Glial Cell Line-Derived Neurotrophic Factor Family Ligands, Players at the Interface of Neuroinflammation and Neuroprotection: Focus Onto the Glia

Abstract

Well-known effects of neurotrophic factors are related to supporting the survival and functioning of various neuronal populations in the body. However, these proteins seem to also play less well-documented roles in glial cells, thus, influencing neuroinflammation. This article summarizes available data on the effects of glial cell line derived neurotrophic factor (GDNF) family ligands (GFLs), proteins providing trophic support to dopaminergic, sensory, motor and many other neuronal populations, in non-neuronal cells contributing to the development and maintenance of neuropathic pain. The paper also contains our own limited data describing the effects of small molecules targeting GFL receptors on the expression of the satellite glial marker IBA1 in dorsal root ganglia of rats with surgery- and diabetes-induced neuropathy. In our experiments activation of GFLs receptors with either GFLs or small molecule agonists downregulated the expression of IBA1 in this tissue of experimental animals. While it can be a secondary effect due to a supportive role of GFLs in neuronal cells, growing body of evidence indicates that GFL receptors are expressed in glial and peripheral immune system cells. Thus, targeting GFL receptors with either proteins or small molecules may directly suppress the activation of glial and immune system cells and, therefore, reduce neuroinflammation. As neuroinflammation is considered to be an important contributor to the process of neurodegeneration these data further support research efforts to modulate the activity of GFL receptors in order to develop disease-modifying treatments for neurodegenerative disorders and neuropathic pain that target both neuronal and glial cells.

The Neuropeptide Cortistatin Alleviates Neuropathic Pain in Experimental Models of Peripheral Nerve Injury

“…These apparent contradictory actions could be due, on one hand, to an inhibitory effect of cortistatin in the release by the central terminal of primary nociceptor at the spinal level of BDNF, thus preventing its capacity to sensitize sensory neurons and promote the development of neuropathic pain [69]; and, on the other hand, to a potential stimulatory effect on Schwann cells at the peripheral level that compensates a downregulation of axonal BDNF. Furthermore, some evidence indicates that BDNF could play pro-inflammatory actions, instead of neurotrophic effects, during neuropathic pain [70], a fact that might support the suppressive activity of cortistain in neuroinflammatory response in the injured nerve at the central and peripheral level. Moreover, we previously found that cortistatin induces the production of BDNF by immune cells [64], and therefore immune cells that are infiltrating the damaged nerve could contribute to compensate a potential loss of BDNF.…”

Role of Glial Cells in Depression and Drug Addiction

“…Interestingly, glial cells contain their own neurotrophic factor, referred to as glial cell line derived neurotrophic factor (GDNF), a class of proteins that also provide trophic support to neuronal cells including DAergic neurons [161]. Indeed, it has been proposed that lacrimal GDNF may serve as a marker in MDD [162].…”

Role of Glial Cells in Neuronal Function, Mood Disorders, and Drug Addiction

“…Astrocytes also express a high level of glial fibrillary astrocytic protein (GFAP), which are commonly used as a marker for their identification, although lately other markers have been added to the list [ 173 ]. More recently, it was reported that astrocytes are the necessary source of TNF-α for the mediation of homeostatic synaptic plasticity [ 174 ]. Similarly, taurine, considered the most abundant free amino acid in the brain required for optimal postnatal brain development, occurs predominantly in astrocytes.…”