Prioritizing Nrf2/HO-1-Mediated Intrinsic Antioxidant Upregulation: The Foremost Neuroprotective Mechanism of Melittin in a Scopolamine-Induced Animal Model of Neural Stress, Preceding Anti- Inflammatory Effects

Abstract

Abstract Oxidative stress is a key driver of neurodegeneration, and the Nrf2/HO-1 pathway serves as a primary defense mechanism against this stress. Melittin, derived from bee venom, has shown promise in mitigating cognitive decline in mild cognitive impairment. This study for the first time investigates whether melittin can revive the compromised Nrf2/HO-1 pathway in neurodegenerative animals’ brains and whether this pathway is the initial target of melittin's action. In a scopolamine-induced neurodegeneration model in mice, melittin administration led to its significant accumulation in the hippocampus, indicating its direct interaction with neural tissues. Comprehensive analysis revealed that melittin's earliest effect was the restoration of the Nrf2/HO-1 system, reinforcing its role as an antioxidant defense against oxidative stress. In vitro studies with mouse hippocampus HT22 cells showed that melittin triggered the translocation of Nrf2 from the cytosol to the nucleus. Notably, the most significant inhibition of melittin's protective effects was observed with an HO-1 inhibitor, suggesting a close association between melittin's action and the HO-1 pathway. In summary, this study demonstrates for the first time melittin's ability to upregulate the compromised Nrf2/HO-1 pathway in neurodegenerative animals, with evidence pointing to its primary action through this pathway. The direct effect of melittin on the Keap-1/Nrf2/HO-1 pathway were further solidified with invitro evidences. These findings enhance our understanding of melittin's neuroprotective mechanisms and its potential as a therapeutic agent for neurodegenerative disorders, warranting further clinical exploration. This evidence strongly corroborates the prevailing trend of harnessing the activation of cellular antioxidation as a potent therapeutic strategy against neurodegeneration.