Byline: Xiao-wen. Jiang, Bin-qing. Zhang, Lu. Qiao, Lin. Liu, Xue-wei. Wang, Wen-hui. Yu
Frankincense can promote blood circulation. Acetyl-11-keto-[sz]-boswellic acid (AKBA) is a small molecule with anti-inflammatory properties that is derived from Boswellia serrata. Here, we hypothesized that it may promote regeneration of injured sciatic nerve. To address this hypothesis, we established a rat model of sciatic nerve injury using a nerve clamping method. Rats were administered AKBA once every 2 days at doses of 1.5, 3, and 6 mg/kg by intraperitoneal injection for 30 days from the 1st day after injury. Sciatic nerve function was evaluated using the sciatic functional index. Degree of muscle atrophy was measured using the triceps surae muscle Cuadros index. Neuropathological changes were observed by hematoxylin-eosin staining. Western blot analysis was used to detect expression of phospho-extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) in injured nerve. S100 immunoreactivity in injured nerve was detected by immunohistochemistry. In vivo experiments showed that 3 and 6 mg/kg AKBA significantly increased sciatic nerve index, Cuadros index of triceps muscle, p-ERK1/2 expression, and S100 immunoreactivity in injured sciatic nerve of sciatic nerve injury model rats. Furthermore, for in vitro experiments, Schwann cells were treated with AKBA at 0-20 [micro]g/mL. Proliferation of Schwann cells was detected by Cell Counting Kit-8 colorimetry assay. The results showed that 2 [micro]g/mL AKBA is the optimal therapeutic concentration. In addition, ERK phosphorylation levels increased following 2 [micro]g/mL AKBA treatment. In the presence of the ERK1/2 inhibitor, PD98059 (2.5 [micro]L/mL), the AKBA-induced increase in p-ERK1/2 protein expression was partially abrogated. In conclusion, our study shows that AKBA promotes peripheral nerve regeneration with ERK protein phosphorylation playing a key role in this process.
Introduction
Peripheral nerve injury (PNI) is common in clinical practice. Following PNI, the distal portion of the affected nerve de-generates (Stoll et al., 2002; Yu et al., 2016), followed by regrowth of the proximal nerve approximately 1 week after the initial injury (Raff et al., 2002; Coleman and Freeman, 2010). Schwann cells (SCs) promote nerve regeneration after axonal injury (Webber and Zochodne, 2010) by supplying neurotrophic factors. These promote axonal growth and also produce neurite-promoting factors that guide the regenerating axon (Dong et al., 1999). SCs at the site of PNI dedifferentiate to a progenitor-like state, then proliferate and clear axonal and myelin debris (Napoli et al., 2012; Wong et al., 2017). SCs can then differentiate, resulting in formation of Bungner bands (Namgung, 2014). These are unique columnar structures formed between SCs and the basement membrane, which guide the regrowing axon (Thomas and King, 1974; Wang et al., 2013), thus enabling repair of damaged peripheral nerves.
Mitogen-activated protein kinases 1 and 2 (also known as extracellular signal-regulated kinase (ERK)1/2) are signaling proteins that play a pivotal role in the cellular signal transduction network (Kitamura et al., 2011; Martensson et al., 2017). The ERK signaling pathway regulates a variety of cellular processes such as cellular proliferation, migration, differentiation, and apoptosis (Sun et al., 2015). Previous research has shown that nerve injury promotes activation of ERK...