VRT-043198 Ameliorates Surgery-Induced Neurocognitive Disorders by Restoring the NGF and BNDF Expression in Aged Mice

Abstract

Background Perioperative neurocognitive disorders (PND) are common surgical complications in the elderly. Pyroptosis-associated inflammation has been suggested to participate in a series of neurocognitive diseases, including Alzheimer’s disease. Given that VRT-043198 can reportedly inhibit caspase-1-induced pyroptosis, this study sought to determine whether VRT-043198 reduced PND in a mouse model following abdominal exploratory laparotomy. Methods 20-month-old male C57/BL mice were used to establish an abdominal exploratory laparotomy (AEL) model of PND. VRT-043198 (1, 10 and 100 mg/kg) was administered intraperitoneally immediately after surgery. Thirty days post-surgery, the mice were evaluated in the Morris water maze test. Their number of neurons, neurotrophin nerve growth factor (NGF) levels and brain-derived neurotrophic factor (BDNF) were measured. In the hippocampus, A1-type astrocytes and M1-type microglia were assessed using an immunofluorescence assay and Western blot, respectively. Caspase-1 activity, IL-1β, IL-18, and PPAR-γ were also measured 24h after surgery. Results VRT-043198 administration increased the time to cross the platform and increased the ratio of distance and time in the targeted quadrant after surgery. Furthermore, it was found that VRT-043198 restored neuronal amount, increased NGF and BDNF and decreased the number of A1-type astrocytes and M1-type microglia. VRT-043198 also attenuated caspase-1 activity, downregulated IL-1β and IL-18, but increased PPAR-γ 24h post-surgery. Conclusion VRT-043198 improved PND in aged mice after abdominal exploratory laparotomy by restoring the NGF and BNDF expression. These results indicate that VRT-043198 may be a potential therapy for PND.

Strain hypothesis and additional evidence of the GluN3A deficiency‐mediated pathogenesis of Alzheimer's disease

“…In their Figure 1C and 1D, the percentage of targeted quadrant occupancy is 30% to 40% with WT mice of 12-17 months old, which was worse than even much older C57BL/6 mice (∼20 months old) that normally show 40% to 60% occupancy. 4,5 These discrepancies indicate abnormal memory of Verhaegheet al's WT mice.…”

To re-examine the intersection of microglial activation and neuroinflammation in neurodegenerative diseases from the perspective of pyroptosis

“…NGF is a growth factor with neuroprotective effects and can promote neuronal growth, differentiation, and survival. Studies have found that microglia can release NGF in the damaged nervous system environment, thereby protecting neurons from pyroptosis (Tang et al, 2022). In addition, NGF can regulate microglial activation and polarization, inducing microglia to transform into a phenotype with anti-inflammatory and neuroprotective functions (Rizzi et al, 2018).…”

“…BDNF is another important neuroprotective factor that has protective, growth, and differentiation effects on neurons. Studies have shown that microglia can release BDNF, protecting neurons from inflammatory damage and oxidative stress-induced pyroptosis (Tang et al, 2022). In addition, BDNF can promote neuronal survival and resistance to cell death signals by regulating signaling pathways such as Akt and MAPK (Colucci-D'Amato et al, 2020).…”