Effects of Glial Cell Line-Derived Neurotrophic Factor Intrathecal Injection on Spinal Dorsal Horn Glial Fibrillary Acidic Protein Expression in a Rat Model of Neuropathic Pain

Object. Glial cell line—derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)—treated dopaminergic neurons in vitro and in vivo. Methods. First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA—induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase—positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. Conclusions. These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor α1. The results of this study support a role for this grafting technique in the treatment of PD.

Download Full-text

Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain

British Journal of Pharmacology ◽

10.1038/sj.bjp.0705550 ◽

2003 ◽

Vol 140 (7) ◽

pp. 1252-1260 ◽

Cited By ~ 41

Author(s):

Masatoshi Nagano ◽

Atsushi Sakai ◽

Naoki Takahashi ◽

Masahiro Umino ◽

Koichi Yoshioka ◽

...

Keyword(s):

Neuropathic Pain ◽

Cell Line ◽

Glial Cell ◽

Neurotrophic Factor ◽

Rat Models ◽

Neurotrophic Factor Signaling

Download Full-text

Resveratrol Mediates Mechanical Allodynia Through Modulating Inflammatory Response via the TREM2-autophagy Axis in SNI Rat Model

10.21203/rs.3.rs-35728/v1 ◽

2020 ◽

Author(s):

Yaping Wang ◽

Yu Shi ◽

Yongquan Huang ◽

Wei Liu ◽

Guiyuan Cai ◽

...

Keyword(s):

Neuropathic Pain ◽

Inflammatory Response ◽

Dorsal Horn ◽

Nerve Injury ◽

Rat Model ◽

Mechanical Allodynia ◽

Spinal Dorsal Horn ◽

Intrathecal Administration ◽

Spared Nerve Injury ◽

Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanism allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, Lentivirus coding TREM2 was intrathecal injected into SNI rats to activate TREM2 and the pain behavior was detected by the Von Frey test. Furthermore, 3-Methyladenine (3-MA, an autophagy inhibitor) was performed to analyze the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, immunofluorescence. Results The TREM2 expression and number of the microglial cell was significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-methyladenine in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

Download Full-text

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

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.679034 ◽

2021 ◽

Vol 15 ◽

Author(s):

Anastasiia Kotliarova ◽

Yulia A. Sidorova

Keyword(s):

Neuropathic Pain ◽

Immune System ◽

Small Molecules ◽

Cell Line ◽

Glial Cell ◽

Glial Cells ◽

Neurotrophic Factor ◽

Neuronal Cells ◽

The Body ◽

Neuronal Populations

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.

Download Full-text