Withaferin A protects against spinal cord injury by inhibiting apoptosis and inflammation in mice

Abstract

Context: Withaferin A (WFA) exhibits diverse pharmaceutical applications on human diseases, including rheumatoid arthritis, cancers and microbial infection.Objective: We evaluated the neuroprotective role of WFA using a mouse model of spinal cord injury (SCI).Materials and methods: BALB/c mice were administrated 10 mg/kg of WFA. Gene expression was measured by real-time PCR, western blot and immunohistochemistry. Cell morphology and apoptosis were determined by H&E staining and TUNEL assay. Motor function was evaluated by the BBB functional scale for continuous 7 weeks.Results: WFA significantly improved neurobehavioural function and alleviated histological alteration of spinal cord tissues in traumatized mice. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) significantly increased in WFA-treated mice. Meanwhile, the expression of Nogo-A and RhoA remarkably decreased in the presence of WFA. Furthermore, the apoptotic cell death was attenuated in mice treated with WFA (31.48 ± 2.50% vs. 50.08 ± 2.08%) accompanied by decreased bax and increased bcl-2. In addition, WFA decreased the expression of pro-inflammatory mediators such as IL-1β (11.20 ± 1.96 ng/mL vs. 17.59 ± 1.42 ng/mL) and TNF-α (57.38 ± 3.57 pg/mL vs. 95.06 ± 9.13 pg/mL). The anti-inflammatory cytokines including TGF-β1 (14.32 ± 1.04 pg/mL vs. 9.37 ± 1.17 pg/mL) and IL-10 (116.80 ± 6.91 pg/mL vs. 72.33 ± 9.35 pg/mL) were elevated after WFA administration.Discussion and conclusion: This study demonstrated that WFA has a neuroprotective role by inhibition of apoptosis and inflammation after SCI in mice.

Withania somnifera (L.) Dunal ameliorates neurodegeneration and cognitive impairments associated with systemic inflammation

“…Various active phytochemicals like withaferin A, withanone, withanolide A, withanoside IV and withanoside VI etc. present in Ashwagandha are found to be involved in its neuroprotective activity [17, 59, 71–73]. Array of secreted factors from activated glia like NO, NO derivatives and cytokines either lead to neuronal death or interfere with cytoskeleton reorganization of neurons which is also implicated in normal functioning of synaptic networks [74, 75].…”

Hyperbaric oxygen improves functional recovery of rats after spinal cord injury via activating stromal cell-derived factor-1/CXC chemokine receptor 4 axis and promoting brain-derived neurothrophic factor expression

“… [33] Besides, increasing evidence supported that SCI induced a robust immune response characterized by the production of chemokines and cytokines. [34] Most of them enhanced inflammation and functional recovery. [34] Neuronal cell death following SCI was an important contributor to neurologic deficits.…”

Towards natural mimetics of metformin and rapamycin

“…It has also been found to selectively induce cell death in multiple types of tumor cells [143,144]. Its anticancer effects are mediated through modulation of a number of pathways, including inhibition of Notch 1 [145], inhibition of STAT3 activation [146–148], downregulation of the MTOR signalling components pS6K and p4E-BP1 [145], downregulation of the prosurvival pathway Akt/NF-kappaB/Bcl-2 [145], induction of c-Jun-NH(2)-kinase-mediated apoptosis [145], induction of apoptosis via upregulation of Bim, t-Bid, caspase-8, and DR5 [149], suppression of constitutive and IL-6-induced phosphorylation of STAT3 (on Tyr705) and consequent down-regulation of the STAT3 regulated genes Bcl-xL, Bcl-2, cyclin D1 and survivin [150], inhibition of heat shock protein 90 [151], downregulation of COX-2 and iNOS by blocking NF-κB activity [121], and down-regulation of TNF-a [152].…”