Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Merighi, Adalberto

doi:10.1517/14728222.2016.1085972

Cited by 26 publications

(25 citation statements)

References 115 publications

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“…This study revealed a novel mechanism of TNFα inhibitors in neuropathic manifestation normalization involves the inactivating of neurotrophic receptor‐expression nociceptors, Ret(+) neurons. Generally, glial cell line‐derived neurotrophic factor (GDNF) regulates the function and morphology of the Ret receptor and is used as an analgesic agent that acts as a ligand to the Ret receptor [29–31]. Sensitization of Ret(+) neurons was reported to mediate the development of mechanical allodynia [7], and the current study demonstrated the changes in TNFα content and Ret(+) neuronal profiles in a parallel fashion.…”

Section: Discussionsupporting

confidence: 51%

Tumor necrosis factor‐α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

Chang

Kan

et al. 2018

The Kaohsiung J of Med Scie

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Neurogenic inflammation is an onset characteristic of small fiber neuropathy (SFN), which is attributed to neuropathic manifestations. Tumor necrosis factor-α (TNFα) is a cytokine that mainly mediates neurogenic inflammation through the ligand receptor TNF receptor 1 (TNFR1), and targeting TNFα/TNFR1 signaling is a direction toward treating inflammatory diseases and injury-induced neuropathy. However, the relationships between TNFα/TNFR1 signaling and Ret signaling, which mediates pain hypersensitivity, remains elusive. This study used resiniferatoxin (RTX), an ultrapotent analog of capsaicin, to generate a mouse model of SFN, leading to marked hindpaw edema (p = 0.013) and parallel the release of TNFα (p = 0.014), which was associated with the upregulation of Ret(+) neurons (p = 0.0043) and partial depletion of TNFR1 caused by colocalization with TRPV1 depleted by RTX. Pharmacological intervention of TNFα with etanercept (Enbrel, Wyeth), a clinical application of TNFα blockers, relieved neurogenic inflammation and caused a reduction in hindpaw thickness (p = 0.03) and TNFα releases (p = 0.01), which were determined to be associated with the normalization of mechanical allodynia (p = 0.22). The extraction of either TNFR1(+) or Ret(+) neurons from total of TNFR1(+):Ret(+) neurons indicated that TNFR1(-)/Ret(+) neurons correlated with the mechanical threshold in an antiparallel fashion (r = -0.84, p < 0.0001) but had no relationship with thermal latencies. This study confirmed that TNFα rather than TNFα mediated neuropathic manifestation through the Ret receptor, specifically mechanical allodynia in RTX neuropathy.

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Section: Discussionsupporting

confidence: 51%

Tumor necrosis factor‐α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

Chang

Kan

et al. 2018

The Kaohsiung J of Med Scie

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“…These observations lead one to hypothesize that the use of Ret inhibitors may offer a novel therapeutic approach for the treatment of IBS [108]. Thus, GFLs and their receptors are potential targets for new inflammatory pain-controlling drugs [109,110].…”

Section: In Pain Sensitivitymentioning

confidence: 99%

Revisiting the Role of Neurotrophic Factors in Inflammation

Morel

Domingues

Zimmer

et al. 2020

Cells

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The neurotrophic factors are well known for their implication in the growth and the survival of the central, sensory, enteric and parasympathetic nervous systems. Due to these properties, neurturin (NRTN) and Glial cell-derived neurotrophic factor (GDNF), which belong to the GDNF family ligands (GFLs), have been assessed in clinical trials as a treatment for neurodegenerative diseases like Parkinson’s disease. In addition, studies in favor of a functional role for GFLs outside the nervous system are accumulating. Thus, GFLs are present in several peripheral tissues, including digestive, respiratory, hematopoietic and urogenital systems, heart, blood, muscles and skin. More precisely, recent data have highlighted that different types of immune and epithelial cells (macrophages, T cells, such as, for example, mucosal-associated invariant T (MAIT) cells, innate lymphoid cells (ILC) 3, dendritic cells, mast cells, monocytes, bronchial epithelial cells, keratinocytes) have the capacity to release GFLs and express their receptors, leading to the participation in the repair of epithelial barrier damage after inflammation. Some of these mechanisms pass on to ILCs to produce cytokines (such as IL-22) that can impact gut microbiota. In addition, there are indications that NRTN could be used in the treatment of inflammatory airway diseases and it prevents the development of hyperglycemia in the diabetic rat model. On the other hand, it is suspected that the dysregulation of GFLs produces oncogenic effects. This review proposes the discussion of the biological understanding and the potential new opportunities of the GFLs, in the perspective of developing new treatments within a broad range of human diseases.

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“…These subunits constitute the tetrodotoxin-resistant Na + channels, which are expressed at high levels in nociceptive neurons of the DRG. The expression of these channels avoids the decay of conduction velocity after axotomy (Cummins et al, 2000 ); hence, and as other authors have proposed, GDNF modulates nociception (Merighi, 2016 ; Salio and Ferrini, 2016 ).…”

Section: Regulation Of Pain and Nociceptionmentioning

confidence: 89%

“…Alternatively, the administration of gliafin, a peptide agonist for the GDNF receptor, induces RET phosphorylation, but studies related to pain reduction are still in progress (Garcia-Bennett et al, 2013 ). The small molecule XIB4035, which binds to GFRα1, has been topically administered to alleviate neuropathic pain in a rodent model of diabetes and achieved excellent results (Merighi, 2016 ). The mechanisms elicited by GDNF are not completely elucidated, but seem to involve a decrease in excitability and glutamate release (Salio et al, 2014 ), even under physiological conditions (Merighi, 2016 ).…”

Section: Regulation Of Pain and Nociceptionmentioning

confidence: 99%

“…In fact, new functions associated with changes in the expression of downstream effector genes were recently described, such as promotion of proliferation and specification, neurite growth, synaptic and electrophysiological maturation, soma expansion and expression of phenotype-specific proteins. Additionally, GDNF might participate in both homeostasis (pain modulation (Merighi, 2016 )) and pathophysiological states (depression (Sharma et al, 2016 ) and attention-deficit/hyperactivity disorder (Bilgiç et al, 2017 )). Because most of the GDNF-associated research has been centered on the promotion of neuronal survival, with a substantial body of knowledge about this function, this review does not cover neuroprotection, but we aim to review the non-survival effects of GDNF.…”

Section: Introductionmentioning

confidence: 99%

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The Non-Survival Effects of Glial Cell Line-Derived Neurotrophic Factor on Neural Cells

Cortés

Carballo-Molina

Castellanos-Montiel

et al. 2017

Front. Mol. Neurosci.

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Glial cell line-derived neurotrophic factor (GDNF) was first characterized as a survival-promoting molecule for dopaminergic neurons (DANs). Afterwards, other cells were also discovered to respond to GDNF not only as a survival factor but also as a protein supporting other cellular functions, such as proliferation, differentiation, maturation, neurite outgrowth and other phenomena that have been less studied than survival and are now more extendedly described here in this review article. During development, GDNF favors the commitment of neural precursors towards dopaminergic, motor, enteric and adrenal neurons; in addition, it enhances the axonal growth of some of these neurons. GDNF also induces the acquisition of a dopaminergic phenotype by increasing the expression of Tyrosine Hydroxylase (TH), Nurr1 and other proteins that confer this identity and promote further dendritic and electrical maturation. In motor neurons (MNs), GDNF not only promotes proliferation and maturation but also participates in regenerating damaged axons and modulates the neuromuscular junction (NMJ) at both presynaptic and postsynaptic levels. Moreover, GDNF modulates the rate of neuroblastoma (NB) and glioblastoma cancer cell proliferation. Additionally, the presence or absence of GDNF has been correlated with conditions such as depression, pain, muscular soreness, etc. Although, the precise role of GDNF is unknown, it extends beyond a survival effect. The understanding of the complete range of properties of this trophic molecule will allow us to investigate its broad mechanisms of action to accelerate and/or improve therapies for the aforementioned pathological conditions.

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Targeting the glial-derived neurotrophic factor and related molecules for controlling normal and pathologic pain

Cited by 26 publications

References 115 publications

Tumor necrosis factor‐α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

Tumor necrosis factor‐α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

Revisiting the Role of Neurotrophic Factors in Inflammation

The Non-Survival Effects of Glial Cell Line-Derived Neurotrophic Factor on Neural Cells

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