Carvacrol Abates NLRP3 Inflammasome Mediated Neuroimmune Aberrations by Augmenting Autophagy and Mitochondrial Quality Control in Neuropathic Pain

Posted: 5 Feb 2020

Date Written: February 3, 2020

Abstract

Inflammasomes are intracellular multiprotein complexes archestrating the production of mature forms of IL-1β and IL-18, whose upregulation has been widely demonstrated in varied inflammatory disease conditions including neuropathic pain. NLRP3 (Nod-like receptor family pyrin domain containing 3) is one of the well explored inflammasomes by scientific community owing to its induction by divergent stress signals and subsequently became an interesting area of therapeutic exploration. However, molecular basis of NLRP3 regulation remains unclear and necessitates understanding of mechanisms governing NLRP3 activation. In this present study, we evaluated the neuroprotective potential of carvacrol (CRC), a monoterpene oregano essential oil against chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats and in LPS induced neuroinflammation in neuroblastoma cells (N2A). CCI resulted in marked (P<0.001) development of hyperalgesia, allodynia, foot deformation and compromised sciatic function which were evident through assessment of corresponding behavioural and functional parameters. Further, at molecular level we found that enhanced NLRP3 inflammasome activation resulted in cleavage of pro IL-1β to its mature IL-1β by activated caspase 1. We also observed increased NF-κβ expression and decline (P<0.001) in mitochondrial transcription factors Tfam, NRF-1 and ATP synthase levels indicative of mitochondrial dysfunction which is accompanied with reduction in activity of basal autophagic machinery evident through decreased (P<0.001) levels of ATG 7, ATG 16 and LCIII expression. CRC administration (30 mg/kg, 60 mg/kg, p.o) significantly (P<0.001 or P<0.01) ameliorated these changes suggesting NLRP3 inhibition by CRC attributed to its actions strengthening autophagy and mitochondrial quality control. Interestingly, pre-treatment of CRC (50 µM & 100 µM) to LPS and ATP primed N2A cells resulted in attenuation of NLRP3 activation which is evident through decreased colocalization of NLRP3 and ASC in CRC treated cells. These findings highlight unique pharmacological efficacy of CRC in inhibiting NLRP3 activation in neurons via autophagy induction and improving mitochondrial quality control and thus providing insights for the development of novel drugs to combat diseases associated with NLRP3 over activation such as neuropathic pain.

Keywords: NLRP3, Neuropathic pain

Suggested Citation

Arruri, Vijay Kumar and Gundu, Chayanika and Kumar, Ashutosh, Carvacrol Abates NLRP3 Inflammasome Mediated Neuroimmune Aberrations by Augmenting Autophagy and Mitochondrial Quality Control in Neuropathic Pain (February 3, 2020). Proceedings of International Conference on Drug Discovery (ICDD) 2020, Available at SSRN: https://ssrn.com/abstract=3530660

Vijay Kumar Arruri (Contact Author)

NIPER Hyderabad ( email )

Hyderabad, Telangana
India

Chayanika Gundu

NIPER ( email )

India

Ashutosh Kumar

NIPER ( email )

India

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