Podcasts about gdnf

In this episode of the Crazy Wisdom Podcast, host Stewart Alsop welcomes Jonathan Dickinson, a specialist in Ibogaine treatment and co-founder/CEO of Ambio Life Sciences and Teregnosis. They discuss the history and therapeutic uses of Iboga and Ibogaine, focusing on its effects in treating heroin addiction, traumatic brain injury, and chronic pain. Jonathan also shares insights into the cultural origins of Iboga, its use in traditional Bwiti ceremonies, and how modern approaches, particularly his work with veterans, expand its applications. More information about Jonathan's work can be found at Ambio Life.Check out this GPT we trained on the conversation!Timestamps00:00 Introduction to the Crazy Wisdom Podcast00:21 Understanding Ibogaine and Its Uses02:00 Ibogaine's Impact on Veterans and Brain Injuries03:57 Psycho-Spiritual and Medical Benefits of Ibogaine07:12 Scientific Studies and Misconceptions18:50 Legalization and Research Challenges25:05 Ibogaine Sourcing and Sustainability31:43 Ibogaine Smuggling and Export Practices32:10 Pharmaceutical Grade Iboga Extract33:36 Challenges of Growing Iboga33:53 Traditional Growth Methods and Cultural Attitudes37:04 Global Cultivation Efforts38:05 Access and Benefit Sharing Agreements38:54 Traditional Knowledge and Bwiti Culture39:40 Historical Context of Iboga Use40:44 Bantu and Pygmy Cultural Exchange42:31 Bwiti Rituals and Practices46:23 Learning from Traditional Practices48:19 Western and Traditional Knowledge Integration55:58 Future of Iboga and Ibogaine59:22 Connecting with AmbioKey InsightsIboga and Ibogaine as Addiction Treatments: Ibogaine is primarily known for its effectiveness in treating heroin addiction. It interrupts the addiction cycle through a powerful psychoactive experience lasting 12-24 hours, which helps individuals detox from drugs like heroin and opioids. After the session, many report being free of withdrawal symptoms and cravings for months, providing a unique pathway out of addiction.Use in Treating Traumatic Brain Injuries (TBI): Jonathan has worked extensively with veterans, especially Navy SEALs, using Ibogaine to address TBIs. These injuries, often from combat-related concussive forces, lead to symptoms that mirror PTSD. Ibogaine appears to regenerate brain function, as seen in a study conducted with Stanford University, where veterans exhibited significant brain activity improvement following treatment.Cultural Roots in Bwiti and African Traditions: Iboga has deep cultural significance in Gabon, particularly in Bwiti spiritual practices, which have been influenced by both indigenous Pygmy traditions and Bantu peoples. Bwiti uses Iboga in ceremonies for psycho-spiritual exploration, healing, and connection to ancestors, a tradition that has persisted for centuries and possibly millennia.Misunderstandings About Noribogaine: Many believe that noribogaine, a metabolite of Ibogaine, remains in the body for up to eight months, contributing to long-lasting effects. However, Jonathan clarifies that noribogaine remains in the system for only a few days or a week. The extended feeling of ease or afterglow people experience may be due to neurotrophic factors like GDNF, which stimulate brain healing and regeneration over time.Emerging Scientific Understanding of Ibogaine: Research into Ibogaine's mechanisms is still developing. It acts on many receptors in the brain, including the Sigma 2 receptor, which has been linked to pain relief and neuroprotective effects. There's also growing interest in its potential role in intracellular processes and energy metabolism, where it appears to improve cellular efficiency, possibly explaining its long-term regenerative effects on brain function.Decentralized Knowledge and Treatment Communities: Unlike tightly regulated pharmaceutical models, Ibogaine treatment has grown in a decentralized, community-driven way, with providers sharing their experiences and knowledge. This echoes the traditions of Bwiti and emphasizes the importance of communal support around Ibogaine therapy, where the intensity of the experience requires a supportive environment and a collective sharing of insights.Sustainability and Ethical Sourcing of Iboga: Jonathan is actively involved in ensuring the sustainable and ethical sourcing of Iboga through his company, Teregnosis. Working with Gabonese communities, Teregnosis follows the Nagoya Protocol to ensure that the benefits of Iboga's growing global interest are shared with the traditional communities that have long relied on this plant, protecting both the ecosystem and cultural heritage.

Send us a textTalia's journey from opioid addiction to healing through the transformative power of Ibogaine is not just inspiring—it's a beacon of hope for those battling similar demons. Her experiences have led her to co-found the Beond Ibogaine Treatment Center. We discuss her efforts and the challenges faced in pushing alternative treatments to the forefront of the fight against the opioid crisis. Talia's personal story of overcoming addiction, beginning with a seemingly innocuous dental procedure, underscores the urgent need for diverse therapeutic options beyond conventional medication assisted therapy and treatments.Exploring Ibogaine's unique properties, we discuss its traditional ties to the Bwiti tribe in Africa and its integration into Western clinical practices. Ibogaine stands out among psychedelics for its multi-faceted impact on the brain and its ability to reframe past memories, providing a sense of lightness and clarity. We delve into the delicate balance between ensuring clinical safety due to potential cardiac risks and embracing the spiritual aspects of the experience. Talia explains how Ibogaine promotes the glial-derived neurotrophic factor (GDNF), supporting neuroplasticity for months, aiding individuals in integrating newfound insights into their daily lives.Our conversation expands on the broader therapeutic potential of Ibogaine, from tackling conditions like Lyme disease to helping those dependent on SSRIs. We reflect on personal anecdotes and stories of individuals who have found profound healing and lasting change through Ibogaine. With the backdrop of advocacy efforts and legal hurdles in traditionally conservative areas, we aim to shine a light on the transformative power of Ibogaine. Join us as we navigate this powerful narrative, touching on healing addiction, spiritual exploration, and the exciting new horizons of psychedelic research.Connect with Beond Ibogaine here: https://beondibogaine.com/And here: https://www.instagram.com/beond.us 1:1 Discovery CallsAre psychedelics right for you on your healing journey? Book a discovery call to ask us anything.ColorsUse code OTHERSIDE15 for 15% offMicrodosifyUse code SYOTOS for 10% off https://www.buzzsprout.com/1982724/support Support the showOur Website:https://linktr.ee/seeyouontheothersidepodcast

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: WTH is Cerebrolysin, actually?, published by gsfitzgerald on August 6, 2024 on LessWrong. [This article was originally published on Dan Elton's blog, More is Different.] Cerebrolysin is an unregulated medical product made from enzymatically digested pig brain tissue. Hundreds of scientific papers claim that it boosts BDNF, stimulates neurogenesis, and can help treat numerous neural diseases. It is widely used by doctors around the world, especially in Russia and China. A recent video of Bryan Johnson injecting Cerebrolysin has over a million views on X and 570,000 views on YouTube. The drug, which is advertised as a "peptide combination", can be purchased easily online and appears to be growing in popularity among biohackers, rationalists, and transhumanists. The subreddit r/Cerebrolysin has 3,100 members. TL;DR Unfortunately, our investigation indicates that the benefits attributed to Cerebrolysin are biologically implausible and unlikely to be real. Here's what we found: Cerebrolysin has been used clinically since the 1950s, and has escaped regulatory oversight due to some combination of being a "natural product" and being grandfathered in. Basic information that would be required for any FDA approved drug is missing, including information on the drug's synthesis, composition, and pharmacokinetics. Ever Pharma's claim that it contains neurotrophic peptides in therapeutic quantities is likely false. HPLC and other evidence show Cerebrolysin is composed of amino acids, phosphates, and salt, along with some random protein fragments. Ever Pharma's marketing materials for Cerebrolysin contain numerous scientific errors. Many scientific papers on Cerebrolysin appear to have ties to its manufacturer, Ever Pharma, and sometimes those ties are not reported. Ever Pharma's explanation of how the putative peptides in Cerebrolyin cross the blood-brain barrier does not make sense and flies in the face of scientific research which shows that most peptides do not cross the blood-brain barrier (including neurotrophic peptides like BDNF, CDNF, and GDNF). Since neurotrophic factors are the proposed mechanism for Cerebrolysin's action, it is reasonable to doubt claims of Cerebrolysin's efficacy. Most scientific research is false. It may have a mild therapeutic effect in some contexts, but the research on this is shaky. It is likely safe to inject in small quantities, but is almost certainly a waste of money for anyone looking to improve their cognitive function. Introduction One of us (Dan) was recently exposed to Cerebrolysin at the Manifest conference in Berkeley, where a speaker spoke very highly about it and even passed around ampoules of it for the audience to inspect. Dan then searched for Cerebrolysin on X and found a video by Bryan Johnson from May 23 that shows him injecting Cerebrolysin. Johnson describes it as a "new longevity therapy" that "fosters neuronal growth and repair which may improve memory." Dan sent the video to Greg Fitzgerald, who is a 6th year neuroscience Ph.D. student at SUNY Albany. Greg is well-versed on the use of neurotrophic peptides for treating CNS disorders and was immediately skeptical and surprised he had not heard of it before. After Greg researched it, he felt a professional responsibility to write up his findings. He sent his writeup to Dan, who then extensively edited and expanded it. Our critique covers three major topics: (1) sketchy marketing practices, (2) shoddy evidence base, and (3) implausible biological claims. But first, it's interesting to understand the history of this strange substance. The long history of Cerebrolysin To our knowledge, the "secret history" of Cerebrolysin has not been illuminated anywhere to date. Cerebrolysin was invented by the Austrian psychiatrist and neurologist Gerhart Harrer (1917 - 2011), who started usin...

Link to original articleWelcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: WTH is Cerebrolysin, actually?, published by gsfitzgerald on August 6, 2024 on LessWrong. [This article was originally published on Dan Elton's blog, More is Different.] Cerebrolysin is an unregulated medical product made from enzymatically digested pig brain tissue. Hundreds of scientific papers claim that it boosts BDNF, stimulates neurogenesis, and can help treat numerous neural diseases. It is widely used by doctors around the world, especially in Russia and China. A recent video of Bryan Johnson injecting Cerebrolysin has over a million views on X and 570,000 views on YouTube. The drug, which is advertised as a "peptide combination", can be purchased easily online and appears to be growing in popularity among biohackers, rationalists, and transhumanists. The subreddit r/Cerebrolysin has 3,100 members. TL;DR Unfortunately, our investigation indicates that the benefits attributed to Cerebrolysin are biologically implausible and unlikely to be real. Here's what we found: Cerebrolysin has been used clinically since the 1950s, and has escaped regulatory oversight due to some combination of being a "natural product" and being grandfathered in. Basic information that would be required for any FDA approved drug is missing, including information on the drug's synthesis, composition, and pharmacokinetics. Ever Pharma's claim that it contains neurotrophic peptides in therapeutic quantities is likely false. HPLC and other evidence show Cerebrolysin is composed of amino acids, phosphates, and salt, along with some random protein fragments. Ever Pharma's marketing materials for Cerebrolysin contain numerous scientific errors. Many scientific papers on Cerebrolysin appear to have ties to its manufacturer, Ever Pharma, and sometimes those ties are not reported. Ever Pharma's explanation of how the putative peptides in Cerebrolyin cross the blood-brain barrier does not make sense and flies in the face of scientific research which shows that most peptides do not cross the blood-brain barrier (including neurotrophic peptides like BDNF, CDNF, and GDNF). Since neurotrophic factors are the proposed mechanism for Cerebrolysin's action, it is reasonable to doubt claims of Cerebrolysin's efficacy. Most scientific research is false. It may have a mild therapeutic effect in some contexts, but the research on this is shaky. It is likely safe to inject in small quantities, but is almost certainly a waste of money for anyone looking to improve their cognitive function. Introduction One of us (Dan) was recently exposed to Cerebrolysin at the Manifest conference in Berkeley, where a speaker spoke very highly about it and even passed around ampoules of it for the audience to inspect. Dan then searched for Cerebrolysin on X and found a video by Bryan Johnson from May 23 that shows him injecting Cerebrolysin. Johnson describes it as a "new longevity therapy" that "fosters neuronal growth and repair which may improve memory." Dan sent the video to Greg Fitzgerald, who is a 6th year neuroscience Ph.D. student at SUNY Albany. Greg is well-versed on the use of neurotrophic peptides for treating CNS disorders and was immediately skeptical and surprised he had not heard of it before. After Greg researched it, he felt a professional responsibility to write up his findings. He sent his writeup to Dan, who then extensively edited and expanded it. Our critique covers three major topics: (1) sketchy marketing practices, (2) shoddy evidence base, and (3) implausible biological claims. But first, it's interesting to understand the history of this strange substance. The long history of Cerebrolysin To our knowledge, the "secret history" of Cerebrolysin has not been illuminated anywhere to date. Cerebrolysin was invented by the Austrian psychiatrist and neurologist Gerhart Harrer (1917 - 2011), who started usin...

Using gene therapy, scientists have discovered that managing the level of the protein GDNF is key to the the correct transmission of dopamine, the feel-good neurotransmitter, in the brain. GDNF levels plummet when alcoholics abstain from drinking, leading to a dopamine shortage and feeling of discomfort, which makes alcoholics resort to drinking. Gene therapy is now thought to 'fix' GDNF levels, which could be a solution for those suffering from alcoholism.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.05.547860v1?rss=1 Authors: Yu, L.-Y., Selberg, S., Teino, I., Nam, J., Ivanova, L., Renzi, B., Seli, N., Kankuri, E., Voutilainen, M. H., Karelson, M., Saarma, M. Abstract: N6-Methyladenosine (m6A) is the most common mRNA base modification in eukaryotes. Methylation of adenosine residues to m6A contributes to the regulation of splicing, transport, stability, and translation of mRNA and two main classes of enzymes regulate it. The formation of m6A is catalysed by a methyltransferase complex containing methyltransferase-like 3 (METTL3), METTL14, and Wilms' tumour 1-associated protein (WTAP) as well as monomeric METTL16. Demethylation of m6A is catalysed by the fat mass and obesity-associated protein FTO and the RNA demethylase AlkB homolog 5 (ALKBH5). The m6A mRNA methylation dysregulation occurs in the nervous system and in Parkinson's disease (PD), but it remains poorly studied. Moreover, the role of m6A mRNA methylation in neuronal survival, neuroprotection, and neuroregeneration is unclear. We have earlier used high-throughput virtual screening of large compound libraries and identified four unique small-molecule ligands that activate m6A mRNA methylation by binding to the METTL3/14/WTAP complex and enhancing the binding of the methylation substrate SAM to nanomolar concentrations. Following this, we now discovered that two methyltransferase activators at 10 nM concentrations supported the survival and protected dopamine (DA) neurons in culture in growth factor deprivation and 6-hydroxydopamine (6-OHDA) neurotoxin models. In contrast, METTL3/14 inhibitor STM2457 triggered death of DA neurons. For clinical translation we also tested the most efficient compound C4 on induced pluripotent stem cell-derived human DA neurons and in animal model of Parkinson's disease (PD). C4 compound protected human DA neurons from 6-OHDA-induced cell death and increased neurite outgrowth and the number of processes demonstrating that it has both neuroprotective and neurorestorative properties. METTL3/14 activator C4 improved motor behaviour and protected DA neurons and their fibres faster and much more efficiently than GDNF in the rat 6-OHDA model of PD. These are the first specific activators of METTL3/14/WTAP and first demonstration that m6A regulators can protect and regenerate neurons. These data demonstrate that m6A mRNA methylation is a novel pathway regulating neuronal survival and regeneration. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.18.533004v1?rss=1 Authors: Raut, N. G., Maile, L. A., Oswalt, L. M., Mitxelena, I., Adlakha, A., Sprague, K. L., Rupert, A. R., Bokros, L., Hofmann, M. C., Patritti-Cram, J., Rizvi, T. A., Queme, L. F., Choi, K., Ratner, N., Jankowski, M. P. Abstract: Pain of unknown etiology is frequent in individuals with the tumor predisposition syndrome Neurofibromatosis 1 (NF1), even when tumors are absent. Schwann cells (SC) were recently shown to play roles in nociceptive processing, and we find that chemogenetic activation of SCs is sufficient to induce afferent and behavioral mechanical hypersensitivity in mice. In mouse models, animals show afferent and behavioral hypersensitivity when SC, but not neurons, lack Nf1. Importantly, hypersensitivity corresponds with SC-specific upregulation of mRNA encoding glial cell line derived neurotrophic factor (GDNF), independent of the presence of tumors. Neuropathic pain-like behaviors in the NF1 mice were inhibited by either chemogenetic silencing of SC calcium or by systemic delivery of GDNF targeting antibodies. Together, these findings suggest that Nf1 loss in SCs causes mechanical pain by influencing adjacent neurons and, data may identify cell-specific treatment strategies to ameliorate pain in individuals with NF1. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this episode I wanted to address the claims made by one particular gentleman with PD, John Pepper, who recently posted a video discussing the role fast walking has played in what he claims is reversing his PD as well as how the protein GDNF can be increased through fast walking. The video where he talks about this can be found here, but know that it is a bit lengthy.  Please know that research is ongoing and there is no certain evidence that fast walking will reverse PD, though it is a fact that it does have a neuroprotective effect.  Please support this podcast and our endeavors by becoming a co-producer of the show! Sign up as a Patreon supporter here at https://www.patreon.com/pdwarriors Also, you can leave a one time tip in our virtual tip jar at: https://paypal.me/hylandptw Don't forget about our YouTube channel!!

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.01.530671v1?rss=1 Authors: Kasanga, E., Han, Y., Navarrete, W., McManus, R., Shifflet, M., Parry, C., Barahona, A., Manfredsson, F., Nejtek, V., Richardson, J. R., Salvatore, M. F. Abstract: Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinsons disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment across all studies began ~8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), and is later than the timing of GDNF treatment in preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemi-parkinsonian rats to determine if expression of GDNF family receptor, GFR-alpha1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) lesion. Whereas GDNF expression changed minimally, GFR-alpha1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-alpha1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred that returned to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-alpha1 and RET expression between the striatum and SN, and cell-specific differences in GFR-alpha1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Sara Schaefer speaks to Alan Whone of the University of Bristol on his retrospective analysis of off-state dyskinesias in Parkinson's disease patients who received serial infusions of GDNF into the putamen. Read the article.

Episode 374 opens up with THE LAWN MOWER STORY that I have talked briefly about on my IG Story! We then dig into our recent competition weekends, discuss some interactions with GDNF and growth hormone, and a whole lot more!   Always support Andy at: www.theperformancevibe.com www.gosuperbrain.com    •••SPONSOR•••   (BEEF) www.skinnybeef.com___use discount code “alex10” to save off your order!   (SUPPLEMENTS) www.tigerfitness.com___use discount code “alex10” to save off your order for MTS Products!   (PEPTIDES) www.real-peptides.com___use discount code “alex10” to save off your order!   •••FIND THE EPISODES•••   ITUNES:https://itunes.apple.com/us/podcast/beastfitness-radios-podcast/id1065532968   LIBSYN:http://beastfitnessradio.libsyn.com   VIMEO: www.vimeo.com/theprepcoach        •••PREP COACH APPAREL•••   https://teespring.com/stores/the-prep-coach-apparel    

*Warning sensitive subject matter about living with Parkinson's and the medication involved will be discussed (among other subjects) PODCAST of LIVE show on Radioparkies.com 2/29/21 were the stories of Vicki Dillon and Gaynor Edwards About Vicki: Vicki was diagnosed with Young Onset Parkinson's Disease (YOPD) in February 2007, aged just 35. Vicki is passionate about speaking about living with Parkinson's and has travelled the word telling her powerful, sad, funny, disturbing, medical-history-making and ultimately heart warming story in her own unique style. Life with Parkinson's is never boring and Vicki's aim is to educate and inspire you - with some laughter, tears and brain surgery along the way. About Gaynor: After a few years experiencing symptoms she attributed to stress, Gaynor Edwards visited her general practitioner and learned that the symptoms instead were caused by something neurological. Nine months of various scans later, she received a diagnosis of Young Onset Parkinson's at the age of 42. “‘You have Parkinson's.' Those are three words no one wants to hear,” she says. Gaynor found support and resources in the UK's major Parkinson's charity, but she quickly discovered that YOPD wasn't a focus there. “I thought, ‘Well, it's needed. We need to start a charity dedicated to Young Onset. I guess I'll have to do it.' So, I did.” Gaynor founded and continues to lead Spotlight YOPD (a registered charity in the UK) *The views expressed are not necessarily the views of 2 Mikes PD Podcast, its hosts, or radioparkies

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.13.286047v1?rss=1 Authors: Adams, S., Purkiss, A. G., Knowles, P. P., Nans, A., Briggs, D. C., Borg, A., Earl, C. P., Goodman, K. M., Nawrotek, A., Borg, A. J., McIntosh, P. B., Houghton, F. M., Kjaer, S., McDonald, N. Q. Abstract: RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFR co-receptors recognise and activate RET stimulating its cytoplasmic kinase function. The principles for RET ligand-co-receptor recognition are incompletely understood. Here we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish RET revealing interdomain flexibility between CLD2-CLD3. Comparison with a cryo-EM structure of a ligand-engaged zebrafish RETECD-GDNF-GFR1 complex indicates conformational changes within a clade-specific CLD3 loop adjacent to co-receptor. Our observations indicate RET is a molecular clamp with a flexible calcium-dependent arm that adapts to different GFR co-receptors, while its rigid arm recognises a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualise linear arrays of RETECD-GDNF-GFR1 suggesting a conserved contact stabilises higher-order species. Our study reveals ligand-co-receptor recognition by RET involves both receptor plasticity and strict spacing of receptor dimers by GFL ligands. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.11.293894v1?rss=1 Authors: Zhai, J., Kim, H., Han, S. B., Manire, M., Yoo, R., Pang, S., Smith, G., Son, Y.-J. Abstract: A major barrier to intraspinal regeneration after dorsal root (DR) injury is the DR entry zone (DREZ), the CNS/PNS interface. DR axons stop regenerating at the DREZ, even if regenerative capacity is increased by a conditioning lesion. This potent blockade has long been attributed to myelin-associated inhibitors and CSPGs, but incomplete lesions and conflicting reports have hampered conclusive agreement. Here we evaluated DR regeneration in adult mice, using novel strategies to facilitate complete lesions and comprehensive analyses, selective tracing of proprio-/mechanoreceptive axons with AAV2, and genetic or viral targeting of Nogo, MAG, OMgp, CSPGs and GDNF. Simultaneously eliminating Nogo/MAG/OMgp elicited little intraspinal penetration of DR axons, even with additional removal of CSPGs and a conditioning lesion. Their absence, however, synergistically enhanced GDNF-elicited intraspinal regeneration. We conclude that myelin inhibitors and CSPGs constrain intraspinal regrowth of DR axons, but that they are not the primary mechanism(s) stopping axons at the DREZ. Copy rights belong to original authors. Visit the link for more info

What is learning and memory? Is amnesia really a loss of stored memories or something more? In this interview, we will discuss where memory goes and if there is a way to retrieve them after trauma. Recent studies have shown that spatial memories are encoded as sparse populations of cells that are activated during learning and are necessary for the retrieval of specific memories. We refer to these cells as "memory engram cells" and the focus of Tomás J Ryan and his team is to understand how engram cells are able to store specific memories as information. Here is a quick summary/breakdown of the video above. The old storage theory of amnesia is WRONG. The problem is the ability to retrieve the memory. Short term memory lasts a few hours. It is very disruptable (long term is not). Long term memory lasts your entire lifetime. It requires transcription and translation of many different genes. We have many different genes that regulate memory. They are different for short term and long term - playing roles at different stages. Most popular was CREB (turns on other genes). Engrams cells are structures in the brain where memories are stored. R They used optigenetics to prove engram cells were important for memory. Engram cells only account for 4-6% of the brain cells in the hippocampus (of mice). V Consolidation idea - a short term memory (unstable) forms into a long term memory (stable), thus stabilizing the engram. Optogenetics - let's us express photoactivatable opsins in whatever region of the brain we want. The brain is electrically active. They put certain opsins into brain cells and then stimulate them with light. These opsins can conduct ions - putting positively charged cations from the external environment of the cell into the neuron. This depolarizes the cell, which results in an action potential (creating neuronal activity). What they did at MIT was integrate optogenetics and memory engram cells. They tested parts of the brain using a transgenetics - they took immediate/early genes (genes that show activity as a function of neuronal spike) and used opsins to only activate those genes. Amnesia and Memory Learning is the enhancement of synaptic connections. Memory is a stable thing in the brain and can last for your entire life. Learning and recall are not "things", they are activities. Learning = process of making a memory. Recall = process of retrieving a memory. So the problem is not memory itself. Amnesic engram cells have a loss of synaptic strength. Increasing the synaptic strength helps get the memory (which is commonly seen in Alzheimer's (AD), Huntington's (HD)). If you increase the synaptic potentiation (increasing the dendritic spine density), esp. of the amnesic engram cells, you can get natural access to those memories. Neurotrophic factors (BDNF, NGF, CNTF, GDNF) do this, but are not localized nor memory specific. Learning something new (about something you are amnesic about) will train your brain to those particular engram cells. Once you activate the engram cells (with optogenetics), you can restore access to old information and add new information on those amnesic memories. Without dealing with the cause, you probably won't be able to really restore memories (in diseases like AD, HD, etc.) In late stages of neurodegeneration, you may actually lose memories. Actions to take for prevention Stay mentally active Engage in physical exercise Actions to take for amnesia (acute memory loss) Do everything to remind yourself of those experiences Retrain on the "forgotten" pieces We briefly discussed gene expression and histone acetylation to enhance memory. https://mybiohack.com/blog/tomas-j-ryan-debunking-amnesia-and-stabilizing-engram-cells

In this podcast, we will discuss nootropics, anti-aging, and healing/enhancement peptides. https://mybiohack.com/blog/cerebrolysin-epitalon-bpc157-ghkcu-lgd4033-ostarine-mk-677 If you can get a prescription from a doctor, then use Tailor Made Compounding for high quality peptides. If you can't then using other high quality sources are also available: Cerebrolysin - combination of BDNF, NGF, GDNF, and CNTF Epitalon - longevity BPC-157 - gut health/neurotransmitter balance GHK-cu - skin health/wound healing Ligandrol (LGD-4033) - prevents muscle wasting Ostarine (MK-2866) - muscle mass Ibutamoren (MK-677) - long acting ghrelin mimetic

In this episode of When Life Gives You Parkinson’s, despite some setbacks there is still an appetite to trial a treatment for Parkinson’s that many believe is the antidote. GDNF or Glial cell line derived neurotrophic factor are naturally occurring and are vital for normal functioning of the brain.But, when GDNF is delivered directly to the brain, for some people, it is as if they’ve never had Parkinson’s. The phase II GDNF trial at University of Bristol, seemingly, was made possible through the sheer will and force of the late Parkinson’s advocate Tom Isaacs and his Cure Parkinson’s Trust. The broadcast of Tom’s BBC Radio 4 documentary, “Chasing a Cure,” about the treatment, was heard by Vicky Dillon. She vowed if it ever came around again she’d sign up. And she did. “We were the guinea pigs basically to see if we would tolerate the surgery and the insertion of all this plumbing in our brains,” she said. “They cut me from my hair line to like the middle part of my head and then put in all four catheters that went deep into the into my brain. And then you had another bit of plumbing that run down the side of your head to a port behind you left ear, which is where the infusions were given. So, there was quite a lot of stuff in there.” Vicky was given GDNF for the better part of two years. Her symptoms improved almost immediately, “By the time I took the second infusion, I noticeably felt different. I remember waking up a couple of days afterwards and there was no Parkinson symptoms for about an hour or so. I thought, ‘oh my God!’. And gradually everything started getting better.” Vicky’s symptom improved 63% and all the participants showed cell regeneration on PET scans, but the trail did not meet its primary end point. “That’s ridiculous,” says Jayne Calder. Her husband Darren was also in the trial and it improved his symptoms more than 50%. “Without any doubt whatsoever in 100 percent of those participants minds we have got the cure for Parkinson's.”  Vicky and Jayne are leading the charge to raise awareness and money for another trial. They have been very vocal. They’ve even recorded a song called “Shine” by the G.D.N.F.ers. Each download includes a donation to another GDNF trial. They have also caught the attention of Parkinson UK. The organization’s chief executive Steve Ford is ready to throw massive amounts of money towards the project if everything on the application looks right. “We spend around eight and a half million pounds annually. That's eleven or twelve million dollars a year on research. We haven't seen the application yet, but we envisage it's going to be in the order of an annual spend on research. So, that's not significant more than we've ever spent before.” Recruiting for the next GDNF trial is expected to begin by the end of 2020 or just after the first of the year 2021. Please comment by leaving us a voice message here: https://www.speakpipe.com/WhenLifeGivesYouParkinsons Links we mentioned and source material for the show: U.S. TRIAL |Phase 1 trial of GDNF is slated for 2022 will test viral vectors for delivering GDNF in escalating doses. RADIO DOCUMENTARY | BBC Radio 4 “Chasing a Cure” with Tom Isaacs WEBSITE | ScienceofParkinsons.com FUNDRAISER | Raise a Million for GDNF by Darren & Jayne Calder FUNDRAISER | “Shine” performed by GDNFers and written by Vicky DIllon EDITORIAL | Where Are We One Year On by Steve Ford, Parkinson UK Follow me, Larry Gifford  Twitter: @ParkinsonsPod Facebook: Facebook.com/ParkinsonsPod Instagram: @parkinsonspod Follow Co-host and Producer Niki Reitmayer Twitter: @Niki_Reitmayer Thank you to my wife and partner in Parkinson’s Rebecca Gifford. Also, thank you to the following contributors and guests. Vicky Dillon Darren & Jayne Calder Steve Ford, Parkinson U.K. Helen Matthews, Cure Parkinson’s Trust BBC Radio 4 Passionate Productions for BBC Our presenting partner is Parkinson Canada http://www.parkinson.ca/ The toll free hotline 1-800-565-3000 Follow them on Twitter @ParkinsonCanada Find the new Parkinson Clinical Guideline www.parkinsonclinicalguideline.ca Our content and promotional partners Parkinson’s IQ + You– A free, series of Parkinson’s events from the Michael J. Fox Foundation Spotlight YOPD – The only Parkinson’s organization dedicated to raising awareness for Young Onset Parkinson’s disease and funds for the Cure Parkinson’s Trust.  WPC2022- Save the date for the sixth World Parkinson Congress, June 7 to 10, 2022 in Barcelona, Spain in 2022. The only inclusive scientific conference opens its doors to people with Parkinson’s and families

This 5 minute podcast summary helps prepare listeners on what they can expect at the4th Annual Patients as Partners Europe event, taking place January 27th and 28th in London. The venue is the Millennium Gloucester Hotel. In a nutshell, Patient as Partners is the first conference in Europe dedicated to understanding how working with patients can drive greater clinical trial efficiencies throughout the entire medicines development process. It is ultimately about how to reduce risk in the development of hugely, costly clinical trials through working with patients. It is a wonderful opportunity for pharma and biotech and patient disease advocacy groups to come together and learn from each other.  The 2020 Summit is chaired by Claire Nolan, of Charities Research Involvement Group, GSK’s Andrew Garvey and Parexel’s Rosamund Round.  Our patient keynote guest is Lesley Gosden. Lesley is a Parkinson’s patient and advocate who participated in the GDNF clinical trial, which was featured on the BBC. For more information, visit the conferenceforum.org.

It is estimated that between 7-10 million people, globally have Parkinson's disease.  Our guest on Pharma Talk Radio, Lesley Gosden is living with Parkinsons and she is an outstanding patient advocate, who experienced the GDNF clinical trial. In this podcast discussion, our guest will give us an insight into living with Parkinson's, about the GDNF clinical trial, lessons for all stakeholders and in particular how the success rate of clinical trials could be improved from the patient’s point of view.  Ms Gosden will be the Keynote patient advocate speaker at the Patients as Partners EU conference taking place in London on January 27th and 28th and for more information, visit theconferenceforum.org.  Guest: Lesley Gosden, Patient Advocate Host: Valerie Bowling, Producer, Pharma Talk Radio For more information about the GDNF Trial: Reflections on the GDNF Trial  

My perspective on the outcomes of the recent GDNFtrial in Parkinson’s disease.

www.success101podcast.com/live30 A few of the topics we discuss in episode “LIVE #30”: The benefits of Lithium that aid in peak performance, and why it might be a great fit for your daily biohacking routine:   1. Neuroprotective  2. Increases BDNF, NGF, GDNF in the brain  3. Increases the autophagy processes occurring in your cells 4.…

EARTH AID NOW! speaks with Christopher Laurance about ibogaine as a solution to addictions. What is iboga and Ibogaine? Ibogaine is the primary active component of the iboga plant. Iboga is plant from West Africa that is used as a visionary medicine by the Bwiti and Pygmy cultures. It is used as an initiation into adulthood and a powerful healer. In the 1960s a heroin addict named Howard Lotsoff accidentally discovered this plant's incredible properties to physically and neurochemically interrupt heroin addiction and other addictions. Since that time, a movement of former addicts treating addicts with iboga has spread worldwide. Ibogaine works like nothing else with regards to addiction, especially opiate addiction. It neurochemically resets the brain to a pre-addictive state. Addicts are able to arrest their drug addiction without, or with minimal withdrawal symptoms, and emerge from the ibogaine experience free of cravings or with cravings greatly reduced. Many people are set free from a lifetime of drug addiction with a single ibogaine treatment. How and Why Ibogaine Works Ibogaine resets the neurochemistry of the brain to a pre-addictive state. Ibogaine promotes the brain's ability to produce GDNF, which is a growth hormone that promotes neuroplasticity and neurological regeneration. This allows for a great deal of pattern changing and new growth that for many people did not seem possible before their ibogaine experience. The period of time after receiving ibogaine is something akin to a neurological second childhood, a place of freedom where old habits can be shed and new patterns can be created. 

Sun, 13 Nov 2011 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16690/ https://edoc.ub.uni-muenchen.de/16690/1/Klein_Pontus.pdf Klein, Pontus ddc:570, ddc:500, Fakultä

Pathological changes in the dopaminergic system account for a number of devastating illnesses including schizophrenia, psychosis, depression, addiction, obsessive compulsive disorder or the most well known Parkinson’s disease (PD). The nigrostriatal pathway is an important component of the dopaminergic (DA) system mediating voluntary movement and originates in the ventral midbrain from where substantia nigra pars compacta (SN) neurons send their axons to the dorsal striatum. Massive loss of SN neurons as seen in PD leads to postural imbalance, rigidity, tremor and bradykinesia, however, the precise mechanisms involved in the maintenance and the demise of SN neurons are poorly understood. Endogenous neurotrophic factors such as the Glial cell line-derived neurotrophic factor (GDNF; signaling via the Ret receptor tyrosine kinase) and Brain-derived neurotrophic factor (BDNF; signaling via the TrkB receptor tyrosine kinase) were reported to have protective and rescuing properties on DA neurons; however, their physiological roles in SN neurons remained unknown. Inactivation of the oxidative stress suppressor DJ-1 causes PD; remarkably, mice lacking DJ-1 function do not display overt SN degeneration, suggesting that additional DJ-1 interactors compensate for loss of DJ-1 function. To begin characterizing the cellular and molecular networks mediating SN neuron survival, I used mouse genetics to investigate the roles and the interaction between GDNF/BDNF-mediated trophic signaling and the DJ-1-mediated stress response in SN neurons. While mice lacking TrkB function specifically in SN neurons display a normal complement of SN neurons up to 24-months, loss of Ret function in DA neurons causes adult-onset and progressive SN degeneration, suggesting that GDNF/Ret signaling is required for long-term maintenance of SN neurons. I then generated and aged mice lacking Ret and DJ-1 and found remarkably that they display an enhanced SN degeneration relative to mice lacking Ret. Thus, DJ-1 promotes survival of Ret-deprived SN neurons. Interestingly, the survival requirement for Ret and DJ-1 is restricted to those SN neurons which express the ion channel GIRK2, project exclusively to the striatum and specifically degenerate in PD. This is the first in vivo evidence for a pro-survival role of DJ-1. To understand how DJ-1 interacts molecularly with Ret signaling, I performed epistasis analysis in Drosophila melanogaster. Although DJ-1 orthologs DJ-1A and DJ-1B are dispensable for fly development, the developmental defects induced by targeting constitutively active Ret to the retina were suppressed in a background of reduced DJ-1A/B function. Moreover, DJ-1A/B interacted genetically with Ras/ERK, but not PI3K/Akt signaling to regulate photoreceptor neuron development. Flies with reduced ERK activity and lacking DJ-1B function had more severe defects in photoreceptor neuron and wing development than flies with reduced ERK function. These observations establish, for the first time, a physiological role for DJ-1B in the intact Drosophila. Our findings suggest that the triple interaction between aging, trophic insufficiency and cellular stress may cause Parkinsonism. Because Ret and DJ-1 show convergence of their pro-survival activities, we predict that striatal delivery of GDNF might be most effective in PD patients carrying DJ-1 mutations. A better understanding of the molecular connections between trophic signaling, cellular stress and aging will accelerate the process of drug development in PD.

Das Glioblastoma multiforme ist ein maligner hirneigener Tumor mit einer bislang infausten Prognose. Humane mesenchymale Progenitorzellen des Knochenmarks (hMSC) zeigen in-vitro und in-vivo einen ausgeprägten glioblastom¬induzierten Tropismus. Sie sind einfach in der Handhabung, weil sie leicht zu gewinnen, in Kultur zu vervielfältigen und anschließend autolog zu transplantieren sind. Diese Eigenschaften machen hMSC zu vielversprechenden Kandidaten für eine zellbasierte Gentherapie des Glioblastoms. Die molekularen Mechanismen, welche zu der gerichteten Migration der hMSC hin zu den Glioblastomzellen führen und die biologischen Wechselwirkungen zwischen Stammzellen und Tumorzellen sind bisher kaum verstanden. Um erste Einblicke in diese Wechselwirkungen zu erlangen, wurden im Rahmen des vorliegenden Promotionsvorhabens in-vitro Untersuchungen zu den Grundlagen des glioblastominduzierten Tropismus von hMSC durchgeführt. Die Fragestellung befasste sich insbesondere damit, welche Chemokine an der Vermittlung der glioblastomgerichteten Migration von hMSC beteiligt sind. Hierzu wurden Migrationsversuche mit einer modifizierten Boyden Kammer durchgeführt, wobei zunächst einige bekannte glioblastomassoziierte Chemokin-kandidaten (IL-8, NT-3, TGF-ß1, EGF, CNTF, GDNF, PDGF und BDNF) getestet wurden. Eine signifikante chemotaktische Eigenschaft auf hMSC wurde hierbei für IL-8, TGF-ß1 und NT-3 beobachtet. Die promigratorische Wirkung dieser drei Chemokine erwies sich hierbei als konzentrationsabhängig. Im Weiteren wurde nachgewiesen, dass die bekannte chemotaktische Wirkung von glioblastom-konditioniertem Medium auf hMSC durch die Zugabe von IL-8, TGF-ß, beziehungs¬weise NT-3 neutralisierenden Antikörpern signifikant reduziert wird. Somit konnte funktionell nachgewiesen werden, dass diese Chemokine tatsächlich eine Rolle beim glioblastominduziertem Tropismus der hMSC spielen. Ergänzend wurde mittels Immunfluoreszenzfärbung die Expression der entsprechenden Chemokin¬rezeptoren auf den hMSC nachgewiesen und die Sekretion der Chemokine durch die Glioblastomzellen mittels ELISA quantifiziert. Aus Vorarbeiten unserer Arbeitsgruppe ist bekannt, dass auch VEGF-A eine chemotaktische Wirkung auf hMSC besitzt. Wie VEGF-A werden auch IL-8, TGF-ß1 und NT-3 von Glioblastomen überexprimiert. Zudem wird über diese Chemokine die Neoangiogenese jener Tumore vermittelt. Dies führt zu der Hypo-these, dass Glioblastome die Migration der hMSC aus dem peripheren Blut in das Tumorgebiet über angiogenetische Signalwege vermitteln. Damit könnten hMSC an dem Prozess der Angiogenese des Glioblastoms beteiligt sein. Ein genaues Verständnis des möglichen Beitrages von hMSC zum Glioblastomwachstum ist eine unabdingbare Voraussetzung für ihre mögliche klinische Anwendung als gentherapeutische Vektoren beim Menschen. Deshalb müssen zukünftig neben weiteren in-vitro vor allem in-vivo Studien mit Langzeit-beobachtungen im Tiermodell durchgeführt werden. In diesen Studien sollten die Auswirkungen einer Transplantation nativer hMSC einerseits und genetisch modifizierter therapeutischer hMSC andererseits auf das Glioblastomwachstum untersucht werden. Die vielversprechenden Ergebnisse der bisher vorliegenden Arbeiten lassen hoffen, dass in nicht allzu ferner Zukunft eine bessere Therapie für Patienten mit Glioblastom gefunden werden kann.

Thu, 13 Dec 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7838/ https://edoc.ub.uni-muenchen.de/7838/1/Knott_Laura.pdf Knott, Laura ddc:500, ddc:

Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.

A major cause of blindness in the Western world is degeneration of photoreceptors as a result of point mutations in genes coding for either phototransduction-related proteins or other proteins important for retinal function. Despite the diversity of mutated genes and proteins involved in this heterogeneous group of progressive retinal dystrophies with homologous phenotypes, the final event leading to blindness is apoptosis of photoreceptors. This has led to intensive studies of the effects of neuroprotective agents on the survival of photoreceptors in animal models of retinitis pigmentosa. One such effective molecule discovered to date to exert substantial rescue of retinal photoreceptors is glial cell line-derived neurotrophic factor (GDNF). However, the molecular mechanism of action underlying GDNF-mediated neuroprotection remains unresolved. This dissertation and the herein described studies were carried out with the goal of elucidating neuroprotective mechanisms using the porcine retina as a model. This species was selected due to its morphological and anatomical similarities to human retina. In order to clarify possible cellular mechanisms involved in neuroprotection, the initial studies involved analysis of GDNF action in porcine retina. It soon became evident that the GDNF-receptive cell in retina was not the photoreceptor itself but rather retinal Mueller glial cells (RMG), which are the major retinal glial cells. Thus, primary RMG cell cultures prepared from porcine retina were established and characterised to analyse this cell type without extraneous effects from the retinal environment. Proteomic profiling revealed profound changes in expression of RMG-specific marker proteins as an effect of in vitro conditions. Thus, the in vitro experiments for studying GDNF-induced signalling were performed with primary RMG cultures in an early state (two weeks in vitro) in order to study cells resembling the in vivo phenotype. GDNF was found to induce the ERK, SAPK and PKB/AKT pathways, as well as upregulating basic fibroblast growth factor (bFGF). Application of bFGF to primary porcine photoreceptors in vitro promoted a concentration-dependent rescue. Therefore a model of RMG-mediated indirect survival promoting mechanism induced by GDNF could be proposed. The finding that RMG are mediators of photoreceptor survival prompted further screenings for RMG-specific, secreted molecules promoting photoreceptor survival. A large-scale primary photoreceptor survival assay (96well format) was developed, in which RMG-conditioned medium (RMG-CM) was tested for survival activity. Conditioned medium was observed as having specific photoreceptor survival-promoting activity stemming from previously unidentified protein/s. Reducing the complexity of RMG-CM by anionic chromatography revealed that the activity does not bind to anionic resins. Mass spectrometric identifications of the mono-Q flow-through identified 23 different proteins from the active fraction, among them three potential new candidates for neuroprotective activity in the context of photoreceptor survival: connective tissue growth factor (CTGF), insulin-like growth factor binding protein 5 (IGFBP5) and insulin-like growth factor binding protein 7 (IGFBP7). Expression cloning and re-testing of these candidates for their ability to promote photoreceptor survival revealed that CTGF and IGFBP5 were effective in protecting photoreceptors when applied in combination with the RMG-conditioned media. Taken together, these results indicate that such survival-promoting activity is multi-factorial. RMG are likely to support photoreceptors by either cell to cell-mediated paracrine signalling or by secreting factors into the intercellular space between retina and retinal pigment epithelium, which consists of a complex matrix of proteins and polysaccharides. This matrix, designated as interphotoreceptor matrix (IPM), directly borders three cell types: photoreceptors, RMG and the retinal pigment epithelium and predisposes the IPM to function as repository of neuroprotective molecules possibly secreted from adjacent cells to protect and support photoreceptors. In order to identify such novel neuroprotective substances, the composition of IPM was investigated in this thesis by comparative proteomics. Over 140 different proteins were identified, the majority of which had never been previously detected in the IPM. Among these, 13 candidates were found, which in other tissue systems have been already reported to have a functional role in neuroprotection.

GDNF (glial cell line-derived neurotrophic factor) und NTN (Neurturin), die zwei zuerst beschriebenen Liganden der GDNF-Familie, fungieren als Überlebens- und Entwicklungsfaktoren für definierte Populationen von zentralen und peripheren Neuronen. GDNF ist darüber hinaus für die Nierenentwicklung erforderlich. Für die Vermittlung ihrer biologischen Wirkung benutzten GDNF und NTN einen Rezeptor, der aus zwei Ketten besteht: Die Signal-transduzierende Komponente RET wird sowohl von GDNF als auch von NTN benutzt. RET wird von 21 Exonen kodiert und kommt in multiplen Spleiß-Varianten vor. Für die Liganden-Spezifität ist eine zweite Rezeptorkomponente verantwortlich, ein Mitglied der GFR-Familie. GFRa-1 bindet präferentiell GDNF, während GFRa-2 NTN stärker als GDNF bindet. Ziel dieser Arbeit war es, mögliche wechselseitige Interaktionen zwischen dem Nerven- und Immunsystem durch die GDNF-Familie zu untersuchen. Zu diesem Zweck wurde zunächst die Expression von GDNF, NTN und ihrer Rezeptoren in gereinigten Immunzell-Subtypen untersucht. Dabei zeigte sich, dass der Prototyp dieser Liganden-Familie, GDNF, von keiner der untersuchten Immunzellen exprimiert wurde. Hingegen wurde das verwandte NTN von T-Zellen, B-Zellen und Monozyten exprimiert wie mit RT-PCR, Western Blot und Immunzytochemie gesehen wurde. Transkripte für das zu NTN und GDNF verwandte Persephin (PSP) wurden in Monozyten und mononukleären Zellen des peripheren Blutes gefunden. Der Transmembran-Rezeptor RET wurde von allen untersuchten Immunzell-Subtypen exprimiert. B-Zellen und T-Zellen exprimierten unterschiedliche Isoformen von RET, sowohl im extrazellulären Liganden-bindenden als auch im intrazellulären Signal-transduzierenden Teil. Die Expression der Isoformen von RET wurde zudem in T-Zellen und B-Zellen noch stark durch Aktivierung reguliert. In CD8+ T-Zellen wurde auch eine bislang noch nicht beschriebene Spleiß-Variante am 5` Ende beobachtet. Im Gegensatz zu T-Zellen und B-Zellen exprimierten Monozyten nur die volle Länge von RET. Auch die Liganden-bindenden Ketten GFRa-1 und GFRa-2 wurden von Immunzellen exprimiert wie mit RT-PCR und FACS gesehen wurde. GFRa-2 war deutlich abundanter als GFRa-1. Von GFRa-2 wurden verschiedene Isoformen in Immunzellen gefunden. In der in T-Zellen und B-Zellen am stärksten exprimierten Isoform ist Exon 2 und 3 nicht enthalten. Dem resultierenden Protein fehlen die N-terminale Cystein-reiche Domäne und eine N-Glykosylierungsstelle, eine Region, die allerdings für die Bindung von NTN und die Interaktion mit RET entbehrlich ist. Mögliche Effekte von GDNF und NTN auf Immunzellen wurden untersucht. Dabei zeigte sich, dass GDNF und NTN an der Regulation von TNF-alpha beteiligt sind. Wenn GDNF oder NTN nach 5 oder 6 Tagen zu LPS+IFN-g stimulierten Blutzellen oder zu ConA aktivierten T-Zellen gegeben wurde, dann war nach weiteren 24 h der TNF-a-Gehalt im Überstand reduziert. Weitere Experimente wiesen daraufhin, dass diese Reduktion des TNF-a-Gehalts auf eine verstärkte Aufnahme oder Verbrauch zurückzuführen ist. Proliferation, Expression von Aktivierungsmarkern (HLA-DR, CD38, CD40, CD69, CD86) oder Produktion von IFN-g und IL-4 wurden durch GDNF und NTN nicht beeinflusst. Zusammenfassend zeigt diese Arbeit, dass Immunzellen den neurotrophen Faktor NTN produzieren und Rezeptoren für GDNF und NTN besitzen. Multiple Isoformen der Signal-transduzierenden Kette RET wurden exprimiert und durch Aktivierung reguliert. NTN und GDNF regulierten in aktivierten T-Zellen und Monozyten die Aufnahme oder den Verbrauch von TNF-a. Diese Befunde weisen daraufhin, dass Immunzellen miteinander und auch mit dem Nervensystem mit Hilfe der GDNF-Familie interagieren können.