Gentiopicroside Ameliorates Diabetic Peripheral Neuropathy by Modulating PPAR- Γ/AMPK/ACC Signaling Pathway

Abstract

Background/Aims: Gentiopicroside is promising as an important secoiridoid compound against pain. The present study aimed to investigate the analgesic effect and the probable mechanism of Gentiopicroside on Diabetic Peripheral Neuropathy (DPN), and to figure out the association among Gentiopicroside, dyslipidemia and PPAR- γ/AMPK/ACC signaling pathway. Methods: DPN rat models were established by streptozotocin and RSC96 cells were cultured. Hot, cold and mechanical tactile allodynia were conducted. Blood lipids, nerve blood flow, Motor Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity (SNCV) were detected. Gene and protein expression of PPAR- γ/AMPK/ACC pathway was analyzed by reverse transcription-quan titative polymerase chain reaction (RT-qPCR) and Westernblot. Besides, PPAR-γ antagonist GW9662 and agonist rosiglitazone, AMPK antagonist compound C and activator AICAR as well as ACC inhibitor TOFA were used to further confirm the relationship between PPAR-γ and AMPK. Results: The results demonstrated that Gentiopicroside markedly ameliorated hyperalgesia with prolonged paw withdrawal latency to heat and cold stimuli and fewer responses to mechanical allodynia compared with DPN model group. Gentiopicroside regulated dyslipidemia, enhanced nerve blood flow and improved MNCV as well as SNCV. Gentiopicroside suppressed ACC expression through the activation of AMPK and PPAR-γ mediated the activation of AMPK and subsequent inhibition of ACC expression. Conclusion: In conclusion, the present study demon strated that Gentiopicroside exerted nerve-protective effect and attenuated experimental DPN by restoring dyslipidmia and improved nerve blood flow through regulating PPAR-γ/AMPK/ACC signal pathway. These results provided a promising potential treatment of DPN.

Therapeutic potential of PPARγ natural agonists in liver diseases

“…More than one decade ago, PPARγ was reported to be closely re- 169,170,172,[193][194][195][196] Kaempferia parviflora, Moringa concanensis Nimmo, Resveratrol 2019 42,95,197,198 signalling. The animal experiments showed that hispidulin administration could suppress tumour growth and lung metastasis.…”

AMPK: a balancer of the renin–angiotensin system

“…Current research shows PPARs and AMPK are also closely related. PPARs may activate AMPK [178][179][180]. One study claims that PPARγ agonists enhanced AMPK phosphorylation [179].…”

“…The other finding suggests that micheliolide ameliorates liver steatosis by upregulating PPAR-γ expression, thereby inhibiting NF-κB-mediated inflammation and activating AMPK/mTOR-dependent autophagy [180]. In Lu et al's [178] study, by using GW9662 (inhibitor of PPARγ) and compound C (inhibitor of AMPK), they suggested that AMPK might be a downstream effector of PPAR-γ. It seems that AMPK also affects the expression of PPARs.…”

Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway

“…AMPK is an important energy receptor in cells that regulates and maintains energy homeostasis. Activated AMPK rapidly inactivates the fatty acid synthesis rate-limiting enzyme, ACC, thereby inhibiting lipid synthesis and reducing energy consumption ( Lu et al, 2018 ). We found that Fra-1 promoted the expression of LKB1 and p-AMPK, which in turn reduced the expression of ACC.…”