Divergent neurovascular protection: Histone deacetylase inhibition preserves neuronal ultrastructure while hypoxia-inducible factor activation maintains vascular integrity after ischemic stroke.

Ischemic stroke triggers severe disruption of the neurovascular unit (NVU), with pathology evident at the ultrastructural level. Hypoxia-inducible factor-1α (HIF-1α) activators such as Prolyl hydroxylase inhibitors e.g., dimethyloxalylglycine (DMOG) and histone deacetylase inhibitors (e.g., Apicidin) are promising therapeutic candidates, but their specific impact on subcellular architecture remains poorly characterized. Endothelin-1 (ET-1) model was used to induce ischemic stroke. Animals were treated intraperitoneally with either DMOG (40 mg/kg), Apicidin (1 mg/kg), or vehicle at reperfusion onset. After 7 days, behavioral analysis was conducted, Cytochrome-C immunohistochemistry and cortical tissue was processed for transmission electron microscopy (TEM) to assess ultrastructural integrity. Severe ultrastructural pathology, such as pyknotic neuronal soma, broken axons, enlarged mitochondria, synaptic disintegration, and reactive microglia and oligodendrocytes, was seen in model animals. With relatively slight improvements in synaptic and glial function and ongoing somatic, axonal, and mitochondrial damage, DMOG therapy offered little protection for neurons. With intact soma and axons, decreased mitochondrial swelling, increased synaptic vesicle density, and enhanced oligodendrocyte and microglial morphology, Apicidin therapy, on the other hand, showed strong neuronal preservation. While Apicidin is more effective at maintaining the integrity of neurons and synapses, DMOG mainly stabilizes the vascular compartment. These results imply that better neuroprotection may be provided by combination therapy that targets both vascular and neuronal components.