CNTF: Its Role in The Body And How To Increase Ciliary Neurotrophic Factor

Ciliary Neurotrophic Factor

Ciliary Neurotrophic Factor (CNTF) is a neurotrophic factor with promising benefits in a wide range of pathologies such as neurodegenerative diseases, spinal cord injuries, retinal degeneration, autoimmune neuroinflammation and obesity-related metabolic diseases. R


  1. Basics
  2. Benefits and Roles in The Body
  3. How To Increase It
  4. Mechanism of Action
  5. Genetics
  6. Caveats
  7. More Research



CNTF got its name when it was discovered as a neurotrophic factor that supported ciliary neurons. R R

It is a protein, a polypeptide hormone, and a neurotrophic factor (like BDNF, NGFGDNF, CDNF, and MANF). R R

It is a hypothalamic neuropeptide that is a potent survival factor for neurons and oligodendrocytes and may be relevant in reducing tissue destruction during inflammatory attacks. R

Receptors for CNTF have been found on retinal ganglion cells, Mueller cells, photo receptors and retinal pigment epithelial cells: R R R R 

CNTF is expressed by glial cells of the spinal cord, atrocytes, Schwann cells, and skeletal muscles. R R R 

CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone-forming cells (osteoblasts). R

Benefits and Roles in The Body

1. Promotes Weight Loss


CNTF increases insulin sensitivity (by upregulating Glut4 and IRS-1 expression in adipocytes). R

During treatment for motor neuron disease, patients produced an unexpected an substantial weight loss. R

CNTF could reduce food intake without causing hunger or stress, making it a favorable for weight control in leptin-resistant subjects (CNTF is believed to operate like leptin, but by a non-leptin pathway). R

This only worked temporarily, as 70% of patients formed antibodies against the drug (Axokin) after 3 months. R

Of those who did not develop antibodies, weight loss averaged about 12.5lbs in a year. R

2. Protects Against Vision Loss


Human cells genetically modified to secrete CNTF have shown to reduce photoreceptor degradation in patients with retinitis pigmentosa. R R

In rats, CNTF treatment enhanced survival of retinal ganglion and photoreceptor cells (by activates STAT3 in ganglion cells). R

Dry age-related macular degeneration (AMD) is a deterioration or breakdown of the eye's macula, resulting in loss of vision. R R

CNTF delivered by encapsulated cell technology implant (NT-501) may slow the progression of vision loss from geographic atrophy in AMD patients, in a dose dependent manner. R

CNTF can regulate energy homeostasis by enahancing b3-adrenergic stimulation of UCP1. R

3. Has Anti-Inflammatory Properties

CNTF is a member of the IL-6 family. The IL-6 family helps regulate the acute-phase response to injury. It is known to have anti-inflammatory and neuronal regenerative effects. R

Multiple sclerosis (MS) is an autoimmune demyelinating disease resulting in oligodendrocyte loss, reactive astroglycotes, axonal pathology and chronic neuroinflammation induced by infiltrating immune cells. R

Daily CNTF injections decreased infiltrating immune cells and enhanced neuron numbers in mice. They also showed an increase in neuronal function recovery and IL-10. R R

CNTF impaired inflammation, was neuroprotective, decreased demyelination, and reduced neuron death (suppressing TNF-alpha and interferon-γ). R

4. Provides Neuroprotection


CNTF can promote neurite outgrowth and neuronal migration (by phosphorlating STAT3). R R

CNTF enhanced BDNF-mediated survival of cholinergic neurons. R

Intranasal CNTF was able to enhance the expression of NGF mRNA in hemorrhagic stroke. R

In animals:

  • It has shown to increase and enhance neurogenesis in Alzheimer's disease and after stroke. R R
  • CNTF infusion prevented learning disabilities, as a result from stroke. R
  • It potentiated neurogenesis in amyloid-β protein precursor transgenic mice. R
  • CNTF prevented the degeneration of motor neurons after axotomy (cutting the nerve) in rats. R
  • Exogenous CNTF prolonged the survival of check embryonic spinal motoneurons. R
  • Central administration of CNTF prevents retrograde death of anterior thalamic neurons in rats. R

5. May Play a Role ALS

Amyotrophic Lateral Sclerosis (ALS) is predominately a sporadic neurodegenerative disease affecting spinal motor neurons rapidly leading to paralysis and dysfunction in the respiratory system. R

CNTF may be dysregulated in ALS patients and rodents. R R R R


How to Increase CNTF

  • Aspirin R
  • Axokine (intolerance at higher concentrations due to low-affinity binding to IL-6R) R R
  • Cerebrolysin (mixture of BDNF, NGFGDNF, CNTFR
  • Chronic Stress R
  • HGF (hepatocyte growth factor synergizes with CNTF) R
  • IL-6 R
  • N-PEP-12 R
  • NT-501 R R
  • P21 R
  • Peptide 6 R
  • Sodium Benzoate R

Decrease CNTF

  • Retinoic acid (downregulated expression) R

Mechanism of Action

CNTF lacks a peptide signal. R

It is believed to be a trauma factor released following glial cell rupture in response to injury. R

CNTF binds to its receptor in a step-wise fashion:  R R R R R

  1. Recruiting the GPI-anchored CNTFRa chain in a 1:1 stoichiometry.
  2. The CNTF/CNTFRa complex subsequently binds to gp130. (signaling chain)
  3. It then recruits the LIFRb chain. (signaling chain)

Human CNTF does not have the capacity to induce the heterodimerisation of gp130 and LIFRb, although IL6 receptor alpha chain (IL6Ra; soluble or membrane-bound) can act as a substitute a chain when CNTF is present in high concentration. R R

While gp130 and LIFRb are broadly distributed, CNTFRa is mainly expressed in the brain, the retina and the skeletal muscles. R R 

Sortilin (a protein) can substitute for CNTFRa. It helps module the immune response by participating in B cell survival regulation, pro-nerve growth factor-induced natural killer cell death as well as IFNg and IL6 secretion. R R R R


  • Increases calcitonin gene-related peptide (CGRP) R
  • Increases somatostatin R
  • Increases vasoactive intestinal polypeptide (VIP) R
  • Mimics Leptin R



CNTF in humans is encoded by the CNTF gene. R R R 

The gene is also cotranscribed with the upstream ZFP91 gene. R

It is located on human chromosome 11. R

A mutation in this gene, which results in aberrant splicing, leads to ciliary neurotrophic factor deficiency, but this phenotype is not causally related to neurologic disease. R

CNTF activates JAK1, JAK2, and TYK2 tyrosine kinases which phosphorylate STAT3 tyrosine in position 705. R R


  • rs1800169
  • rs8373
  • rs660339
  • rs1800795



Systemic CNTF administration does not cross the blood-retina barrier well. R

CNTF is safe for the human retina even with severely compromised photoreceptors. R

Subjects producing antibodies (against Axokine) may eventually suffer severe adverse effects, as these antibodies could potentially interfere with the neuroprotective functions of endogenous CNTF. R

There were no reported major side effects with NT-501. R

CNTF may make you sleepy, as it is structurally similar to IL-6. R

More Research

  • Expression of SHP-2 in the NBFL (neuroblastoma cell line) increased CNTF induction of VIP (vasoactive instestinal peptide receptor gene. It resulted in an upregulation of endogenous VIP and SP (substance P) gene expression. R
  • All CNTF variants retained the ability to bind to CNTFR. CV-1, CV-2, and CV-5, however, lost the ability to bind to IL-6R. R
  • Axokine, an analog of CNTF, produces delayed upregulation of total STAT3 and STAT1 protein in rat retina. STAT3 is activated in the retina after exposure to subtoxic bright light, mechanical trauma, and systemic administration of the alpha(2)-adrenergic agonist xylazine, all of which have been shown previously to condition photoreceptors to resist light-induced degeneration. R
  • In males, CNTF enhances cortical growth, but is an inhibitor of trabecular bone formation in females. R
  • In vitro, CNTF induced neuronal precursors to switch from serotogenic to choleinergice phenotype. R
  • CNTF is expressed in pancreatic beta-cells, potentiating the beta-cell inhibitor effect of IL-beta, with increased iNOS expression and NO synthesis. R
  • Deletion of Socs3, a suppressor of signaling through the Jak-STAT pathway, also promotes regeneration by enhancing the efficacy of ciliary neurotrophic factor (CNTF) R