GDNF: What It Is and 67+ Natural Ways To Increase Glial Cell Line-Derived Neurotrophic Factor

Glial Cell Line-Derived Neurotrophic Factor

Glial Derived Neurotrophic Factor (GDNF) is an essential growth factor for the kidneys, spinal cord, exerting a wide range of effects on addiction, Alzheimer’s, Parkinson’s, neuropathy, gut inflammation, and more. R




  1. Basics
  2. Benefits
  3. How To Increase GDNF
  4. Caveats
  5. Mechanism of Action
  6. Genetics
  7. More Research


GDNF was discovered in 1991 by researchers at Syngeren in Boulder, Colorado. R

GDNF is a neurotrophic protein (like BDNF, NGFCNTFCDNF, and MANF). R

It promotes the survival of many types of neurons. R

It promotes learning and memory. R

GDNF also regulates kidney development and spermatogenesis, and it affects alcohol consumption. R


1. Improves Parkinson’s Disease



GDNF regulates dopamine in the brain. R

GDNF and dopamine are known to be down-regulated in Parkinson’s disease (PD) patients. R R

GDNF has regenerative properties for brain cells and shows may be potential treatment for PD. R

Monkeys with PD showed less trembling with taking GDNF. R

In humans, neuronal fibers grew in part of the brain that were exposed to GDNF. R

Animal models of PD have shown that several neurotrophic factors, including GDNF and other compounds, reduce apoptosis and increase resistance of dopamine neurons to neurotoxins in vitro. R

GDNF’s effects for healing PD are more effective when combined with CDNF or MANF. R R

2. Helps Alcoholism



GDNF reduces the motivation to consume and seek alcohol (via activation of the MAPK pathway). R

It does this by inhibiting the need to binge drinking. R

3. Plays A Role in Kidney Development

GDNF helps the kidneys develop by promoting the branching of the ureteric bud. R

Kidneys that developed without the GDNFr gene, displayed significant branching abnormalities. R

4. Helps Peripheral Nervous System Functions

GDNF regulates neurite branching, synaptic plasticity, and phenotypes of several neuronal populations. R

It promoted differentiation of:

  • Kidney R
  • Lung R
  • Pancreas R
  • Germ cells R
  • Myocytes
  • Thymocytes R

5. May Help Treat Addiction



Reduced levels of endogenous GDNF created changes in (dorsal striatal and accumbal) dopaminergic transmission. R

Endogenous GDNF may regulate dopamine in treating addiction. R

For example, repeated morphine administration increases GDNF expression (by stimulating VTA dopaminergic neurons). R

Another example, GDNF helped rats crave less cocaine. R R

Essentially, rats that expressed less GDNF or had lower levels craved more stimulants and opioids. R R

6. Plays a Role in ALS and Alzheimer’s Disease

GDNF has been shown to be dysregulated in in Alzheimer’s patients’ brains. R

In Alzheimer’s patients, GDNF was higher in CSF and plasma, but decreased serum concentration. R R

Also, GDNF administration can protect against Alzheimer’s from aluminum. R

7. Supports Neuronal Health



NGF, GDNF, and GFLs are crucial for the development and maintenance of distinct sets of central and peripheral neurons. R

Exogenous GDNF supports survival of:

  • noradrenergic neurons R
  • spinal motor neurons R R
  • peripheral sensory and autonomic neurons R 
  • forebrain cholinergic and GABAergic neurons R 

8. Protects the Brain

GDNF protected the brain from stroke (by blocking the increase of NO during stroke). R

GDNF injected two days before a full artery blockage prevented the loss of hippocampal neurons. R

GDNF also helps with seizures and epilepsy by acting as a anticonvulsant. R

9. Helps Neuropathy

Neuropathic pain arises as a debilitating consequence of nerve injury. R

GDNF both prevented and reversed sensory abnormalities that developed in neuropathic pain. R

GDNF may be a therapeutic treatment for neuropathic pain. R

10. Plays A Role in the Pancreas

Exogenous GDNF supports the survival of pancreatic  β-cells. R

Over expression of GDNF may be a sign for pancreatic cancer. GDNf may also be important for pancreatic cancer development. R

It does this by upregulating the expression and enzymatic activity of MMP-9. R

So it’s probably better to not try to increase GDNF if you have pancreatic cancer. 

11. May Be Useful After LCSD

Left cardiac sympathetic denervation (LCSD) is an important therapeutic option for patints with (LQTS) long QT syndrome and (CPVT) catecholaminergic polymorphic ventricular tachycardia. R

In rats, GDNF was produced for nerve regeneration. This may be helpful for patients recovery after LCSD. R

12. Important for the Gut

Chronic inflammatory bowel disease (IBD) is most commonly categorized into Crohn’s disease (CD) and ulcerative colitis (UC) and afflicts primarily the distal small and large intestine. R

In patients with CD, GDNF was increased. Reducing GDNF in the gut may help patients with CD. R

GDNF enhances the migration of colon cancer cells (by increasing VEGF-VEGFR interaction). R

In early stage gastric cancer, GDNF (along with MINT25) were molecular markers for the disease. R

13. May Improve Auditory Perception



GDNF along with chronic electrical stimulation in cochlear implant recipients may improve their auditory perception. R

14. May Help the Testes

Sertoli cells are in the testicles responsible for producing sperm and testes formation. R R R 

GDNF stimulates the proliferation of immature Sertoli cells (by activation of ERK1/2 signaling pathway). R

15. May Help with Mood Disorders

Lower GDNF levels might be involved in the pathophysiology of mood disorders. R R

GDNF may be lower in patients with major depression and bipolar disorder. R



How To Increase GDNF




  • Calorie Restriction (Ketogenic Diet) R
  • Exercise (like HIST) R R
  • Green Tea R
  • Intermittent Fasting R
  • Plantains R
  • Stress Reduction (GDNF is suppressed by stress) R




  • Apomorphine (see below about downregulation) R
  • Amitriptyline R
  • BT13 R
  • Cabergoline R
  • Clomipramine R
  • Fluoxetine R
  • GDNF Peptide (can be taken intranasally) R R
  • Ibogaine/Noribogaine R R
  • Ladostigil R
  • Leu-Ile R
  • M30 R
  • Mazidol R
  • Mianserin R
  • Nicotine R
  • NSI-189 R
  • Paroxetine R
  • PRE-084 R
  • Pulichalconoid B R
  • Ragasaline R
  • Riluzole R
  • Selegiline (as well as desmethylselegiline) R
  • Telmisartan R
  • Valproic Acid R


  • Electroconvulsive Therapy R
  • Electro Acupuncture R
  • Photobiomodulation R
  • Radiation Therapy R
  • Semen R
  • Transcranial Magnetic Stimulation (as well as chronically/repeated TMS) R

Decrease GDNF

  • Amphetamines (including methamphetamines) R
  • Arsenic R
  • BPA R
  • Caffeic Acid R
  • Chronic morphine or cocaine exposure (increases GDNF then decreases) R
  • Dopamine (as a negative feedback loop) R
  • Dysbiosis R
  • Indole-3-carbinol R
  • Melatonin (conflicting if decreases GDNF, but does increase NGF and BDNFR R
  • Lithium R
  • Spaceflight R
  • Stress R
  • Yohimbine R
  • Zinc R


GDNF is upregulated in children with ADHD. R

Mechanism of Action

GDNF, together with three related molecules, neurturin, artemin, and persephin, constitutes the GDNF family ligands. R

The neurotrophic effect of GDNF, except in motoneurons, requires the presence of TGF- β, which activates the transport of GFRα1 to the cell membrane. R R

It recruits either RET or NCAM for intracellular signaling. R


  • GDNF administration helps detox ROS: superoxide dismutase, catalase and glutathione peroxidase. R 
  • In PD, α-syn downregulates transcription factor Nurr1 and consequently GDNF signaling receptor RET, disrupting GDNF signalling in DA neurons. R
  • GDNF is required for the development of the enteric nervous system and together with NRTN they are critical regulators of the development of parasympathetic neurons. R
  • GDNF is not able to rescue DA neurons in α-synuclein overexpression models of PD. R
  • In the eyes, administration of neurturin or GDNF with BDNF had additive effects on the survival of axotomized retinal ganglion cells. R
  • In sperm cells, JAG1 regulates GDNF expression. R
  • Increases dopamine (increases TH levels and sprouting of TH-reactive fibers, as well as increase in dopamine turnover and stimulus-induced dopamine release). R R
  • Increases tyrosine hydroxylase (TH) neurons R
  • Suppresses LDH leakage R
  • Upregulates B cell lymphoma 2 (BCL2) R
  • Upregulates heat shock 60 kDa protein 1 (HSP60) levels R




This gene encodes a secreted ligand of the TGF-beta superfamily of proteins. R

Mutations in this gene may be associated with Hirschsprung’s disease. R 


  • rs3096140 – C allele May be involved in the genetic background of smoking, independent of anxiety characteristics R
  • rs36119840 – Mutations may be associated with Tourette syndrome. R
  • rs3812047 – A allele showed a significantly higher anxiety and depression mean score then subjects with G allele R

    More Research

    • High doses of GDNF inhibited REM sleep in rabbits. R
    • Human T cells, B cells, and monocytes produce NTN but not GDNF. R
    • GDNF and Forskolin targeted different subpopulations of TH/TFF1 neurons. R
    • Administration of GDNF improved saliva production. R
    • GDNF-RET signaling promoted the survival of aromatase inhibitor-resistant cells and elicited resistance in aromatase inhibitor-sensitive cells, during treatment of breast cancer. R