GDNF is a protein that helps nourish neurons. It is important for learning and memory, may help with brain injuries and mood disorders, and may even increase sperm production. Read on to learn many roles of GDNF in health and disease and various factors that boost its production.
When it comes to the brain, 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. There is a special molecule from these cells that helps nourish neurons: Glial Cell line-Derived Neurotrophic Factor (GDNF) .
GDNF is a “neurotrophic factor,” which means it affects when, where, and how much the nerves grow. Like its neurotrophic factor cousins, NGF and BDNF, it also affects many systems outside the brain. GDNF is primarily produced by glial cells, the “support cells” of the brain. It is also produced by some neurons .
- 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 .
These then activate the RET receptor, which sends signals into the cell to influence how the cell behaves.
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 .
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 .
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 its 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 .
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 [27, 24].
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.
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 .
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 .
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 .
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 .
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 .
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 .
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 .
Because GDNF is involved in complex processes, teasing apart cause, mere correlation, and compensatory responses is challenging.
Additionally, many of the studies used animal models. These serve as useful analogies to human systems, but sometimes do not directly translate to us.
GDNF levels are a marker of brain health. Low or high levels don’t necessarily indicate a problem if there are no symptoms or if your doctor tells you not to worry about it. Improving your GDNF levels won’t necessarily improve brain health.
The following is a list of complementary approaches to support the brain that may also increase GDNF levels. Despite the promising preliminary research, additional large-scale studies are needed. Remember to talk to your doctor before making any major changes to your day-to-day routine.
- Calorie restriction – Significantly increases GDNF (along with other neurotrophic factors such as BDNF and neurotrophin-3) in the brain and gut nervous systems [52, 53].
- Exercise – Exercise increases GDNF in the spinal cords of both young and old rats .
- Stress reduction – Stress negatively impacts GDNF levels, and avoiding it can be a great way to boost GDNF, along with many other health benefits .
- Sunlight exposure: stimulates the production of Vitamin D, which can greatly increase GDNF levels .
- Avoiding canned food – Especially while pregnant (unless BPA free). BPA decreases GDNF .
- Ketogenic diet – Similar effects to those seen with calorie restriction have been observed with the ketogenic diet .
- Ashwagandha (Withaferin A) – Following spinal cord injury in mice, it significantly increased GDNF while decreasing multiple inflammatory markers and reducing cell death .
- EGCG (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 .
- 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 .
- Naringin/grapefruit – Shown to increase GDNF in a rodent model of Parkinson’s disease .
- 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 .
- Transcranial magnetic stimulation (TMS) (rodent model) .
- Photobiomodulation (monkeys) .
- 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) [75, 74].
- 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 (rats) [77, 78].
- 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 [48, 82].
- 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 .
- 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 .
- 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 [93, 94, 95].
- 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 .