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03-26-2012, 10:43 AM | #1 | |||
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http://www.accessphysiotherapy.com/s...searchSource=1 Each time I read about GDNF and the BBB problems, I am reminded of the following compound and wonder WHY no one has looked at it for PD. One answer I received is that the drug induces hallucinations for the initial 24 hr period after it is given. Oh yeah--ignore that sinemet does the same though having to take it daily means the hallucinations are spread out over a much longer period of time. Have attempted to find the researcher/author, but have failed to do so. Madelyn Former posting: (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.
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