scholarly journals Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy

2021 ◽  
Vol 118 (15) ◽  
pp. e2006050118 ◽  
Author(s):  
Grace Ji-eun Shin ◽  
Maria Elena Pero ◽  
Luke A. Hammond ◽  
Anita Burgos ◽  
Atul Kumar ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Therapeutic Potential ◽  
Sensory Neuropathy ◽  
Nociceptive Neuron ◽  
Cellular Mechanisms ◽  
Recycling Endosomes ◽  
Nociceptive Neurons ◽  
Nociceptive Responses ◽  
Peripheral Sensory ◽  
Paclitaxel Treatment

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

scholarly journals Integrins protect nociceptive neurons in models of paclitaxel-mediated peripheral sensory neuropathy

2019 ◽  
Author(s):  
Grace Ji-eun Shin ◽  
Maria Elena Pero ◽  
Luke A. Hammond ◽  
Anita Burgos ◽  
Samantha E. Galindo ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Therapeutic Potential ◽  
Sensory Neuropathy ◽  
Cellular Mechanisms ◽  
Nociceptive Neurons ◽  
Nociceptive Responses ◽  
High Prevalence ◽  
Neuronal Maintenance ◽  
Peripheral Sensory ◽  
Paclitaxel Treatment

SummaryChemotherapy induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN primarily affects unmyelinated nociceptive sensory terminals. Despite the high prevalence of CIPN, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused sensory neuron degeneration, altered the terminal branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-mediated cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. We used primary dorsal root ganglia neuron cultures to test conservation of integrin-mediated protection. We show that overexpression of a human integrin β subunit 1 (ITGB1) also prevented degeneration following paclitaxel treatment. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring integrin levels to antagonize paclitaxel-mediated toxicity in sensory neurons.

scholarly journals Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release

2021 ◽  
Vol 22 (16) ◽  
pp. 8826
Author(s):  
Wanzhi Wang ◽  
Miaomiao Kong ◽  
Yu Dou ◽  
Shanghai Xue ◽  
Yang Liu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sensory Neurons ◽  
Transient Receptor Potential ◽  
Safety Concern ◽  
Unmet Need ◽  
Nociceptive Neurons ◽  
Neuropeptide Release ◽  
Selective Expression ◽  
Peripheral Sensory Neurons ◽  
Peripheral Sensory

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; NPY2R, neuropeptide Y receptor Y2; GPR52, G protein-coupled receptor 52; SCN9A, sodium voltage-gated channel alpha subunit 9; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

scholarly journals Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats

2020 ◽  
Vol 132 (4) ◽  
pp. 867-880 ◽  
Author(s):  
Doaa M. Mohamed ◽  
Mohammed Shaqura ◽  
Xiongjuan Li ◽  
Mehdi Shakibaei ◽  
Antje Beyer ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mineralocorticoid Receptor ◽  
Mineralocorticoid Receptors ◽  
Mineralocorticoid Receptor Antagonist ◽  
Aldosterone Synthase ◽  
Nociceptive Neurons ◽  
Processing Enzyme ◽  
Peripheral Sensory Neurons ◽  
Synthase Inhibitor ◽  
Peripheral Sensory

Abstract Background Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. Methods In male Wistar rats (n = 5 to 8 per group) with Freund’s complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase–polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. Results In rats with Freund’s complete adjuvant–induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). Conclusions Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals THE GABA-ERGIC SYSTEM DOES NOT CONTROL THE NOCICEPTIVE RESPONSES OF PRIMARY SENSORY NEURON

2019 ◽  
Vol 19 (1S) ◽  
pp. 44-45
Author(s):  
V A Penniyaynen ◽  
S A Podzorova ◽  
S G Terekhin ◽  
B V Krylov ◽  
V B Plakhova
Keyword(s):  
Sensory Neuron ◽  
Sensory Neurons ◽  
Nervous Tissue ◽  
Molecular Mechanisms ◽  
Primary Sensory Neuron ◽  
Nociceptive Neuron ◽  
Wide Range ◽  
Nociceptive Responses ◽  
Activation Gating

The aim of the study was to elucidate the molecular mechanisms of the interconnection of the GABA-ergic and nociceptive systems at the level of the peripheral division of the CNS. The data obtained indicate that GABA does not affect the activation gating device of the NaV1.8 channel of the primary sensory neuron responsible for coding pain signals.This agent in a wide range of concentrations also does not affect the growth of neurites of sensory neurons of embryonic nervous tissue. These results confirm our assumption, expressed earlier that the asynaptic membrane of the primary nociceptive neuron is not under the control of the GABA-ergic system.

scholarly journals Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

2021 ◽  
Author(s):  
Yingli Gu ◽  
Flora Guerra ◽  
Mingzheng Hu ◽  
Alexander Pope ◽  
Kijung Sung ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Mitochondrial Fission ◽  
Sensory Neuropathy ◽  
Selective Vulnerability ◽  
Mitochondrial Morphology ◽  
Physiological Level ◽  
Charcot Marie Tooth ◽  
Mitochondrial Movement ◽  
And Function ◽  
Peripheral Sensory

Recent evidence has uncovered an important role of Rab7 in regulating mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigated how mitochondrial morphology and function were impacted by the CMT2B associated Rab7V162M mutation in fibroblasts from human CMT2B patients as well as in a knockin mouse model. In contrast to recently published results from studies of using heterologous overexpression systems, our results have demonstrated significant mitochondrial fragmentation in fibroblasts of both human CMT2B patients and CMT2B mouse embryonic fibroblasts (MEFs). Furthermore, we have shown that mitochondria were fragmented and axonal mitochondrial movement was dysregulated in primary cultured E18 dorsal root ganglion (DRG) sensory neurons, but not in E18 hippocampal and cortical primary neurons. We also show that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalized the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study has revealed, for the first time, that expression of CMT2B Rab7 mutation at physiological level enhances Drp1 activity to promote mitochondrial fission, that may potentially underlie selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

scholarly journals Trigeminal Nociceptors Express TLR-4 and CD14: a Mechanism for Pain due to Infection

2006 ◽  
Vol 85 (1) ◽  
pp. 49-53 ◽  
Author(s):  
R. Wadachi ◽  
K.M. Hargreaves
Keyword(s):  
Sensory Neurons ◽  
Bacterial Infections ◽  
Bacterial Species ◽  
Nociceptive Neurons ◽  
Odontogenic Infections ◽  
Trigeminal Neurons ◽  
Human Dental Pulp ◽  
Peripheral Sensory ◽  
Caries Lesions ◽  
Immunohistochemical Analyses

Although certain bacterial species appear to be risk factors for pain due to odontogenic infections, comparatively little is known about the potential mechanisms mediating this effect. In this study, we tested the hypothesis that trigeminal nociceptive neurons express the TLR4 or CD14 receptors, thus enabling sensory neurons to detect and respond to tissue levels of bacterial substances such as lipopolysaccharide (LPS). Immunohistochemical analyses of human and rat trigeminal neurons demonstrated that a capsaicin-sensitive subclass of nociceptors (defined by expression of TRPV1, a capsaicin receptor) expresses both TLR4 and CD14. Moreover, human dental pulp collected from patients with caries lesions demonstrated co-localization of TLR4 and CD14, with markers of peripheral sensory neurons. Collectively, these studies indicate that the capsaicin-sensitive subclass of trigeminal nociceptors expresses TLR4 and CD14. These results indicate that pain due to bacterial infections may result, in part, from direct activation of nociceptors by bacterial products such as LPS.

scholarly journals D-Propranolol Impairs EGFR Trafficking and Destabilizes Mutant p53 Counteracting AKT Signaling and Tumor Malignancy

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3622
Author(s):  
Jonathan Barra ◽  
Javier Cerda-Infante ◽  
Lisette Sandoval ◽  
Patricia Gajardo-Meneses ◽  
Jenny F. Henriquez ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Akt Signaling ◽  
Single Daily Dose ◽  
Mutant P53 ◽  
Inhibitory Pathway ◽  
Recycling Endosomes ◽  
Oncogenic Pathways ◽  
Daily Dose ◽  
High Concentrations ◽  
Novel Therapeutic

Cancer therapy may be improved by the simultaneous interference of two or more oncogenic pathways contributing to tumor progression and aggressiveness, such as EGFR and p53. Tumor cells expressing gain-of-function (GOF) mutants of p53 (mutp53) are usually resistant to EGFR inhibitors and display invasive migration and AKT-mediated survival associated with enhanced EGFR recycling. D-Propranolol (D-Prop), the non-beta blocker enantiomer of propranolol, was previously shown to induce EGFR internalization through a PKA inhibitory pathway that blocks the recycling of the receptor. Here, we first show that D-Prop decreases the levels of EGFR at the surface of GOF mutp53 cells, relocating the receptor towards recycling endosomes, both in the absence of ligand and during stimulation with high concentrations of EGF or TGF-α. D-Prop also inactivates AKT signaling and reduces the invasive migration and viability of these mutp53 cells. Unexpectedly, mutp53 protein, which is stabilized by interaction with the chaperone HSP90 and mediates cell oncogenic addiction, becomes destabilized after D-Prop treatment. HSP90 phosphorylation by PKA and its interaction with mutp53 are decreased by D-Prop, releasing mutp53 towards proteasomal degradation. Furthermore, a single daily dose of D-Prop reproduces most of these effects in xenografts of aggressive gallbladder cancerous G-415 cells expressing GOF R282W mutp53, resulting in reduced tumor growth and extended mice survival. D-Prop then emerges as an old drug endowed with a novel therapeutic potential against EGFR- and mutp53-driven tumor traits that are common to a large variety of cancers.

Sign in / Sign up

Export Citation Format

Share Document