Dl-3-n-Butylphthalide Improves Neuroinflammation in Mice with Repeated Cerebral Ischemia-Reperfusion Injury through the Nrf2-Mediated Antioxidant Response and TLR4/MyD88/NF-κB Signaling Pathway.

Abstract

Increasing evidence shows that oxidative stress and neuroinflammation play a crucial role in the pathology of vascular dementia (VD). Previously, we have found that Dl-3-n-butylphthalide (NBP) has antioxidant and anti-inflammatory activities in VD, whereas little is known about its mechanism. Therefore, the objective of our study was to explore the contribution of nuclear factor erythroid-2 related factor 2 (Nrf2) to NBP and its effects on anti-inflammatory activity in a mouse model of VD. Our studies revealed that NBP could effectively mitigate cognitive deficits, neuron cell loss, and apoptosis in mice subjected to repeated cerebral ischemia-reperfusion (RCIR). Additionally, NBP promoted both the expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in hippocampus tissue. NBP exhibited antioxidant activity by enhancing Nrf2 nuclear accumulation, increasing HO-1 and NQO1 expression, enhancing SOD activity, and inhibiting RCIR-induced MDA and 8-iso PGF2α generation in the hippocampus. NBP also significantly inhibited TLR4/MyD88/NF-κB signaling and suppressed microglial proliferation and the production of proinflammatory mediators in RCIR mice. Importantly, the antioxidant, antineuroinflammatory, and neuroprotective effects of NBP above were abolished by Nrf2 knockout. Collectively, these results indicated the effects of NBP on neuroinflammation were strongly associated with the Nrf2 pathway. Modulation of TLR4/MyD88/NF-κB pathway by Nrf2 is involved in the neuroprotective effect of NBP against VD induced by RCIR injury. With antioxidant and anti-neuroinflammatory properties, NBP could be a promising drug candidate for the prevention and/or treatment of VD and other neuroinflammatory disorders.

• Authors: Yaran Gao, Ming Hu, Xiaoli Niu, Meixi Li, Lili Xu, Yining Xiao, Jiawei Zhang, Hebo Wang, Litao Li, Bao Chu, Peiyuan Lv
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2022 Pg. 8652741 ( 2022) ISSN: 1942-0994 [Electronic] United States
• PMID: 35615581 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Yaran Gao et al.

Chemical References

• 3-n-butylphthalide
• Antioxidants
• Benzofurans
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Neuroprotective Agents
• NF-E2-Related Factor 2
• NF-kappa B
• Tlr4 protein, mouse
• Toll-Like Receptor 4

Topics

• Animals
• Mice
• Antioxidants (pharmacology)
• Benzofurans (pharmacology)
• Brain Ischemia (pathology)
• Dementia, Vascular (drug therapy)
• Disease Models, Animal
• Myeloid Differentiation Factor 88 (metabolism)
• Neuroinflammatory Diseases (metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• NF-E2-Related Factor 2 (metabolism)
• NF-kappa B (metabolism)
• Reperfusion
• Reperfusion Injury (drug therapy)
• Signal Transduction
• Toll-Like Receptor 4 (metabolism)