| Topics | Addiction Ibogaine |
| Keywords | Neuroprotection Brain protection Neurological protection Neuroprotective mechanisms Brain health Neuropsychiatric disorders Mental health Brain disorders Neurological disorders Substance abuse Drug discovery Drug development Pharmaceutical research Novel compounds Therapeutic compounds Pharmacology Drug research Xl-008 Neurotrophic factors Growth factors Brain signaling Gdnf Fgf2 Neurotrophins Brain pathways |
| Citations | 23 |
| Key points | XL-008 induces GDNF release and potentiates FGF2-induced GDNF release in C6 glioma cells via MEK and PI3K pathways. |
Abstract
Modulation of growth factor signaling pathways in the brain represents a new experimental approach to treating neuropsychiatric disorders such as depression, anxiety, and addiction. Neurotrophins and growth factors exert synaptic, neuronal, and circuit level effects on a wide temporal range, which suggests a possibility of rapid and lasting therapeutic effects. Consequently, identification of small molecules that can either enhance the release of growth factors or potentiate their respective pathways will provide a drug-like alternative to direct neurotrophin administration or viral gene delivery and thus represents an important frontier in chemical biology and drug design. Glial cell line-derived neurotrophic factor (GDNF), in particular, has been implicated in marked reduction of alcohol consumption in rodent addiction models, and the natural product ibogaine, a substance used traditionally in ritualistic ceremonies, has been suggested to increase the synthesis and release of GDNF in the dopaminergic system in rats. In this report, we describe a novel iboga analog, XL-008, created by unraveling the medium size ring of the ibogamine skeleton, and its ability to induce release of GDNF in C6 glioma cells. Additionally, XL-008 potentiates the release of GDNF induced by fibroblast growth factor 2 (FGF2), another neurotrophin implicated in major depressive disorder, increasing potency more than 2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture was found to be mediated through the MEK and PI3K signaling pathways but not through PLCγ in C6 glioma cells.
Comparable studies
Other experimental studies on ibogaine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Noribogaine is a G-protein biased κ-opioid receptor agonist. | 2015 | Experimental study with binding experiments, functional assays, and computational simulations | |
| Anti-addiction drug ibogaine inhibits hERG channels: a cardiac arrhythmia risk. Human cells | 2014 | Experimental study | |
| Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: a study to assess the drug's cardiac ion channel profile. Heterologously expressed human ion channels and guinea pig cardiomyocytes | 2013 | Experimental study | |
| Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation. Rat brain models | 2002 | Review with experimental data | |
| Anti-addiction Drug Ibogaine Prolongs the Action Potential in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Human ventricular-like cardiomyocytes derived from induced pluripotent stem cells | 2017 | Experimental study |
Citations in the library
Cited by 8
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Ibogaine Administration Modifies GDNF and BDNF Expression in Brain Regions Involved in Mesocorticolimbic and Nigral Dopaminergic Circuits. Frontiers in Pharmacology 2019
- A Single Administration of the Atypical Psychedelic Ibogaine or Its Metabolite Noribogaine Induces an Antidepressant-Like Effect in Rats. ACS Chemical Neuroscience June 3, 2020
- Tropane-Based Ibogaine Analog Rescues Folding-Deficient Serotonin and Dopamine Transporters. ACS Pharmacology & Translational Science April 9, 2021
- Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview. Journal of psychopharmacology (Oxford, England) December 1, 2023
and 3 more in the library
Cites 13
- Treatment of acute opioid withdrawal with ibogaine. The American Journal on Addictions 1999
- Effects and aftereffects of ibogaine on morphine self-administration in rats. European Journal of Pharmacology April 3, 1991
- Inhibitory effects of ibogaine on cocaine self-administration in rats. European Journal of Pharmacology September 14, 1993
- Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures. Annals of the New York Academy of Sciences September 1, 2000
- Attenuation of alcohol intake by ibogaine in three strains of alcohol-preferring rats. Pharmacology, biochemistry, and behavior November 1, 1995
and 8 more in the library