GDNF Protein: Health Effects + Factors That Increase It

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.

What Is Glial Cell-Derived Neurotrophic Factor (GDNF)?

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) [1].

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 [2].

It is involved in many important brain functions, especially in brain regions where dopamine is the main neurotransmitter [3, 4].

GDNF Functions

As a neurotrophic factor, GDNF has three main functions [1, 2, 4]:

1. protective, meaning that it prevents brain cells from dying.
2. “trophic,” meaning that it promotes the growth of new and existing brain cells.
3. 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 [4].

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 [4].

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, within the brain [5].

It works by activating [6, 7]:

• GDNF receptor alpha-1 (GFRA1)
• GDNF receptor alpha-2 (GFRA2)

These then activate the RET receptor, which sends signals into the cell to influence how the cell behaves.

Although there is a lot we know about GDNF, many of its properties are still unknown [8, 9].

The Roles of GDNF in Health

1) May Decrease Brain Inflammation

Brain inflammation is linked to neurodegenerative disease progression [10].

GDNF strongly inhibits the inflammatory glial cells known as “microglia,” thereby decreasing inflammation, and perhaps slowing neurodegeneration [11].

2) Important for Learning and Memory

Connections between brain cells determine how the nervous system processes information. GDNF is essential to creating new links across different brain areas, making it essential for learning [12, 9].

GDNF also helps make new connections after brain cells are damaged, and replaces lost connections when brain cells die [13, 9].

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) [14].

GDNF increases several enzymes that help prevent oxidative stress, including [15]:

• glutathione peroxidase (GPx)
• superoxide dismutase (SOD)
• catalase

4) Protects and Repairs Neurons

Throughout the body, GDNF aids in nerve cell repair and survival [16, 17].

These healing effects have been demonstrated in adult and young rats, suggesting that GDNF plays critical roles in mammals both during development and adulthood [18, 17, 19].

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 [20].

Myelination is critical for proper neural function. It can increase intelligence and is one of the primary physical processes that enable learning [21].

Finally, GDNF protects neurons against cell death after injury. In rats, GDNF increased BCL2, an important protein that prevents cell death [22].

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.

In rodent studies, GDNF increased the length and number of serotonin neuron “axons,” the branching arms of neurons that transmit signals to other neurons [23].

In cell studies, it increases the number of dopamine neurons by increasing the rate at which dopamine is built up from the precursor tyrosine [24].

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 [25].

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 [26].

6) May Combat Neurodegenerative Diseases

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 [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 [28].

In Parkinson’s disease, alpha-synuclein decreases the GDNF receptor RET, disrupting GDNF activity in dopamine-responsive neurons [29].

These considerations leave the potential of increasing GDNF for treating Parkinson’s disease uncertain, though much research is currently underway.

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 [30].

Injecting GDNF into the brain of rabbits protected them against Alzheimer’s-like symptoms caused by aluminum exposure [31].

Age-Related Neuron Damage

GDNF improves age-related spatial learning deficits in rats and improves motor function in aged monkeys [32, 33].

It also appears to protect brain cells from oxidative stress, one of the most common causes of age-related cellular damage [15, 34].

Other

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 [35].

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 [22].

8) Important for Male Reproductive Health

GDNF may improve testicular function. In mice, GDNF is necessary for the continued creation of sperm-producing stem cells [36].

It appears this extends to humans as well: men with certain types of infertility produce less GDNF from testicular cells than their fertile counterparts [37].

GDNF helps immature cells mature into functional sperm-producing cells. It also helps these now-mature cells multiply, and likely increases sperm production [38].

9) May Help Mental Disorders

Patients with major depression have lower GDNF levels [39].

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 [40].

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 [41].

Addiction

GDNF reduced the 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 [42].

Boosting GDNF levels in rats also reduced adaptation to chronic cocaine and opiate abuse, and weakened the rewarding effects of cocaine and methamphetamine [43, 44].

Similar to the effect seen with alcohol, increasing GDNF levels in rats’ brains (striatum) decreased cocaine consumption [45, 46].

Furthermore, increased GDNF appears to be the underlying mechanism of how the drug ibogaine helps treat addiction [47, 48].

The Roles of GDNF in Disease

1) May Promote Cancer Growth

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 [49].

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 [50].

2) May Be Toxic 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 [51].

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 [51].

Limitations and Caveats

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.

Low GDNF? Ways to Support the Brain

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.

Behavior and Lifestyle Changes

1. 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].
2. Exercise – Exercise increases GDNF in the spinal cords of both young and old rats [54].
3. Stress reduction – Stress negatively impacts GDNF levels, and avoiding it can be a great way to boost GDNF, along with many other health benefits [55].
4. Sunlight exposure: stimulates the production of Vitamin D, which can greatly increase GDNF levels [56].
5. Avoiding canned food – Especially while pregnant (unless BPA free). BPA decreases GDNF [57].
6. Ketogenic diet – Similar effects to those seen with calorie restriction have been observed with the ketogenic diet [53].

Food and Supplements

1. Ashwagandha (Withaferin A) – Following spinal cord injury in mice, it significantly increased GDNF while decreasing multiple inflammatory markers and reducing cell death [58].
2. EGCG (Green Tea) – Following spinal cord injury, rats injected with EGCG had greater GDNF and BDNF levels [59].
3. Ginkgo biloba – Bilobalide, a major ingredient of the Ginkgo plant, increased GDNF and VEGF levels in rat glial cells [60].
4. Ginseng – significantly increased GDNF levels as well as sperm count (spermatogenesis) in rats [61].
5. Vitamin D3 – Taking vitamin D3 daily for seven days prior to and for 4 weeks following brain damage in rodents increased GDNF levels [62].
6. Royal jelly – Oral dosage given to mice increases GDNF production in the hippocampus [63].
7. Vitamin A – Increased GDNF activity by increasing its receptor number (GFRA1) in developing cells of the rat nervous system [64].
8. Flavonoids (calycosin, isorhamnetin, luteolin, and genistein) – Induced GDNF, BDNF, and NGF in rat glial cells [65].
9. Cistanche – This plant increased GDNF production in a rodent model of Parkinson’s disease [66].
10. Harpagoside (Devil’s Claw) – Increased GDNF in mice [67].
11. Docosahexaenoic acid (DHA) – Increased GDNF in adult rats (hippocampus) [25].
12. Butyrate – Increased the production of GDNF in rodents infected with pneumococcal meningitis [68].
13. Calcitriol – Increased GDNF production and prevented the death of rodent dopamine neurons [69].
14. Naringin/grapefruit – Shown to increase GDNF in a rodent model of Parkinson’s disease [70].

Other Factors That Increase GDNF

Experimental Therapies

1. 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 [71].
2. Transcranial magnetic stimulation (TMS) (rodent model) [72].
3. Photobiomodulation (monkeys) [73].

Antidepressant Drugs

1. 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 [74].
2. Fluoxetine (Prozac) – One of the most common antidepressants, fluoxetine increased GDNF release similarly to Clomipramine [74].
3. Paroxetine (Paxil) – Another very common antidepressant, paroxetine also increased GDNF release similarly to clomipramine [74].
4. 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].
5. Selegiline (Emsam) – Elevated GDNF, NGF, and BDNF levels in mouse glial cells [76].
6. Mianserin (Tolvon) – An antidepressant, mianserin increased GDNF release, similarly to clomipramine [74].
7. NSI-189 – A new experimental drug for treating depression (rats) [77, 78].

Other Drugs That Increase GDNF

1. Nicotine – Increased GDNF in glial cells (but not neurons) of rodents [79].
2. 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 [80].
3. Cabergoline – An amplifier of dopamine activity, cabergoline increased GDNF levels in rat glial cells [81].
4. Ibogaine / Noribogaine – An anti-addiction drug that increases GDNF levels in human neural cells [48, 82].
5. Ladostigil – A treatment for Alzheimer’s Disease that increases GDNF production in rat neurons [83].
6. Leu-Ile – A dipeptide of amino acids isoleucine and leucine, Ile-Leu increased GDNF production levels in rat hippocampal neurons [84].
7. 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) [85].
8. Riluzole – A brain-protecting drug used to treat amyotrophic lateral sclerosis, riluzole increased the production of GDNF, BDNF, and NGF in mouse glial cells [86].
9. Telmisartan – Increased GDNF and BDNF levels in a mouse model of Parkinson’s disease [87].
10. Valproic acid – A histone deacetylase inhibitor, valproic acid injected directly into the brain (substantia nigra) increased GDNF and BDNF production [88].

Hormones That Increase GDNF

1. 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 [89].
2. Incretin hormones GIP and GLP-1 – In mouse glial cells (microglia), GIP and GLP-1 increased levels of GDNF, NGF, and BDNF [90].
3. Progesterone – A 48-hour treatment of progesterone elevated GDNF levels in rat glia for at least 72 hours post-treatment [91].
4. Testosterone – Increased GDNF levels in rat testes cells necessary for sperm production [92].

Neurotransmitters/Cytokines/Pathways That Increase GDNF

1. 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].
2. TNF-alpha – Activated GDNF in rat bone marrow stem cells [96].
3. TLR2 signaling – TLR2 is necessary for sufficient GDNF levels in the gut nervous system during development in mice [97].