The piperine derivative HJ105 inhibits Aβ1–42-induced neuroinflammation and oxidative damage via the Keap1-Nrf2-TXNIP axis

Piperine is a great lead compound, as a phytopharmaceutical with reported neuroprotective effects in neurodegenerative diseases. HJ105, a piperine derivative with high affinity to Keap1 receptor, attracts increasing attention in Alzheimer's disease (AD) treatment. This work mainly aimed to study HJ105’s therapeutic effects on Aβ1–42-associated AD and the underpinning mechanisms. In the in vivo part, a rat model of AD was established by bilateral intra-hippocampal administration of aggregated Aβ1–42, followed by a month of intragastric HJ105 or donepezil administration. Spatial and learning memories were detected by the Morris water maze assay, passive avoidance learning as well as Y-maze test. The morphology of hippocampal neurons was assessed by hematoxylin-eosin (H&E) staining. In addition, the amounts of the IL-1β and TNF-α were obtained with specific ELISA kits. More importantly, apoptosis-related proteins and factors involved in Nrf2/TXNIP/NLPR3 pathways were detected by Western blot, while the interaction between Keap1 and Nrf2 was assessed by co-immunoprecipitation. In the in vitro part, human neuroblastoma (SH-SY5Y) cells were applied to evaluate the role of HJ105 on Aβ1–42-induced neuronal damage. Treatment of HJ105 not only reversed memory impairment, but also protected neurons in the hippocampus by inhibiting Bax/Bcl2 ratio increase. HJ105 decreased TXNIP expression, suppressing NLRP3 inflammasome activation in the hippocampus, which in turn counteracted the upregulation of IL-1β and TNF-α. Notably, HJ105 exerted an inhibitory effect on Keap1-Nrf2 interaction and upregulated nuclear Nrf2, which conversely increased the expression levels of superoxide dismutase, catalase and glutathione peroxidase and downregulated malondialdehyde. Additionally, neurotoxicity induced by Aβ1–42 in SH-SY5Y cells was alleviated by HJ105. Overall, HJ105 exerts neuroprotective effects in SH-SY5Y cells induced by Aβ1–42 as well as in experimental rats with AD by decreasing apoptosis, oxidative stress and neuroinflammation, partly via suppression of Keap1-Nrf2 complex generation. HJ105 might represent a promising compound for AD treatment.