Glial Cell Line-derived Neurotrophic Factor (GDNF) in the Treatment of Seizures

Research by Simonato and colleagues sought to observe the effects of a neurotrophic factor called “glial cell line-derived neurotrophic factor” or GDNF on seizures in epileptic rats. They published their findings in The Journal of Neuroscience in an article titled, “Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy.”

Purpose

• Neurotrophic factors are peptides (short chains of amino acids) that are critical for growth and survival of developing and mature neurons (nerve cells).
• One such neurotrophic factor is called glial cell line-derived neurotrophic factor (GDNF).
• Previous studies suggest the use of neurotrophic factors in treating epilepsy. However, a practical issue in using them as therapies include difficulties in achieving a stable concentration in the desired, targeted brain region.
• In the current study, the researchers used a novel technology to deliver GDNF - an encapsulated cell technology.
• They sought to find out if a targeted, continuous delivery of GDNF to specific regions of the brain would be effective in reducing seizures.

Description of Study

• The researchers used an experimental model of epilepsy, where rats were given a chemoconvulsant called pilocarpine. Care was taken to ensure that the animals did not feel undue pain.
• Implants released GDNF continuously into hippocampi of epileptic rats.
  • The “experimental” group was given GDNF. The control group was given a substance that was similar to GDNF but was not active.
  • The hippocampus was chosen because of its importance in generating and sustaining seizures.
• GDNF was chosen as a viable therapeutic target because previous studies had suggested that increasing levels of GDNF in the hippocampus could decrease seizures.

Results

• The researchers first confirmed that the implants did indeed release GDNF continuously and targeted to the hippocampus.
• Rats given GDNF showed a decrease in spontaneous seizures compared to control rats.
  • Surprisingly, this effect of GDNF was seen even after the implant was removed, suggesting long-term effects of using neurotrophic factor.
• Additional studies showed that rats given GDNF did not have the neuronal abnormalities that are typical of chronic epilepsy.
  • It is possible that the beneficial effects of GDNF in epilepsy are due to its capacity to cause long-lasting changes in neuronal circuitry.

What does this mean?

• There is a great need for novel, more effective therapies for epilepsy.
• This study suggests the potential usefulness of GDNF as a candidate for a novel treatment for epilepsy.
• More research is needed before GDNF can be used the clinic. However, this study showed that an encapsulated system that delivers GDNF continuously to the hippocampus can reduce seizures in rats.

Reference

Paolone G, et al. Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy. J Neurosci. 2019 Mar 13;39(11):2144-2156.