Neuronal plasticity in chronic pancreatitis is mediated via the neurturin/GFRα2 axis.

Abstract

The glial cell line-derived neurotrophic factor (GDNF) family member neurturin (NRTN) and its receptor GFRα2 play a deciding role in the normal development of pancreatic parasympathetic innervation. In this study, we aimed at investigating the role of NRTN/GFRα2 axis in pancreatic neuropathy in human chronic pancreatitis (CP). Expression of NRTN/GFRα2 was compared between normal human pancreas (NP) and CP tissues via immunohistochemistry, immunoblotting, and quantitative RT-PCR and correlated to abdominal pain sensation. To elucidate the impact of NRTN in pancreatic neuroplasticity, neuronal phenotype and glial density were quantified via an in vitro neuroplasticity assay in dissociated newborn rat dorsal root ganglia (DRG) cultured 1) in CP tissue extracts depleted from NRTN, 2) in NP, 3) in untreated CP tissue extracts, and 4) CP extracts in which nerve growth factor, glial cell derived-neurotrophic factor, or TGF-β(1) was depleted. NRTN and GFRα2 were highly upregulated in CP, especially in intrapancreatic nerves and the extracellular matrix. CP tissue demonstrated increased amounts of mature multimeric NRTN and elevated levels of GFRα2. The noticeable neurotrophic effect of CP tissue extracts on DRG neurons was diminished upon blockade of NRTN from these extracts. However, blockade of NRTN from CP extracts did not influence the density of DRG glia cells. In conclusion, the NRTN/GFRα2 axis is activated during the course of CP and represents a major key player in the reactive neural alterations in CP. This is the first study to provide functional evidence for the contribution of neurotrophic factors to neuroplasticity in CP.

• Authors: Ihsan Ekin Demir, Kun Wang, Elke Tieftrunk, Nathalia A Giese, Baocai Xing, Helmut Friess, Timo Kehl, Güralp O Ceyhan
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 303 Issue 9 Pg. G1017-28 (Nov 01 2012) ISSN: 1522-1547 [Electronic] United States
• PMID: 22961804 (Publication Type: Journal Article)

Chemical References

• Glial Cell Line-Derived Neurotrophic Factor
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• Neurturin

Topics

• Abdominal Pain (etiology, physiopathology)
• Animals
• Disease Models, Animal
• Ganglia, Spinal (metabolism, physiopathology)
• Glial Cell Line-Derived Neurotrophic Factor (metabolism)
• Glial Cell Line-Derived Neurotrophic Factor Receptors (metabolism)
• Humans
• Immunoblotting
• Immunohistochemistry
• Neuronal Plasticity (physiology)
• Neurturin (metabolism)
• Pancreas (innervation, metabolism)
• Pancreatitis, Chronic (complications, metabolism, physiopathology)
• Parasympathetic Nervous System (metabolism, physiopathology)
• Rats
• Real-Time Polymerase Chain Reaction