Pharmacometabolomic Study of Pulmonaria officinalis Polyphenol Extracts Reveals Neuroprotective Effects in LPS-Induced Alzheimer’s Disease through AChE Inhibition and TLR4 Modulation

Background Acetylcholinesterase (AChE) and toll-like receptor 4 (TLR4) inhibitions are used in neurodegenerative disorder treatment strategies, including Alzheimer’s disease (AD), a major cause of mortality and morbidity worldwide. Pulmonaria officinalis (PO; lungwort) has in vitro antioxidant, anti-inflammatory, and AChE inhibition. Their biological property is lacking in vivo literature.” Methods This study aimed to characterize the metabolomic profile and antioxidant activities of different PO fractions, specifically butanol (BuOH) and ethyl acetate (EtOAc), using colorimetric, spectrophotometric, and chromatographic methods. In addition, studying their neuroprotective effect in lipopolysaccharide (LPS)-triggered Alzheimer’s in mice. The qualitative phytochemical analysis revealed that the fractions of PO contain alkaloids, glycosides, phenols, flavonoids, terpenoids, and tannins. Results The lungwort plant was identified 36 active compounds in the two fractions. Extractions of EtOAc and BuOH lungworts were rich in polyphenolic compounds identified by HPLC and HPLC-mass spectrometry (HPLC-MS) analysis. In regard to phenolic, tannin, and flavonoid content, PO showed that the EtOAc and BuOH fractions were more significant than the other fractions. Moreover, this fraction exhibited more potent antioxidant activity than other fractions in DPPH• ⁻ and ABTS• ⁺ assays. In the in vivo experiment, mice were randomly divided into four groups, each comprising eight animals. Group I was designated as the normal control, whereas Group II was administered lipopolysaccharide (LPS; 250 µg/kg, intraperitoneally).Groups III and IV were administered PO butanol and ethyl acetate fractions (400 mg/kg, orally) for seven consecutive days along with LPS treatment. PO fractions ameliorated cognitive dysfunction elevated the memory via suppressing AChE and amyloid beta, inhibited neuroinflammatory cytokines Interleukin 1 beta (IL-1β) and TLR4, and alleviated neurodegeneration. Conclusions P. officinalis , for the first time, was studied in vivo and was proved to have a neuroprotective effect against AD through the presence of catechin, methyl gallate, astragalin, nicotiflorin, quercetin 3-O-β-glucoside, cinnamic acid, catechin, daidzein, kaempferol 3-O-(6-malonyl-glucoside) and epigallocatechin. PO holds potential for future pharmacological research and is a promising candidate for therapeutic applications in treating various chronic and infectious diseases.