In summary, this study supported the neuroprotective effects of PNGL on cerebral I/R injury, and the potential mechanisms may be largely associated with the inhibition of HMGB1-triggered inflammation, reduction of pro-inflammatory mediators including IL-6, TNF-α, IL-1 β, MMP-9, MMP-2, and ICAM-1, and attenuation of neuronal apoptosis and loss caused by ischemia via suppressing the activation of MAPKs and NF-κB signaling pathways. This evidence concerns the gene IL6 and ischemia.