The 6-paradol��s efficacy on microglial responses remains even after 3 days following M/R challenge, which is obvious in periischemic regions where the penumbra lies. It would be noteworthy that most of therapeutic interventions have been developed to protect the ischemic penumbra region. Therefore, the observed 6-paradol��s efficacy on microglial responses suggests that it may salvage the periischemic zone. In addition, the neuroprotective effect of 6-paradol was obvious when administered even after reperfusion, indicating that this compound possesses a therapeutic potential against cerebral ischemia. The observed in vivo neuroprotection by 6-paradol is associated with the reduced expression of iNOS and TNF-��, both of which are well-known pathogenetic ABT-199 components in cerebral ischemia even though there is debate regarding the latter. There are several cell types where these two neurotoxic molecules are upregulated or produced upon activated, which includes microglia, astrocytes, or infiltrated immune cells. In this study, we also observed that 6-paradol reduced NO production, Bortezomib accompanied with the downregulation of iNOS expression, and TNF-�� production in LPS-stimulated microglia. Therefore, the neuroprotective effects of 6-paradol in cerebral ischemia might be partly due to reducing expression levels of iNOS and TNF-�� in microglia. It is still possible that neuroprotection could be from reduced production of those molecules in other cell types associated with neuroinflammation, such as reactive astrocytes or infiltrated immune cells. Nevertheless, the inhibitory effects of 6-paradol on iNOS and TNF-�� can be applied to other many CNS disorders where these molecules are the main pathogenetic components, such as cerebral ischemia, multiple sclerosis, AD, PD, amyotrophic lateral sclerosis, or spinal cord injury. In particular, the effect on TNF-�� could be an important therapeutic potential because controlling TNF-�� production would allow researchers to overcome the challenges of treating many of the previously mentioned CNS disorders. Paradol, a non-pungent metabolite of shogaol by enzymatic reduction, is known to possess anti-inflammatory activities. Current in vitro findings demonstrate that the inhibitory properties of 6-paradol in treating neuroinflammation in microglia correlates to the in vivo therapeutic potential for cerebral ischemia. This study not merely provides evidence of 6-paradol��s neuroprotective efficacy in cerebral ischemia but also indicates its potential use in the treatment of other CNS disorders in which neuroinflammation is a pathological feature. This study may also explain the mechanism of action of 6-shogaol in diverse CNS disorders as it related to the biotransformation of 6-shogaol. In addition, if 6-paradol is shown to be effective in other CNS disorders, its non-pungent property has the advantage of fewer side effects on the stomach, which means it can be taken long-term, unlike that of ginger or ginger��s components likely 6-shogaol.