Ibogaine, GDNF and Parkinson's disease
 

(seems researchers have been thinking about/looking into utilizing Ibogaine for PD:)
https://www.mcmp.purdue.edu:4443/sem...elabstract.pdf

Benjamin Chemel September 6, 2005
GDNF and Ibogaine: Developing a Cure for Parkinson’s Disease
Glial cell line-derived neurotrophic factor (GDNF) is a disulfide-linked,
homodimeric protein that promotes the survival and morphological differentiation
of midbrain dopamine neurons (7).The ability of GDNF to act as a growth factor
for dopamine neurons suggests that it could be a valuable treatment for
Parkinson’s Disease (PD), a debilitating neurodegenerative disorder caused by a
loss of dopamine neurons in the substantia nigra. (5). The loss of dopaminergic
neurons in PD leads to deficient levels of dopamine in the striatum and
subsequent dysregulation of motor control. Current PD treatments, including
methods of dopamine replacement, are limited to ameliorating symptoms. In
contrast, an ideal therapeutic approach would aim to halt the progressive cell
loss or improve function in spared neurons.

It has been hypothesized that GDNF represents a neuroprotective
and neurorestorative treatment for the symptoms and pathology of PD (3).
In chemically induced animal models of PD, GDNF has demonstrated the safety
and efficacy prerequisites for clinical trials in humans (2). Because this 134
amino acid protein cannot cross the blood brain barrier, new techniques are
being developed to deliver GDNF into target tissues deep within the brain (1).
One such approach, which employs an intraparenchymal catheter to infuse
recombinant protein directly into the midbrain, was utilized in a recent phase I
clinical trial (10). In this open-label trial, symptomatic evaluations were conducted
using the Universal Parkinson’s Disease Rating Scale (UPDRS), while midbrain
neuronal function was assessed using 18F-dopa positron emission tomography
(PET) imaging. The results suggested that the long-term, continuous infusion of
GDNF was well tolerated, with no apparent side effects. Additionally, all test
subjects displayed a significant amelioration of their PD disease state. Improved
motor skills and quality of life were correlated with increased function of midbrain
dopaminergic neurons, as evidenced by 18F-dopa PET imaging. Additional
molecular evidence suggested that neuronal sprouting may have contributed to
this enhanced cellular activity (8). Phase II studies were aborted by the parent
company, citing lack of functional improvements and safety concerns, yet for the
patients and researchers involved, GDNF remains a promising treatment for PD.

A pharmacological means of regulating endogenous GDNF could improve
safety and delivery issues. One such compound is the hallucinogenic alkaloid,
ibogaine. The ability of ibogaine to treat drug addiction and withdrawal has been
anecdotally reported and verified in animal models of opiate, stimulant, and
alcohol abuse (6). GDNF signaling is reportedly diminished by drugs of abuse
(9), suggesting that GDNF may be involved in the attenuation of addiction by
ibogaine (4).


These observations provide evidence for my original
hypothesis, that ibogaine represents a novel means of regulating GDNF
and can be used to treat Parkinson’s Disease. In a recent study, ibogaine was
found to upregulate GDNF expression in the midbrain and increase GDNF
secretion and GDNF-dependent activation of downstream signaling pathways in
vitro (4). These data suggest that ibogaine may represent a powerful new
method to upregulate GDNF in the treatment of neurodegenerative disorders.
Multidisciplinary research, using ibogaine as a lead compound, could reshape
the lives of those afflicted with Parkinson’s Disease.



References
1. Aebischer, P., and J. L. Ridet. 2001. Recombinant proteins for
neurodegenerative diseases: the delivery issue. Trends In Neurosciences
24:533-540.
2. Bjorklund, A., and O. Lindvall. 2000. Parkinson disease gene therapy
moves toward the clinic. Nature Medicine 6:1207-1208.
3. Grondin, R., and D. M. Gash. 1998. Glial cell line-derived neurotrophic
factor (GDNF): a drug candidate for the treatment of Parkinson's disease.
Journal Of Neurology 245:P35-P42.
4. He, D. Y., N. N. H. McGough, A. Ravindranathan, J. Jeanblanc, M. L.
Logrip, K. Phamluong, P. H. Janak, and D. Ron. 2005. Glial cell linederived
neurotrophic factor mediates the desirable actions of the antiaddiction
drug ibogaine against alcohol consumption. Journal Of
Neuroscience 25:619-628.
5. Kirik, D., B. Georgievska, and A. Bjorklund. 2004. Localized striatal
delivery of GDNF as a treatment for Parkinson disease. Nature
Neuroscience 7:105-110.
6. Levi, M. S., and R. F. Borne. 2002. A review of chemical agents in the
pharmacotherapy of addiction. Current Medicinal Chemistry 9:1807-1818.
7. Lin, L. F. H., D. H. Doherty, J. D. Lile, S. Bektesh, and F. Collins. 1993.
Gdnf - A Glial-Cell Line Derived Neurotrophic Factor For Midbrain
Dopaminergic-Neurons. Science 260:1130-1132.
8. Love, S., P. Plaha, N. K. Patel, G. R. Hotton, D. J. Brooks, and S. S.
Gill. 2005. Glial cell line-derived neurotrophic factor induces neuronal
sprouting in human brain. Nature Medicine 11:703-704.
9. Messer, C. J., A. J. Eisch, W. A. Carlezon, K. Whisler, L. Shen, D. H.
Wolf, H. Westphal, F. Collins, D. S. Russell, and E. J. Nestler. 2000.
Role for GDNF in biochemical and behavioral adaptations to drugs of
abuse. Neuron 26:247-257.
10. Patel, N. K., M. Bunnage, P. Plaha, C. N. Svendsen, P. Heywood, and
S. S. Gill. 2005. Intraputamenal infusion of glial cell line-derived
neurotrophic factor in PD: A two-year outcome study. Annals Of Neurology
57:298-302.
11. Sariola, H., and M. Saarma. 2003. Novel functions and signalling
pathways for GDNF. Journal Of Cell Science 116:3855-3862.

science blog w/topic of ibogaine
 

http://thescientistblog.blogspot.com...to-act-on.html

"...A naturally occurring hallucinogen advocated by some clinicians as a potent anti-addiction drug has been rigorously studied for the first time, confirming its ability to block alcohol craving in rodents, and clarifying how it works in the brain. The new research findings about the drug Ibogaine open the way for development of other drugs to reverse addiction without Ibogaine's side effects, potentially adding to the small arsenal of drugs that effectively combat addiction.

Derived from a West African shrub, Ibogaine has been championed for years by a cadre of clinicians and drug treatment advocates impressed with its ability to reverse withdrawal symptoms and craving for alcohol and various drugs of abuse. It has been used outside of the U.S. to treat addiction by American and other clinicians. But its side effects, including hallucinations, which made it popular in the 1960s drug culture, and evidence of toxicity to certain nerve cells in rodent studies have discouraged careful studies of its clinical potential against drug and alcohol addiction. The FDA has not approved use of Ibogaine in the U.S.

Scientists at UCSF's Ernest Gallo Clinic and Research Center have now shown definitively in experiments with mice and rats that Ibogaine does reduce alcohol consumption, and they have determined that it does so by increasing the level of a brain protein known as glial cell line-derived neurotrophic factor, or GDNF. In a separate study, they demonstrated that GDNF by itself decreases alcohol consumption.

The research is being published in the January 19 issue of The Journal of Neuroscience...
...The scientists confirmed in a cell model that Ibogaine stimulated GDNF activity. Finally, they showed that a known inhibitor of GDNF blocked Ibogaine's ability to decrease alcohol craving in the rats, suggesting a direct link between Ibogaine's desirable actions and GDNF.

'If we can alter the GDNF pathway, we may well have a new treatment against alcohol and drug addiction without the unwanted side effects of Ibogaine,' Ron said.

Colleagues in the research and coauthors on the paper are postdoctoral fellows Dao-Yao He, PhD, Nancy N.H. McGough, PhHD; Ajay Ravindranathan, PhD; Jerome Jeanblanc, PhD; Marian Logrip, BA, UCSF neurology graduate student; and Khanhky Phamluong, BA, research associate, all at the Gallo Center.

The research is supported by funds provided by the State of California through UCSF for medical research on alcohol and substance abuse, and by the Department of Defense.

Source : University of California, San Francisco