Berbamine alleviates neuropathic pain via suppressing spinal TMEM34/SGK1/FOXO3 axis

The pathologic mechanism of neuropathic pain (NP) is still not fully understood, and efficient and safe therapeutic options are limited.

Seeking new treatment options for neuropathic pain.

Exploring new therapeutic target for NP and finding analgesic medications derived from traditional Chinese medicines against the target is urgent.

Chronic constriction injury (CCI) model was used for behavioral assays. In vitro assay was conducted by using primary neurons, glial cells, as well as PC12, C6, and BV2 cells. The mechanical and thermal withdrawal threshold was assessed using Von Frey filaments and Hargreaves method. RNA sequencing (RNA-Seq), immunofluorescence, western blot, and quantitative RT-PCR were also used.

Spinal transmembrane34 (TMEM34) was firstly found to be elevated in CCI induced NP. Knocking-down spinal TMEM34 obviously alleviated NP, while overexpressing TMEM34 promoted NP and induced allodynia in naïve rats. Furthermore, TMEM34 was expressed in spinal neurons and astrocytes but not in microglia to activate them in CCI rats. Serum and glucocorticoid inducible kinase-1 (SGK1) was similarly expressed in astrocytes and neurons, and its expression trend is compatible with that of TMEM34. p-SGK1 expression was also suppressed by blocking TMEM34 in CCI rats. In addition, TMEM34/SGK1 was found to prevent Forkhead box O3 (FOXO3) from activating neurons and astrocytes and promoting NP. Berbamine (BBM), an active compound in Stephania epigaea H. S. Lo, was screened to block the TMEM34/SGK1/FOXO3 axis, hence relieving NP.

Our findings highlighted the significance of TMEM34 as a critical factor in NP and found a prospective medication that inhibited TMEM34 to reduce NP.