What Is Glial Cell-Derived Neurotrophic Factor (GDNF)?
When it comes to brains, neurons get all the love. But what if there were other brain cell types that are more common than neurons? It turns out that there are: glial cells!
“Glial” is Latin for “glue,” coming from the idea that these cells mainly hold the neurons together. It turns out that they matter…a lot. What’s more, there is a special molecule from these cells that help nourish neurons and increase sperm production, and these cells may even treat Parkinson’s disease: Glial Cell line-Derived Neurotrophic Factor (GDNF).
GDNF is a “neurotrophic factor,” which means it affects when, where, and how much brain cells grow.
GDNF is primarily produced by glial cells, the “support cells” of the brain. It is also produced by some neurons.
As a neurotrophic factor, GDNF has three main functions. It is:
- protective, meaning that it prevents brain cells from dying.
- “trophic,” meaning that it promotes the growth of new and existing brain cells.
- restorative, meaning that it changes how neurons “talk” to each other in order to enhance certain brain functions.
Together, these three functions mean that GDNF plays many important roles in well-being and disease.
While the neurotrophic factors BDNF, NGF, and GDNF all play similar overall roles in the brain, they each affect different types of neurons. This allows them to influence brain cell growth in unique ways .
For example, both BDNF and GDNF affect protein production in the brain’s serotonin system, but BDNF is more common in the cortex and hippocampus while GDNF mainly affects the striatum .
However, unlike BDNF, GDNF cannot cross the blood-brain barrier. This means it cannot be taken directly and must be increased indirectly through other means. This also means that GDNF must be made within the brain .
It works by activating:
GDNF: The Good
1) May Decrease Brain Inflammation
Brain inflammation is linked to neurodegenerative disease progression .
GDNF strongly inhibits the inflammatory glial cells known as “microglia,” thereby decreasing inflammation, and perhaps slowing neurodegeneration .
2) Is Important for Learning and Memory
3) Increases Antioxidant Activity
Some dopamine neuron damage in Parkinson’s disease stems from unstable molecules (“free radicals”) which damage mitochondria (the “powerhouse” of the cell) .
GDNF increases several enzymes that help prevent oxidative stress, including:
4) Protects and Repairs Neurons
Spinal cord nerve regrowth is enhanced by GDNF. In a rodent model, GDNF increased nerve survival following spinal cord injury by increasing myelination and promoting the growth of new neural connections .
Myelination is critical for proper neural function. It can increase intelligence and is one of the primary physical processes that enable learning .
5) Stimulates the Growth of Neurons
As a “neurotrophic” compound, one of the main roles of GDNF is to boost the growth of neurons, a process known as neurogenesis.
Adding GDNF to rat retinal precursor cells increased their survival rate and improved mitochondrial function. This suggests GDNF has a protective effect on the visual system during development .
In a cell study, neurturin (a neurotrophic protein in the same family as GDNF) improved the survival and recovery of cells in the retina of the eye after injury .
6) May Combat Neurodegenerative Diseases
GDNF May Help Parkinson’s Disease
Parkinson’s disease is primarily caused by the death of dopamine neurons in brain regions that control movement. GDNF can help slow this loss and perhaps even reverse it by protecting and regenerating these neurons [25, 22].
However, the ability of GDNF to improve symptoms of Parkinson’s disease in rodents depends on the disease model used. For example, GDNF is not able to help in models where alpha–synuclein is overproduced .
In Parkinson’s disease, alpha-synuclein decreases the GDNF receptor RET, disrupting GDNF activity in dopamine-responsive neurons .
These considerations leave the potential of increasing GDNF for treating Parkinson’s disease uncertain, though much research is currently underway.
GDNF May Combat Alzheimer’s Disease
Neurotrophic factors are lower in patients with Alzheimer’s disease. In a study of 134 older adults, GDNF levels decreased in Alzheimer’s patients, especially those with cognitive impairments. This decrease in neurotrophic factors might play a role in Alzheimer’s development .
Injecting GDNF into the brain of rabbits protected them against Alzheimer’s–like symptoms caused by aluminum exposure .
GDNF May Help Slow Other Neurodegenerative Diseases
Because GDNF protects and restores nerve cells, it has been connected to nearly all common neurodegenerative diseases. Therefore, increasing GDNF levels may be a general way to treat many more of these disorders.
For example, GDNF induces growth and protects against damage in noradrenergic neurons (locus coeruleus). These neurons are targeted in Huntington’s disease and amyotrophic lateral sclerosis, implicating GDNF as a potential therapeutic target for these diseases .
7) Improves Mitochondrial Health
Following neuron damage in rodents, GDNF increased HSPD1, which helps correctly fold proteins of the mitochondria. GDNF also allowed mitochondria to continue generating energy by reducing leakage of lactate dehydrogenase, an enzyme needed for mitochondrial function .
8) Is Important for Male Reproductive Health
GDNF may improve testicular function. In mice, GDNF is necessary for the continued creation of sperm-producing stem cells .
It appears this extends to humans as well: men with certain types of infertility produce less GDNF from testicular cells than their fertile counterparts .
GDNF helps immature cells mature into functional sperm-producing cells. It also helps these now-mature cells multiply, and likely increases sperm production .
9) May Combat Age-Related Neuron Damage/Loss
10) Reduces Damage from Strokes
Yet again highlighting its protective role in the nervous system, GDNF levels are increased following stroke .
According to studies in rodents, this reaction decreases the frequency of cell death (from apoptosis) .
11) May Prevent Seizures
12) May Help Mood Disorders
Furthermore, even a single dose of SSRI medication (the most common drug prescribed for depression) raises GDNF levels. This suggests that GDNF may be part of the mechanism that improves depression symptoms in SSRI therapy .
GDNF levels appear to change during different stages of bipolar disorder, which suggests that stabilizing GDNF levels might also be a useful way to treat bipolar patients .
13) May Help Type 1 Diabetes
GDNF promotes beta-cell survival in the pancreas and correlates with improved blood sugar control in mice. Both are critical for type 1 diabetics .
14) Helps Battle Addiction
GDNF reduced motivation to drink alcohol in rats (via the MAPK signaling pathway) by acting on the ventral tegmental area, a major player in the reward system of the brain .
GDNF: The Bad
1) GDNF May Promote Cancer Growth and Spread
GDNF may increase the growth and spread (metastasis) of cancerous cells in the colon. It appears to do this by helping tumors recruit new blood vessels .
Similarly, higher GDNF levels are associated more strongly with metastasized pancreatic tumors than with benign tumors. This suggests that GDNF in the pancreas may worsen the prognosis for cancer patients .
2) GDNF May Be Neurotoxic to Some Neurons
Though most studies have shown a positive effect of GDNF on neuron health, neurons vary across brain regions in how they respond to this factor. In rhesus monkeys, increased GDNF levels have been found to cause the death of neurons in the cerebellum, an important part of the brain helps coordinate voluntary movement .
Why these cells died is unclear, but the current view is that GDNF may leak into the fluid encasing the brain, resulting in cell death instead of cell protection in this brain region .
Limitations and Caveats
Because GDNF is involved in so many processes, teasing apart cause, mere correlation, and compensatory responses is challenging.
Many of the studies referenced used animal models. These serve as useful analogies to human systems, but sometimes do not directly translate to us.
How to Increase GDNF
Intranasal delivery systems for increasing GDNF levels have been tested on rats, although these are probably a long way off from being available to human users .
Nonetheless, while GDNF cannot be directly ingested, there are many lifestyle changes, supplements, and drugs that can help boost GDNF levels.
Most people likely stand to benefit from more GDNF, but those with cancer may be ill-advised to increase it.
Behavior and Lifestyle Changes to Increase GDNF
- Calorie restriction – Significantly increases GDNF (along with other neurotrophic factors such as BDNF and neurotrophin-3) in the brain and gut nervous systems [56, 57].
- Ketogenic diet – Similar effects to those seen with calorie restriction have been observed with the ketogenic diet .
- Exercise – Exercise increases GDNF in the spinal cords of both young and old rats .
- Stress reduction – Stress negatively impacts GDNF levels, and learning how to avoid common causes of stress can be a great way to boost GDNF, along with many other health benefits .
- Getting out in the sun – Sunlight stimulates the production of Vitamin D, which can greatly increase GDNF levels .
- Avoiding canned food – Especially while pregnant (unless BPA free). BPA decreases GDNF .
Food and Supplements to Increase GDNF
- Ashwagandha (Withaferin A) – Following spinal cord injury in mice, it significantly increased GDNF while decreasing multiple inflammatory markers and reducing cell death .
- Epigallocatechin-3-gallate (Green Tea) – Following spinal cord injury, rats injected with EGCG had greater GDNF and BDNF levels .
- Ginkgo biloba – Bilobalide, a major ingredient of the Ginkgo plant, increased GDNF and VEGF levels in rat glial cells .
- Panax ginseng – significantly increased GDNF levels as well as sperm count (spermatogenesis) in rats .
- Vitamin D3 – Taking vitamin D3 daily for seven days prior to and for 4 weeks following brain damage in rodents increased GDNF levels .
- Royal jelly – Oral dosage given to mice increases GDNF production in the hippocampus .
- Vitamin A – Increased GDNF activity by increasing its receptor number (GFRA1) in developing cells of the rat nervous system .
- Flavonoids (calycosin, isorhamnetin, luteolin, and genistein) – Induced GDNF, BDNF, and NGF in rat glial cells .
- Cistanche – This plant increased GDNF production in a rodent model of Parkinson’s disease .
- Harpagoside (Devil’s Claw) – Increased GDNF in mice .
- Docosahexaenoic acid (DHA) – Increased GDNF in adult rats (hippocampus) .
- Butyrate – Increased the production of GDNF in rodents infected with pneumococcal meningitis .
- Calcitriol – Increased GDNF production and prevented the death of rodent dopamine neurons .
- Catalpol – It increased levels of GDNF, dopamine transporter, and dopamine precursor enzyme (tyrosine hydroxylase) in a rodent model of Parkinson’s disease .
- Naringin/grapefruit – Shown to increase GDNF in a rodent model of Parkinson’s disease .
- Puerarin – Significantly increased GDNF levels in dopamine neurons (striatum) of rats with Parkinson’s disease .
- Pulichalconoid B – A compound isolated from the desert plant Pulicaria incisa, pulichalcanoid B quadrupled GDNF levels in rat glial cells (both astrocytes and microglia) .
Therapies That Increase GDNF
- Transcranial magnetic stimulation (TMS) – In a rodent model of Parkinson’s disease, GDNF and BDNF were increased following repeated “transcranial magnetic stimulation,” a new therapy where neurons are activated using magnets from outside the head. However, no such results have been shown in healthy animals nor human studies .
- Photobiomodulation – Refers to the application of red/infrared light directly to the brain through fiber optic cables. This treatment was previously shown to improve Parkinson’s disease symptoms and was tested on monkeys and rats. The monkeys receiving photobiomodulation (but not the rats) showed a significantly increased number of dopamine-responsive (tyrosine hydroxylase-positive) neurons, accompanied by increased GDNF production .
- Radiation therapy – Shown to increase GDNF gene expression, although is likely a response to cell damage. This should not be thought of as a way to increase GDNF for health benefit .
- Electroconvulsive therapy – Blood levels of GDNF were increased by 58% in depression patients that did not respond to drug treatment but did respond to electroconvulsive therapy .
Antidepressant Drugs That Increase GDNF
- Clomipramine (Anafranil) – This antidepressant increased GDNF release in rat glial cells when given alongside amitriptyline An antidepressant, it increased GDNF release in rat glial cells .
- Fluoxetine (Prozac) – One of the most common antidepressants, fluoxetine increased GDNF release similarly to Clomipramine .
- Paroxetine (Paxil) – Another very common antidepressant, paroxetine also increased GDNF release similarly to clomipramine .
- Amitriptyline (Elavil) – This tricyclic antidepressant increased the production and release of GDNF in several studies of rat cells (both glial cells and astrocytes) [82, 81].
- Selegiline (Emsam) – Elevated GDNF, NGF, and BDNF levels in mouse glial cells .
- Mianserin (Tolvon) – An antidepressant, mianserin increased GDNF release, similarly to clomipramine .
- NSI-189 – A new experimental drug for treating depression and promoting brain cell growth small molecule drug candidate, NSI-189 increased GDNF and BDNF levels in rats following stroke [84, 85].
Other Drugs That Increase GDNF
- Nicotine – Increased GDNF in glial cells (but not neurons) of rodents .
- Apomorphine – This drug used to treat Parkinson’s disease increased GDNF in mouse glial cells 1.8 times. The effect was much greater on NGF, however, which increased 122 times .
- Cabergoline – An amplifier of dopamine activity, cabergoline increased GDNF levels in rat glial cells .
- Ibogaine / Noribogaine – An anti-addiction drug that increases GDNF levels in human neural cells [51, 89].
- Ladostigil – A treatment for Alzheimer’s Disease that increases GDNF production in rat neurons .
- Leu-Ile – A dipeptide of amino acids isoleucine and leucine, Ile-Leu increased GDNF production levels in rat hippocampal neurons .
- M30 – A neuroprotective molecule that removes excess iron from the brain, M30 increased GDNF levels in some areas of the mouse nervous system (hippocampus, spinal cord) but not in others (striatum, cortex) .
- Riluzole – A brain-protecting drug used to treat amyotrophic lateral sclerosis, riluzole increased the production of GDNF, BDNF, and NGF in mouse glial cells .
- Telmisartan – Increased GDNF and BDNF levels in a mouse model of Parkinson’s disease .
- Valproic acid – A histone deacetylase inhibitor, valproic acid injected directly into the brain (substantia nigra) increased GDNF and BDNF production .
Hormones That Increase GDNF
- Estrogen – Increases GDNF levels in brain cells of developing mice; however, whether this effect extends to humans and if it persists beyond development is unclear .
- Incretin hormones GIP and GLP-1 – In mouse glial cells (microglia), GIP and GLP-1 increased levels of GDNF, NGF, and BDNF .
- Progesterone – A 48-hour treatment of progesterone elevated GDNF levels in rat glia for at least 72 hours post-treatment .
- Testosterone – Increased GDNF levels in rat testes cells necessary for sperm production .
Neurotransmitters/Cytokines/Pathways That Increase GDNF
- Serotonin – Increases GDNF levels in rat glioma cells in a time and dose-dependent manner; interestingly, excess serotonin had the opposite effect and decreased GDNF production [100, 101, 102].
- TNF-alpha – Activated GDNF in rat bone marrow stem cells .
- TLR2 signaling – TLR2 is necessary for sufficient GDNF levels in the gut nervous system during development in mice .
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