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.…”

Iron Brain Menace: The Involvement of Ferroptosis in Parkinson Disease

“…Non-neuronal cells, glia, including the microglia, astrocytes, and oligodendrocytes, are major mediators of neuroinflammation. Glia cells regulate CNS tissue recovery, and their dysfunction is possibly contributory to neurodegeneration [ 127 ]. Recent evidence suggests that the brain’s major resident immune cells, microglia, provide disease-modifying regulation of other major glial populations, including astrocytes and oligodendrocytes.…”

The sigma‐1 receptor curtails endogenous opioid analgesia during sensitization of TRPV1 nociceptors

“…Non‐peptidergic C‐nociceptors do not express TRPV1 but can be labelled with Isolectin B4 (IB4) and sensitized by other factors, such as glial cell line‐derived neurotrophic factor (GDNF) (Álvarez et al, 2012). These peripheral sensitizers are produced in a variety of pathological pain states and play a pivotal role in pain generation (Ji et al, 2016; Kotliarova & Sidorova, 2021). We and others have recently reported that sigma‐1Rs are present in every DRG neuron (Bravo‐Caparrós et al, 2020; Montilla‐García et al, 2018; Shin et al, 2020), although the role of these receptors in the periphery has not been well studied.…”