Molecular\nImaging Reveals Antineuroinflammatory Effects\nof HDAC6 Inhibition in Stroke Models

Ischemic\nstroke is a devastating disease that causes neuronal death,\nneuroinflammation, and other cerebral damage. However, effective therapeutic\nstrategies for ischemic stroke are still lacking. Histone deacetylase\n6 (HDAC6) has been implicated in the pathogenesis of ischemic stroke,\nand the pharmacological inhibition of HDAC6 has shown promising neuroprotective\neffects. In this study, we utilized positron emission tomography (PET)\nimaging with the HDAC6-specific radioligand [<sup>18</sup>F]PB118\nto investigate the dynamic changes of HDAC6 expression in the brain\nafter ischemic injury. The results revealed a significant decline\nin [<sup>18</sup>F]PB118 uptake in the ipsilateral hemisphere on the\nfirst day after ischemia, followed by a gradual increase on days 4\nand 7. To evaluate the therapeutic potential of HDAC6 inhibitors,\nwe developed a novel brain-permeable and potent HDAC6 inhibitor, PB131,\nand assessed its neuroprotective effects in an ischemic stroke mouse\nmodel. PET imaging studies demonstrated that PB131 treatment alleviated\nthe decline in [<sup>18</sup>F]PB118 uptake and reduced the infarct\nsize in middle cerebral artery occlusion mice. Furthermore, PET imaging\nwith the TSPO-specific radioligand [<sup>18</sup>F]FEPPA revealed\nthat PB131 significantly suppressed neuroinflammation in the ischemic\nbrain. These findings provide insights into the dynamic changes of\nHDAC6 in ischemic stroke and the potential of HDAC6 inhibitors as\nnovel therapeutic agents for this condition.