Macelignan mitigates oxidative and inflammatory damage in hypoxic neurons through PPARγ-dependent pathways:...

Oxidative injury under hypoxic conditions constitutes an important pathological factor in the progression of neuronal loss in Alzheimer's disease (AD). Macelignan, a natural lignan from Myristica fragrans, possesses antioxidant and anti-inflammatory activities, yet its neuroprotective mechanisms remain unclear. In this study, we aimed to elucidate the molecular targets and signaling pathways by which macelignan protects neurons from hypoxia-induced oxidative damage. Neuronal damage was modeled in vitro in HT22 murine hippocampal neurons using cobalt (II) chloride (CoCl2) or conditioned medium from CoCl2-activated BV2 microglia, and in vivo in Wistar rats subjected to bilateral common carotid artery occlusion (BCCAo) to mimic hypoxic injury. We found that macelignan significantly improved neuronal viability, attenuated apoptosis, reduced intracellular and mitochondrial reactive oxygen species (ROS) levels, and preserved mitochondrial membrane potential(ΔΨm). Peroxisome proliferator-activated receptor-γ (PPARγ), a ligand-activated transcription factor regulating oxidative metabolism and limiting neuroinflammation, was identified via molecular docking as a potential target of macelignan. Functional assays demonstrated that macelignan acts as a PPARγ agonist, activating the Nrf2/HO-1 antioxidant pathway and suppressing NF-κB-mediated inflammation. These effects were diminished by the PPARγ antagonist GW9662. In BV2 microglia, macelignan modulated polarization toward anti-inflammatory phenotypes, reduced pro-inflammatory cytokine release, and mitigated secondary neuronal injury in HT22 cells. In BCCAo rats, macelignan alleviated hippocampal pathology and improved spatial and recognition memory. In summary, macelignan mitigates hypoxia-induced neuronal injury by targeting PPARγ, leading to coordinated activation of antioxidant defenses and suppression of neuroinflammation. These results provide new insight into the therapeutic potential of macelignan for hypoxia-associated AD.