p-hydroxy benzaldehyde revitalizes the microenvironment of peri-infarct cortex in rats after cerebral ischemia-reperfusion

The formation of glial scar around the ischemic core following cerebral blood interruption exerts a protective effect in the subacute phase but impedes neurorepair in the chronic phase. Therefore, the present study aimed to explore whether p-hydroxy benzaldehyde (p-HBA), a phenolic compound isolated from Gastrodia elata Blume, can cut the Gordian knot of glial scar and promote brain repair after cerebral ischemia.The effects of p-HBA on neurorepair were evaluated using a rat model of transient middle cerebral artery occlusion (tMCAO). The motor functions were evaluated by neurobehavioral tests, the pathophysiological processes in the peri-infarct cortex (PIC) were detected by viral-based lineage tracking or immunofluorescence staining, and the putative signaling pathway was analyzed by western blot.Administration of p-HBA in the acute stage after stroke onset alleviated the motor impairment in tMCAO rats in a time-dependent manner. The corresponding cellular events were inhibition of astrogliosis, facilitating the conversion of reactive astrocytes (RAs) into neurons, and prompting angiogenesis in PIC, thereby protecting the structure of the neurovascular unit (NVU). One of the underlying molecular mechanisms is the activation of the neurogenic switch of the Wnt/β-catenin signaling pathway. Notably, p-HBA only promotes astrocyte-to-neuron conversion in the PIC, and only partial RAs were converted to neurons. This pattern of conversion ensures that the brain structure remains unaltered, and the beneficial role of glial scarring is preserved during the subacute phase after ischemia.These results provided a potential approach to address the dilemma of glial scarring after brain injury, i.e., the pharmacological promotion of astrocyte-to-neuron conversion in the PIC without interfering with normal brain tissue, which mitigates but does not eliminate the glial scar. Subsequently, the neuron rescue-unfriendly environment is switched to a beneficial reconstruction milieu in PIC, which is conducive to neurorepair. Moreover, p-HBA could be a candidate for pharmacological intervention.