Herkinorin ameliorates neuronal damage in a pentylenetetrazol-induced epilepsy rat model through altering microglial and astrocytic activation by inhibiting PARP1 and NF-κB.

BACKGROUND

Altered astrocytic and microglial functions have been shown to mediate inflammation and oxidative stress in epilepsy. Herkinorin, a novel mu opioid receptor (MOR) agonist, has a neuroprotective role in ischemic brain injury. In this report, we sought to explore the effects and mechanism of herkinorin in the treatment of epilepsy and neuronal damage.

METHODS

SH-SY5Y cells were treated with pentylenetetrazol (PTZ) and herkinorin. The viability, reactive oxygen species (ROS) release, and apoptosis of the cells were detected. A rat epilepsy model was induced via PTZ injection, and herkinorin was used for pretreatment. Immunofluorescence staining and immunohistochemistry were used to observe neuronal damage and microglial and astrocyte activation in the hippocampal CA1/3 region. Western blotting was used to determine the expression profiles of PARP1 and NF-κB.

RESULTS

PTZ substantially facilitated SH-SY5Y cell apoptosis, induced oxidative stress and promoted NLRP3-ASC-Caspase-1 inflammasome activation. Herkinorin attenuated SH-SY5Y cell damage mediated by PTZ and suppressed PARP1 and NF-κB. The activation of PARP1 by lipopolysaccharide (LPS) aggravated SH-SY5Y cell injury, and herkinorin treatment reversed these LPS-mediated effects. In in vivo experiments, herkinorin hampered epileptic seizures in rats and weakened PTZ-induced neuronal damage in the hippocampus. Moreover, herkinorin reduced PTZ-induced neuroinflammation, resulting in "M1" to "M2" polarization of microglia and "A1" to "A2" polarization of astrocytes. Moreover, herkinorin inhibited the expression of PARP1 and NF-κB phosphorylation in the hippocampus.

CONCLUSION

Herkinorin ameliorates PTZ-induced neuroinflammation in epileptic rats by inhibiting PARP1 and NF-κB and regulating microglial and astrocytic activation.