Carvacrol abates NLRP3 inflammasome activation by augmenting Keap1/Nrf-2/p62 directed autophagy and mitochondrial quality control in neuropathic pain

Arruri, Vijay Kumar; Gundu, Chayanika; Kalvala, Anil Kumar; Sherkhane, Bhoomika; Khatri, Dharmendra Kumar; Singh, Shashi Bala

doi:10.1080/1028415x.2021.1892985

Cited by 21 publications

(10 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More and more evidence shows that NLRP3 inflammasome is involved in inflammatory pain. NLRP3 inflammasome activation, ASC rapidly distributes from the nucleus to the cytoplasm and participates in the activation of caspase-1 precursors [ 15 , 22 , 23 ]. Regardless of the CCI, SCI, or SNL-induced mouse model, NLRP3, caspase-1, and ASC expressions were not only increased in peripheral dorsal root ganglia and neurons but also expressed in microglia and astrocytes [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CY-09 Inhibits NLRP3 Inflammasome Activation to Relieve Pain via TRPA1

Fan

Xue

Chen

et al. 2021

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

Peripheral tissue damage leads to inflammatory pain, and inflammatory cytokine releasing is the key factor for inducing the sensitization of nociceptors. As a calcium ion channel, TRPA1 plays an important role in pain and inflammation, thus becoming a new type of anti-inflammatory and analgesic target. However, there is no consensus on the role of this channel in mechanical hyperalgesia caused by inflammation. Here, we aim to explore the role and underlying mechanism of the inflammasome inhibitor CY-09 in two classic inflammatory pain models. We evaluated pain behavior on animal models, cytokine levels, intracellular Ca2+ levels, transient TRPA1 expression, NF-κB transcription, and NLPR3 inflammasome activation. Consistently, CY-09 reduced the production of inflammatory cytokines, intracellular Ca2+ levels, and the activation of TRPA1 by inhibiting the activation of inflammasomes, thereby reducing the proinflammatory polarization of macrophages and alleviating animal pain and injury. Importantly, AITC (TRPA1 agonist) significantly reversed the analgesic effect of CY-09, indicating that TRPA1 was involved in the analgesic effect of CY-09. Our findings indicate that CY-09 relieves inflammation and pain via inhibiting TRPA1-mediated activation of NLRP3 inflammasomes. Thus, NLRP3 inflammasome may be a potential therapeutic target for pain treatment and CY-09 may be a pharmacological agent to relieve inflammatory pain, which needs further research.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Many researchers have discovered that IL-1 β and IL-18 secrete during the process of inflammatory pain and promote NLRP3 inflammasome assembling [ 14 , 15 ]. Activated NLRP3 and ASC form a scaffold to stimulate procaspase-1 and promote the hydrolysis of pro-IL-1 β and pro-IL-18.…”

Section: Introductionmentioning

confidence: 99%

CY-09 Inhibits NLRP3 Inflammasome Activation to Relieve Pain via TRPA1

Fan

Xue

Chen

et al. 2021

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

show abstract

“…Followed by incubation with secondary anti-rat antibody conjugated with rhodamine (Santa Cruz Biotechnology Inc., CA, USA) or FITC (Fluorescein isothiocyanate) Sigma) for 2 h in dark at room temperature. After washing and mounting with Fluoroshield DAPI, then cells are subjected to visualization using confocal microscopy ( Arruri et al., 2021 ).…”

Section: Methodsmentioning

confidence: 99%

GSK2606414 attenuates PERK/p-eIF2α/ATF4/CHOP axis and augments mitochondrial function to mitigate high glucose induced neurotoxicity in N2A cells

Gundu

Arruri

Sherkhane

et al. 2022

Current Research in Pharmacology and Drug Discovery

Self Cite

View full text Add to dashboard Cite

Neuronal dysfunction and subsequent apoptosis under high glucose conditions during diabetes contribute majorly to the manifestation of diabetic peripheral neuropathy (DPN). PERK (protein kinase RNA (PKR)-like ER kinase) one among the three canonical arms of unfolded protein response (UPR), is believed to play a crucial role in determining the cell fate during endoplasmic reticulum stress (ERS/ER stress) conditions. We evaluated the role of PERK inhibitor GSK2606414 in high glucose (30 mM) treated neuroblastoma (N2A) cells. High glucose resulted in disruption of ER proteostasis by activation of UPR which is evident through increased (p < 0.001) expression of GRP78, p-PERK, p-eIF2α, ATF-4 and CHOP when compared to normal cells. It is accompanied with enhanced GRP78 localization in Endoplasmic Reticulum (ER) lumen evident from ER labeling Immunofluorescence (IF) staining. PERK activation resulted in altered mitochondrial function evident by increased mitochondrial superoxide production and compromised mitochondrial homeostasis with decrease in Mfn-2 levels. Additionally, ER stress induced neuronal apoptosis was attenuated by GSK2606414 treatment via inhibiting the PERK-eIF2α-ATF4-CHOP axis that not only curtailed the levels of apoptotic proteins like Bax and caspase 3 but also elevated the levels of anti-apoptotic Bcl-2. Collectively, our findings revealed the neuroprotective potential of GSK2606414 against high glucose induced neurotoxicity in N2A cells.

show abstract

“…Targeted mechanisms reported involved either increasing the Nrf2 activity [ 104 , 114 , 116 , 117 , 119 , 120 ], enhancing the translocation of Nrf2 while suppressing the spinal NOD-like receptor protein 3 (NLRP3) inflammasome and NF-κB [ 115 ], or inhibiting PARP activation [ 117 ]. For example, Arruri et al reported that carvacrol attenuated CCI-induced neuropathic pain by inhibiting NLRP3 and activating autophagy via the Keap1/Nrf-2/p62 forward-feedback loop and augmenting mitochondrial quality control (MCQ) [ 121 , 122 ]. To ensure cell homeostasis, MCQ operates through the coordination of various processes, including proteostasis, biogenesis, dynamics, and mitophagy operates [ 123 ].…”

Section: Nrf2 Signaling and Its Inducers In Different Peripheral Neur...mentioning

confidence: 99%

The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain

et al. 2022

View full text Add to dashboard Cite

Oxidative stress, resulting from an imbalance between the formation of damaging free radicals and availability of protective antioxidants, can contribute to peripheral neuropathic pain conditions. Reactive oxygen and nitrogen species, as well as products of the mitochondrial metabolism such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are common free radicals. Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor encoded by the NFE2L2 gene and is a member of the cap ‘n’ collar subfamily of basic region leucine zipper transcription factors. Under normal physiological conditions, Nrf2 remains bound to Kelch-like ECH-associated protein 1 in the cytoplasm that ultimately leads to proteasomal degradation. During peripheral neuropathy, Nrf2 can translocate to the nucleus, where it heterodimerizes with muscle aponeurosis fibromatosis proteins and binds to antioxidant response elements (AREs). It is becoming increasingly clear that the Nrf2 interaction with ARE leads to the transcription of several antioxidative enzymes that can ameliorate neuropathy and neuropathic pain in rodent models. Current evidence indicates that the antinociceptive effects of Nrf2 occur via reducing oxidative stress, neuroinflammation, and mitochondrial dysfunction. Here, we will summarize the preclinical evidence supporting the role of Nrf2 signaling pathways and Nrf2 inducers in alleviating peripheral neuropathic pain.

show abstract

Carvacrol abates NLRP3 inflammasome activation by augmenting Keap1/Nrf-2/p62 directed autophagy and mitochondrial quality control in neuropathic pain

Cited by 21 publications

References 61 publications

CY-09 Inhibits NLRP3 Inflammasome Activation to Relieve Pain via TRPA1

CY-09 Inhibits NLRP3 Inflammasome Activation to Relieve Pain via TRPA1

GSK2606414 attenuates PERK/p-eIF2α/ATF4/CHOP axis and augments mitochondrial function to mitigate high glucose induced neurotoxicity in N2A cells

The Effects of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (Nrf2) Activation in Preclinical Models of Peripheral Neuropathic Pain

Contact Info

Product

Resources

About