Dl-3-n-Butylphthalide Promotes Remyelination and Suppresses Inflammation by Regulating AMPK/SIRT1 and STAT3/NF-κB Signaling in Chronic Cerebral Hypoperfusion

Abstract

Demyelination in vascular dementia (VD) is partly attributable to inflammation induced by chronic cerebral hypoperfusion (CCH). Remyelination contributes to the recovery of cognitive impairment by inducing the proliferation and differentiation of oligodendrocyte progenitor cells. It was previously reported that Dl-3-n-butylphthalide (NBP) promotes cognitive improvement. However, whether NBP can stimulate remyelination and suppress inflammation after CCH remains unclear. To answer this question, the present study investigated the effects of NBP on remyelination in a rat model of CCH established by bilateral carotid artery occlusion. Functional recovery was evaluated with the Morris water maze (MWM) test, and myelin integrity, regeneration of mature oligodendrocytes, and inhibition of astrocyte proliferation were assessed by immunohistochemistry and histologic analysis. Additionally, activation of 5 AMP-activated protein kinase (AMPK)/Sirtuin (SIRT)1 and Signal transducer and activator of transcription (STAT)3/nuclear factor (NF)-κB signaling pathways was evaluated by western blotting. The results showed that NBP treatment improved memory and learning performance in CCH rats, which was accompanied by increased myelin integrity and oligodendrocyte regeneration, and reduced astrocyte proliferation and inflammation. Additionally, NBP induced the activation of AMPK/SIRT1 signaling while inhibiting the STAT3/NF-κB pathway. These results indicate that NBP alleviates cognitive impairment following CCH by promoting remyelination and suppressing inflammation via modulation of AMPK/SIRT1 and STAT3/NF-κB signaling.

Clemastine Ameliorates Perioperative Neurocognitive Disorder in Aged Mice Caused by Anesthesia and Surgery

“…Recent studies have shown that enhanced remyelination reverses cognitive dysfunction in a murine model of Alzheimer's disease (Chen et al, 2021a). This finding was also confirmed in the chronic cerebral hypoperfusion rat model (Li et al, 2020). In this study, the down-regulation of MBP caused by anesthetic and surgical factors in the hippocampus of aged mice suggesting the appearance of demyelination.…”

Neuroprotective Effects of Theobromine in Permanent Bilateral Common Carotid Artery Occlusion Rat Model of Cerebral Hypoperfusion

“…Brain insult in the form of traumatic brain injury (TBI), CH, excitotoxic pathways, and several neurotoxins (free radicals) (Negre-Salvayre et al, 2008) can galvanize the NF-κB action resulting in an upsurge in cell degrading enzymes (e.g., matrix metalloproteinases), cytokines (e.g., IL-6, C-reactive protein), and in ammatory molecules (e.g., selectins, integrins, iNOS, cyclooxygenase-2) (Liu et al, 2017;Duncombe et al, 2017). In harmony with previous conclusions (Li et al, 2020), CH signi cantly enhanced the brain in the existing pre-clinical investigation. Treatment with theobromine (100 mg/kg) attenuated the CH-induced brain NF-κB levels that might have contributed to lowering in ammatory cytokines (TNF-α, IL-1β, IL-6).…”

Epac1 Requires AMPK Phosphorylation to Regulate HMGB1 in the Retinal Vasculature

“… 20 Similar results have been found in vascular dementia. 21 Further linking AMPK and our previous work on HMGB1 regulation, we found novel information regarding IGFBP-3 and AMPK in RECs. Our findings agree with studies involving 3T3 cells and mice on a high-fat diet that found that Lactobacillus plantarum (Ln4) could increase both IGFBP-3 levels and AMPK actions.…”