Rosmarinic acid exerts a neuroprotective effect on spinal cord injury by suppressing oxidative stress and inflammation via modulating the Nrf2/HO-1 and TLR4/NF-κB pathways

Zhanjun Ma,Yubao Lu,Fengguang Yang,Shaoping Li,Xuegang He,Yicheng Gao,Guangzhi Zhang,Enhui Ren,Yonggang Wang,Xuewen Kang

doi:10.1016/j.taap.2020.115014

Zhanjun Ma, Yubao Lu + Show 8 more

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https://doi.org/10.1016/j.taap.2020.115014

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Spinal cord injury (SCI) is a severe central nervous system injury for which few efficacious drugs are available. Rosmarinic acid (RA), a water-soluble polyphenolic phytochemical, has antioxidant, anti-inflammatory, and anti-apoptotic properties. However, the effect of RA on SCI is unclear. We investigated the therapeutic effect and underlying mechanism of RA on SCI. Using a rat model of SCI, we showed that RA improved locomotor recovery after SCI and significantly mitigated neurological deficit, increased neuronal preservation, and reduced apoptosis. Also, RA inhibited activation of microglia and the release of TNF-α, IL-6, and IL-1β and MDA. Moreover, proteomics analyses identified the Nrf2 and NF-κB pathways as targets of RA. Pretreatment with RA increased levels of Nrf2 and HO-1 and reduced those of TLR4 and MyD88 as well as phosphorylation of IκB and subsequent nuclear translocation of NF-κB-p65. Using H2O2– and LPS-induced PC12 cells, we found that RA ameliorated the H2O2-induced decrease in viability and increase in apoptosis and oxidative injury by activating the Nrf2/HO-1 pathway. Also, LPS-induced cytotoxicity and increased apoptosis and inflammatory injury in PC-12 cells were mitigated by RA by inhibiting the TLR4/NF-κB pathway. The Nrf2 inhibitor ML385 weakened the effect of RA on oxidant stress, inflammation and apoptosis in SCI rats, and significantly increased the nuclear translocation of NF-κB. Therefore, the neuroprotective effect on SCI of RA may be due to its antioxidant and anti-inflammatory properties, which are mediated by modulation of the Nrf2/HO-1 and TLR4/NF-κB pathways. Moreover, RA activated Nrf2/HO-1, which amplified its inhibition of the NF-κB pathway.

Highlights

Spinal cord injury (SCI) is a severe type of central nervous system (CNS) injury that can cause spinal cord nerve cell death and glial scar formation [1]
Primary antibodies against GFAP, NeuN, NF-H, BDNF, Iba1, Nuclear factor erythroid-derived 2-related factor 2 (Nrf2), HO-1, Toll-like receptor 4 (TLR4), myeloid differentiation factor–88 (MyD88), IκBα, p-IκBα, IKKα/β, p-IKKα/β, and nuclear factor kappa beta (NF-κB) p65 were purchased from Cell Signaling Technology (Danvers, MA)
At 3 days after injury, there was no significant difference in BBB scores between the SCI and Rosmarinic acid (RA) treatment groups

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Spinal cord injury (SCI) is a severe type of central nervous system (CNS) injury that can cause spinal cord nerve cell death and glial scar formation [1]. The pathogenesis of SCI involves primary and secondary injury. Primary injury refers to the mechanical damage caused to the spinal nerves during trauma and irreversible vascular structural damage, axonal rupture, and nerve cell death. Secondary injury refers to ischemia-reperfusion injury, glutamate excitotoxicity, oxidative stress, intracellular calcium overload, neuronal apoptosis, and glial scar formation adjacent to the injury site [2, 3]. The neuronal death caused by primary injury cannot be reversed [4]. Spinal cord injury (SCI) is a severe central nervous system injury for which few efficacious drugs are available. We investigated the therapeutic effect and underlying mechanism of RA on SCI in vivo and in vitro

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