Gardenia jasminoides J. Ellis extract GJ-4 attenuates hyperlipidemic vascular dementia in rats via regulating PPAR-γ-mediated microglial polarization

Abstract

Background: GJ-4 is extracted from Gardenia jasminoides J. Ellis (Fructus Gardenia) with crocin composition and has been demonstrated to improve memory deficits in several dementia models in our previous studies.Objective: This study aimed to evaluate the effects of GJ-4 on hyperlipidemic vascular dementia (VD) and explore the underlying mechanisms. Design: In the current study, we employed a chronic hyperlipidemic VD rat model by permanent bilateral common carotid arteries occlusion (2-VO) based on high-fat diet (HFD), which is an ideal model to mimic the clinical pathogenesis of human VD. Results: Our results showed that GJ-4 could significantly reduce serum lipids level and improve cerebral blood flow in hyperlipidemic VD rats. Additionally, treatment with GJ-4 remarkedly ameliorated memory impairment and alleviated neuronal injury. Mechanistic investigation revealed that the neuroprotective effects of GJ-4 might be attributed to the inhibition of microglia-mediated neuro-inflammation via regulating the M1/M2 polarization. Our data further illustrated that GJ-4 could regulate the phenotype of microglia through activating the peroxisome proliferator-activated receptor-γ (PPAR-γ) and subsequently inhibited nuclear factor-κB (NF-κB) nuclear translocation and increased CCAAT/enhancer-binding protein β (C/EBPβ) expression. Conclusion:Our results implied that GJ-4 might be a promising drug to improve VD through the regulation of microglial M1/M2 polarization and the subsequent inhibition of neuro-inflammation.Popular scientific summary 1. Gardenia jasminoides J. Ellis extract GJ-4 remarkedly improved dyslipidemia and memory disorders in hyperlipidemic vascular dementia (VD) rats. 2. The study showed that GJ-4 significantly inhibited microglial activation and modified microglial M1/M2 polarization by regulating PPAR-γ signaling pathway. 3. GJ-4 might be a promising drug to improve VD through the regulation of microglial M1/M2 polarization and the subsequent inhibition of neuro-inflammation.

Neuroprotective mechanism of human umbilical cord mesenchymal stem cell‐derived extracellular vesicles improving the phenotype polarization of microglia via the PI3K/AKT/Nrf2 pathway in vascular dementia

“…Targeting M1/M2 polarization balance to modulate neuroinflammation is beneficial for a variety of neurodegenerative diseases including VaD (Liu et al., 2022). Interactions between inflammatory processes and aberrant oxidative stress are found in VaD, and these hazard factors cause blood–brain barrier failure and endothelial damage (Iadecola, 2013).…”

“…Cerebral hypoperfusion is a principal risk factor for VaD, and during the recovery phase of cerebral ischemia, converting M1 microglia into the M2 phenotype can reduce inflammatory responses and stimulate neurobehavioral property recovery (Luo et al., 2018). GJ‐4 improves VaD by regulating the M1/M2 polarization of microglia and the subsequent repression of neuroinflammation (Liu et al., 2022). The phosphatidylinositol‐3‐kinase (PI3K)/protein kinase B (AKT) pathway is a crucial modulator of cell proliferation and survival, which is expressed widely in the CNS and is a well‐known pathway involved in neuronal survival promotion (Wang et al., 2021).…”

Recent evaluation about inflammatory mechanisms in nonalcoholic fatty liver disease

“…However, in a mouse model of NASH, a diet fed polyunsaturated fatty acids activates PPARα signaling and inhibits hepatic de novo fat synthesis, but does not prevent steatohepatitis ( Ishida et al, 2021 ), which is likely to high levels of hepatic lipid peroxidation in this model abolished the protective effect of PPARα activation and resulted in lipotoxic hepatocyte injury and inflammatory cells recruitment. Similar to PPARα, PPARγ activation attenuates inflammation through multiple mechanisms, including decreased NF-κB activity and decreased TNF-α and IL-1β synthesis in monocytes and macrophages ( Liu et al, 2022 ). As a master regulator of macrophage polarization, activation of PPARγ promotes the transition of macrophages from an M1-dominant phenotype to an M2 phenotype, thereby attenuating inflammation in experimental NASH ( Luo et al, 2017 ; Valenzuela et al, 2017 ).…”