Effects of intrathecal caffeic acid phenethyl ester and methylprednisolone on oxidant/antioxidant status in traumatic spinal cord injuries.
To examine the effect of intrathecally given caffeic acid phenethyl ester (CAPE) on peroxidation and total oxidant and antioxidant systems, and the effect of intrathecally given methylprednisolone (MP) in spinal cord injury (SCI) models.
Four groups of 10 rats were formed: (1) Laminectomy, intrathecal saline injection, no SCI (sham: S); (2) Laminectomy, intrathecal saline injection, SCI (control: SCI); (3) Laminectomy, intrathecally given single dose of 3 mg/kg MP, SCISCI (SCI + MP). 4) Laminectomy, intrathecally given single dose of 1 µg/kg CAPE, SCI (SCI + CAPE). Malondialdehyde (MDA), total oxidant activity (TOA), total antioxidant capacity (TAC), superoxide dismutase (SOD), and glutathione peroxidase (GPx) values in the spinal cord tissue were evaluated.
When group S and group SCI were compared, MDA, TOA, and SOD parameters increased post-SCI (p < 0.01). When compared with group SCI, it was observed that CAPE and MP decreased the MDA, TOA, and SOD levels (p < 0.01). This decrease was more pronounced in the SCI + CAPE group. When group S and group SCI were compared, a statistically substantial decrease was observed in the post-SCI TAC levels. When compared with group SCI, it was shown that CAPE and MP treatment substantially increased TAC levels (p < 0.001).
Intrathecal injection of both CAPE and MP inhibits lipid peroxidation and increase of oxidants in SCIs.
Gocmez C
，Celik F
，Kamasak K
，Kaplan M
，Uzar E
，Arıkanoglu A
，Evliyaoglu O
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Caffeic acid phenethyl ester inhibits neuro-inflammation and oxidative stress following spinal cord injury by mitigating mitochondrial dysfunction via the SIRT1/PGC1α/DRP1 signaling pathway.
The treatment of spinal cord injury (SCI) has always been a significant research focus of clinical neuroscience, with inhibition of microglia-mediated neuro-inflammation as well as oxidative stress key to successful SCI patient treatment. Caffeic acid phenethyl ester (CAPE), a compound extracted from propolis, has both anti-inflammatory and anti-oxidative effects, but its SCI therapeutic effects have rarely been reported.
We constructed a mouse spinal cord contusion model and administered CAPE intraperitoneally for 7 consecutive days after injury, and methylprednisolone (MP) was used as a positive control. Hematoxylin-eosin, Nissl, and Luxol Fast Blue staining were used to assess the effect of CAPE on the structures of nervous tissue after SCI. Basso Mouse Scale scores and footprint analysis were used to explore the effect of CAPE on the recovery of motor function by SCI mice. Western blot analysis and immunofluorescence staining assessed levels of inflammatory mediators and oxidative stress-related proteins both in vivo and in vitro after CAPE treatment. Further, reactive oxygen species (ROS) within the cytoplasm were detected using an ROS kit. Changes in mitochondrial membrane potential after CAPE treatment were detected with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide. Mechanistically, western blot analysis and immunofluorescence staining were used to examine the effect of CAPE on the SIRT1/PGC1α/DRP1 signaling pathway.
CAPE-treated SCI mice showed less neuronal tissue loss, more neuronal survival, and reduced demyelination. Interestingly, SCI mice treated with CAPE showed better recovery of motor function. CAPE treatment reduced the expression of inflammatory and oxidative mediators, including iNOS, COX-2, TNF-α, IL-1β, 1L-6, NOX-2, and NOX-4, as well as the positive control MP both in vitro and in vivo. In addition, molecular docking experiments showed that CAPE had a high affinity for SIRT1, and that CAPE treatment significantly activated SIRT1 and PGC1α, with down-regulation of DRP1. Further, CAPE treatment significantly reduced the level of ROS in cellular cytoplasm and increased the mitochondrial membrane potential, which improved normal mitochondrial function. After administering the SIRT1 inhibitor nicotinamide, the effect of CAPE on neuro-inflammation and oxidative stress was reversed.On the contrary, SIRT1 agonist SRT2183 further enhanced the anti-inflammatory and antioxidant effects of CAPE, indicating that the anti-inflammatory and anti-oxidative stress effects of CAPE after SCI were dependent on SIRT1.
CAPE inhibits microglia-mediated neuro-inflammation and oxidative stress and supports mitochondrial function by regulating the SIRT1/PGC1α/DRP1 signaling pathway after SCI. These effects demonstrate that CAPE reduces nerve tissue damage. Therefore, CAPE is a potential drug for the treatment of SCI through production of anti-inflammatory and anti-oxidative stress effects.
Zhang Y
，Deng Q
，Hong H
，Qian Z
，Wan B
，Xia M
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《Journal of Translational Medicine》
ResearchGate
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