[Ibogaine] Huge amount of ibogaine press

slowone at hush.ai slowone at hush.ai
Sat Jan 22 23:38:43 EST 2005


Thanks for pointing that out.

>From a brief look into GDNF, it seems to have both brain and 
stomach effects, plus there seems to be a linkage of low GDNF with 
insufficient breathing. Here are some items:

>From http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600837

"Boucher et al. (2000) demonstrated that glial cell line-derived 
neurotrophic factor (GDNF) both prevented and reversed sensory 
abnormalities that developed in neuropathic pain models, without 
affecting pain-related behavior in normal animals. GDNF reduced 
ectopic discharges within sensory neurons after nerve injury. 
Boucher et al. (2000) hypothesized that this may arise as a 
consequence of reversal by GDNF of the injury-induced plasticity of 
several sodium channel subunits, and argued that their findings 
provide a rational basis for the use of GDNF as a therapeutic 
treatment for neuropathic pain states."

"In rodents, GDNF stimulates an increase in midbrain dopamine 
levels, protects dopamine neurons from some neurotoxins, and 
maintains injured dopamine neurons. Gash et al. (1996) extended the 
rodent studies to rhesus monkey by evaluating the effects of GDNF 
injected intracerebrally into monkeys that had had the 
symptomatology and pathophysiologic features of Parkinson disease 
induced by MPTP. The recipients of GDNF displayed significant 
improvements in 3 of the cardinal symptoms of parkinsonism: 
bradykinesia, rigidity, and postural instability. "

"Experimental application of growth factors can alter the density 
and distribution of axon branches; hence, growth factor release may 
be one means by which target cells regulate the number of synaptic 
connections they receive. Nguyen et al. (1998) generated several 
lines of transgenic mice that overexpress GDNF under a muscle-
specific (myogenin; 159980) promoter. They found that 
overexpression of GDNF by muscle greatly increased the number of 
motor axons innervating neuromuscular junctions in neonatal mice. 
The extent of hyperinnervation correlated with the amount of GDNF 
expressed in 4 transgenic lines. Overexpression of GDNF by glia and 
overexpression of NTF3 and neurotrophin-4 (NTF4; 162662) did not 
cause hyperinnervation. During the period of greatest 
hyperinnervation (birth to 3 weeks postnatal), the Myo-GDNF mice 
exhibited a tremor. At neonatal ages, the shaking was sufficiently 
obvious that transgenic animals could be distinguished from their 
littermates without error. The severity of the tremor waned as 
multiple innervation diminished. Normal rodent neonates have a 
tremor that is most obvious during the first few postnatal days and 
gradually subsides over the next week. This tremor may be analogous 
to 'jitteriness' in human neonates. Disappearance of tremor 
corresponded to the loss of multiple innervation in each transgenic 
line, as it did in wildtype animals. "

It looks like some people were administered GDNF directly, but 
unlike the announcement, the result is not in the top Google hits. 
>From a news announcement on the part of 6 doctors, web page dated 
2002:

"Developed by Amgen Inc., GDNF is a natural growth factor for 
dopamine neurons and is found in low levels in the adult human 
brain. It is believed the destruction of these neurons in the mid-
brain causes the symptoms of Parkinson’s disease; current FDA-
approved treatments improve the symptoms but do not alter the 
underlying disease process.  Laboratory studies have demonstrated 
that GDNF both protects and promotes regeneration of injured 
midbrain dopamine neurons, and thus may directly influence the 
degenerative disease process. 

"This new investigational treatment uses a version of the Medtronic 
SynchroMed® Infusion System, a surgically implantable, programmable 
pump developed by Medtronic Inc. and pre-clinically tested at UK. 
The system will deliver GDNF directly into the patient’s brain. 
This new therapeutic approach makes possible treatments with drugs 
that cannot be used at present because they do not cross the blood 
brain barrier."

http://www.mc.uky.edu/parkinsons/HTM/GDNF.htm

Here's another study which sounds the same but the authors are 
different:

"Gill et al. (2003) delivered GDNF directly into the putamen of 5 
Parkinson patients in a phase 1 safety trial. One catheter needed 
to be repositioned and there were changes in the MRIs that 
disappeared after lowering the concentration of GDNF. After 1 year, 
there were no serious clinical side effects, a 39% improvement in 
the off-medication motor subscore of the Unified Parkinson Disease 
Rating Scale (UPDRS), and a 61% improvement in the activities of 
daily living subscore. Medication-induced dyskinesias were reduced 
by 64% and were not observed off medication during chronic GDNF 
delivery. Positron emission tomography (PET) scans of [18F]dopamine 
uptake showed a significant 28% increase in putamen dopamine 
storage after 18 months, suggesting a direct effect of GDNF on 
dopamine function."

GenAtlas has an interesting bunch of data:

http://www.dsi.univ-paris5.fr/genatlas/fiche.php?symbol=GDNF

Looking for possible ibogaine connections (there is much more, 
including the DNA sequence):

"physiological period:  fetal, pregnancy - developing gut, kidney, 
mesenchyma, developing and regenerating peripheral nerves and 
central nervous system, gut and kidney  
"SUBCELLULAR LOCATION:  extracellular  
"basic FUNCTION: 
 - promoting survival and differentiation of subpopulations of 
central and peripheral neurons including several groups; 
stimulating Schwann cell migration via NCAM but independently of 
RET 
 - playing an essential role in neural crest stem cell migration"

Brain cells allowed to change sounds familiar.

"cellular process: cell life, antiapoptosis 
"text: neurogenesis,development and maintenance of intrahippocampal 
circuitry and neuronal function and neuromuscular synapse"

I wonder if 'neuromuscular synapse' could have anything to do with 
ibogaine's ataxic effect.

"signaling:  signal transduction  
"associated pathology: 
 - many neurodegenerative disorders
 - gliomas
"susceptibility:  susceptibility to Hirschsprung disease and to 
phaeochromocytoma"

I wonder if people with these problems would react differently to 
ibogaine. Perhaps it would be worth adding a question about this to 
any data-gathering on takers of ibogaine.

Random info from other sites:

"Nonmetastatic testicular tumors were regularly formed in older 
GDNF-overexpressing mice."

"This gene encodes a highly conserved neurotrophic factor. The 
recombinant form of this protein was shown to promote the survival 
and differentiation of dopaminergic neurons in culture, and was 
able to prevent apoptosis of motor neurons induced by axotomy."

"Function: Neurotrophic factor that enhances survival and 
morphological differentiation of dopaminergic neurons and increases 
their high-affinity dopamine uptake."

"Disease: defects in gdnf may be a cause of hirschsprung disease 
(hscr) [mim:142623]. In association with mutations of RET gene, 
defects in GDNF may be involved in Hirschsprung's disease. This 
genetic disorder of neural crest development is characterized by 
the absence of intramural ganglion cells in the hindgut, often 
resulting in intestinal obstruction.
"Disease: defects in gdnf are a cause of congenital central 
hypoventilation syndrome (cchs) [mim:209880]; also known as 
congenital failure of autonomic control or Ondine's curse. CCHS is 
a rare disorder characterized by abnormal control of respiration in 
the absence of neuromuscular or lung disease, or an identifiable 
brain stem lesion. A deficiency in autonomic control of respiration 
results in inadequate or negligible ventilatory and arousal 
responses to hypercapnia and hypoxemia"

"hypercapnia: [n]  the presence of an abnormally high level of 
carbon dioxide in the circulating blood"
[hypercapnia: not breathing enough]
"Hypoxemia, or reduced oxygen in the blood,"

"On the Aug 2004 Human genome, NCBI 35 version of the human genome:
8 genes relate directly or indirectly to GDNF"

"10 bioalma disease relationships for GDNF are shown 
Disease                               Score        Articles   
hirschsprung disease                  135.29         78 
parkinson disease                      83.87        171 
neurodegenerative diseases             79.31        114 
multiple endocrine neoplasia           63.44         31 
amyotrophic lateral sclerosis          49.99         49 
multiple endocrine neoplasia type 2a   40.92         26 
nerve degeneration                     31.33         36 
other motor neuron diseases            25.89          2 
thyroid carcinoma, familial medullary  23.94          5 
multiple endocrine neoplasia type 2b   21.82         12 "

"10 bioalma chemical compound relationships for GDNF are shown
Compound                              Score        Articles  
tyrosine                               69.02        247  
heparan sulphate glycosaminoglycan     43.07          3 
dopamine                               38.88        120 
mesencephalic dopamine                 34.79          6 
neurotoxin 6-hydroxydopamine           33.55          6 
6-hydroxydopamine                      33.07         27 
glycosyl-phosphatidylinositol          29.39          9 
ototoxin                               24.97          2 
rasagiline                             24.79          3 
phosphatidylinositide                  22.84          5 "

There is lots more out there..

>"The paper looks very solid," says Stanley Glick, a 
>neuropharmacologist at Albany Medical Center in New York, who has 
studied ibogaine for many years. "They may indeed be on to a major 
finding." However, both Glick and Ron point out that boosting GDNF 
>may be only one of several mechanisms by which ibogaine acts to 
>ease addiction.
>
>A synthetic ibogaine compound, 18-methoxycoronaridine, which Glick 

>has shown can help addicts with fewer harmful side effects than 
>ibogaine, may also work by controlling GDNF levels. In preliminary 

>studies with cultured nerve cells, Ron's team found that 18-MC 
also 
>raises GDNF levels.

I wonder what else may also raise GDNF levels, from antidepressants 
to ayahuasca.

>
>But the team is not pursuing the ibogaine approach. Instead, Ron 
>thinks it is time to narrow her focus. "Our idea now is to move 
>away from ibogaine and concentrate on GDNF," she says. Her team 
>plans to look for ways to stimulate GDNF without side effects.




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