An Aqueous Extract of Herbal Medicine ALWPs Enhances Cognitive Performance and Inhibits LPS-Induced Neuroinflammation via FAK/NF-κB Signaling Pathways

Abstract

Recent studies have shown that Liuwei Dihuang pills (LWPs) can positively affect learning, memory and neurogenesis. However, the underlying molecular mechanisms are not understood. In the present study, we developed ALWPs, a mixture of Antler and LWPs, and investigated whether ALWPs can affect neuroinflammatory responses. We found that ALWPs (500 mg/ml) inhibited lipopolysaccharide (LPS)-induced proinflammatory cytokine IL-1β mRNA levels in BV2 microglial cells but not primary astrocytes. ALWPs significantly reduced LPS-induced cell-surface levels of TLR4 to alter neuroinflammation. An examination of the molecular mechanisms by which ALWPs regulate the LPS-induced proinflammatory response revealed that ALWPs significantly downregulated LPS-induced levels of FAK phosphorylation, suggesting that ALWPs modulate FAK signaling to alter LPS-induced IL-1β levels. In addition, treatment with ALWPs followed by LPS resulted in decreased levels of the transcription factor NF-κB in the nucleus compared with LPS alone. Moreover, ALWPs significantly suppressed LPS-induced BV2 microglial cell migration. To examine whether ALWPs modulate learning and memory in vivo, wild-type C57BL/6J mice were orally administered ALWPs (200 mg/kg) or PBS daily for 3 days, intraperitoneally injected (i.p.) with LPS (250 μg/kg) or PBS, and assessed in Y maze and NOR tests. We observed that oral administration of ALWPs to LPS-injected wild-type C57BL/6J mice significantly rescued short- and long-term memory. More importantly, oral administration of ALWPs to LPS-injected wild-type C57BL/6J mice significantly reduced microglial activation in the hippocampus and cortex. Taken together, our results suggest that ALWPs can suppress neuroinflammation-associated cognitive deficits and that ALWPs have potential as a drug for neuroinflammation/neurodegeneration-related diseases, including Alzheimer’s disease (AD).

Inflammatory response and oxidative stress attenuated by sulfiredoxin‑1 in neuron‑like cells depends on nuclear factor erythroid‑2‑related factor 2

“…However, to the best of our knowledge, the definite role of SRX1 in SCI has remained elusive. LPS, which is composed of lipids and polysaccharides, is a constituent of the outer cell wall of Gram-negative bacteria and typically induces oxidative stress and an inflammatory response in cells (35,36). In the present study, the mRNA and protein expression levels of SRX1 were downregulated in PC12 cells exposed to 0.625-5 µg/ml LPS in a dose-dependent manner.…”

The Involvement of Renin-Angiotensin System in Lipopolysaccharide-Induced Behavioral Changes, Neuroinflammation, and Disturbed Insulin Signaling

“…NF-κB signaling plays a fundamental role in response to inflammatory activator such as LPS (Lee et al, 2018). To further explore the mechanisms, we then analyzed the essential members of NF-κB family (Figure 5A).…”

ALWPs Improve Cognitive Function and Regulate Aβ Plaque and Tau Hyperphosphorylation in a Mouse Model of Alzheimer’s Disease

“…After adaptation for 1 week, the mice were randomly divided into three groups: Y-maze: (1) control (PBS, n = 13); (2) scopolamine (SCO, 1 mg/kg; n = 13); and (3) ALWPs (200 mg/kg) + SCO (1 mg/kg; n = 14); NOR: (1) control (PBS, n = 12); (2) SCO (1 mg/kg; n = 12); and (3) ALWPs (200 mg/kg) + SCO (1 mg/kg; n = 13). The doses of ALWPs were determined based on our previous report (Lee et al, 2018). The mice were orally administered PBS or ALWPs (200 mg/kg) daily for 11 days (days 1–11).…”

“…Y-maze and NOR tests were performed to assess cognitive function as described previously (Lee et al, 2018). All experiments were performed under low red light (4–5 lux).…”

“…Based on the literature on LWPs and antler, we hypothesized that ALWPs containing antler and LWPs might have synergistic effects on LPS-induced neuroinflammation and LPS-induced memory impairment. Indeed, we recently demonstrated that ALWPs have additive effects on LPS-mediated neuroinflammatory responses compared with the individual components of ALWPs (Lee et al, 2018). In addition, we found that oral administration of ALWPs improved short-term and long-term memory in LPS-injected wild-type (WT) mice (Lee et al, 2018).…”