4-Phenylbutyric acid protects against vasculitic peripheral neuropathy induced by ischaemia–reperfusion through attenuating endoplasmic reticulum stress

Chen, Cay‐Huyen; Shih, Ping Cheng; Lin, Han-Yu; Wang, Po-Kai; Pan, Po‐Ting; Chuang, Ching‑Wei; Kao, Ming‐Chang

doi:10.1007/s10787-019-00604-6

Cited by 10 publications

(9 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, ATF4 and its downstream factor C/EBP homologous protein (CHOP) were capable of modulating ATG (autophagy related) genes. Also, the IRE1 pathway is implicated in the autophagy induction process (Chen et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

Liu

Wang

et al. 2020

Front. Neurosci.

View full text Add to dashboard Cite

Studies demonstrated that spinal autophagy was impaired in spinal nerve ligation (SNL) rats. However, the relationship of endoplasmic reticulum (ER) stress and ERphagy and whether dexmedetomidine (DEX) modulates ER-phagy remain unclear. In this study, male Sprague-Dawley (SD) rats and the SNL animal model were used. 4-Phenylbutyric acid (4-PBA), tunicamycin (TM), rapamycin (RAP), and 3-methyladenine (3-MA) were intrathecally administered, respectively to demonstrate the relationship of ER stress and ER-phagy. Dexmedetomidine (30 µg/kg) was administered as treatment. Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests were performed to evaluate nociceptive hypersensitivity. Protein expressions were examined by Western blot, and the location of glucose-regulated protein 78 (Grp78) was examined by immunofluorescence staining. SNL induced ER stress and ERphagy impairment. ER stress was altered in rostral ventromedial medulla (RVM); 4-phenylbutyric acid induced analgesic effect via inhibiting ER stress and unfolded protein response (UPR) pathways to induce ER-phagy; tunicamycin led to worsening pain through enhancing ER stress and UPR pathways to further impair ER-phagy. Rapamycin provided analgesic effect through enhancing ER-phagy to relieve SNLinduced ER stress and UPR pathway activation; 3-methyladenine deteriorated pain via further impairing ER-phagy to aggravate ER stress. Dexmedetomidine provided analgesic effect through elevating ER-phagy. In conclusion, ER stress led to ER-phagy impairment in the spinal cord of SNL rats and participated in the nociceptive descending system. ER-phagy impairment was both a trigger and an effector of ER stress via UPR pathways in SNL rats. Dexmedetomidine targeted ER-phagy to provide analgesic effect.

show abstract

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

Liu

Wang

et al. 2020

Front. Neurosci.

View full text Add to dashboard Cite

show abstract

“…15,17 Emerging evidence is now demonstrating that ER stress may also be a significant factor for developing pain hypersensitivity in various animal models across a variety of cell types. [18][19][20][21][22][23][24][25] In this study, we investigated whether ER stress in DRG neurons contributes to the well characterized pain hypersensitivity that occurs in the EAE model and by extension in MS. 7,26 2 | MATERIALS AND METHODS…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress in the dorsal root ganglia regulates large‐conductance potassium channels and contributes to pain in a model of multiple sclerosis

et al. 2020

View full text Add to dashboard Cite

Neuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post‐mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4‐phenylbutyric acid (4‐PBA), reduced pain hypersensitivity. In vitro, 4‐PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca2+ transients in putative DRG nociceptors. We went on to assess disease‐mediated changes in the functional properties of Ca2+‐sensitive BK‐type K+ channels in DRG neurons. We found that the conductance‐voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

show abstract

“…These observations demonstrate that MS pathology extends beyond the CNS into the PNS. Several recent reports have implicated ER stress in mediating pain hypersensitivity in various models of neuropathy, including diabetic neuropathy (18,20,36), spinal nerve ligation (24,37), vasculitic peripheral neuropathy (22) and CFA-induced orofacial neuropathy (38).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the chemical chaperone, 4-phenylbutyric acid (4-PBA), has been shown to ameliorate neuropathic pain by reducing ER stress (18,22,30). We wanted to investigate if daily systemic treatment with 4-PBA (200 mg/kg) starting at the onset of disease (Fig.…”

Section: -Pba Treatment Alleviates Mechanical and Facial Hypersensitmentioning

confidence: 99%

“…If the stressor is particularly severe or prolonged however, the UPR can drive the cell into an apoptotic program of regulated cell death (15,17). Emerging evidence is now demonstrating that ER stress may also be a significant factor for developing pain hypersensitivity in various animal models across a variety of cell types (18)(19)(20)(21)(22)(23)(24)(25). In this study, we investigated whether ER stress in DRG neurons contributes to the well characterised pain hypersensitivity that occurs in the EAE model and by extension in MS (7,26).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

Yousuf¹,

Samtleben²,

Lamothe

et al. 2020

Preprint

View full text Add to dashboard Cite

AcknowledgementsWe would like to thank Drs. Simonetta Sipione, Christine Webber, and Jason Plemel (University of Alberta) for graciously sharing select equipment and software. ABSTRACTNeuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post-mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4phenylbutyric acid (4-PBA), reduced pain hypersensitivity. In vitro, 4-PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca 2+ transients in putative DRG nociceptors. We went to assess disease-mediated changes in the functional properties of Ca 2+ -sensitive BK-type K + channels in DRG neurons. We found that the conductance-voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

show abstract

4-Phenylbutyric acid protects against vasculitic peripheral neuropathy induced by ischaemia–reperfusion through attenuating endoplasmic reticulum stress

Cited by 10 publications

References 48 publications

Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

Endoplasmic reticulum stress in the dorsal root ganglia regulates large‐conductance potassium channels and contributes to pain in a model of multiple sclerosis

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

Contact Info

Product

Resources

About