Untargeted Metabolomic and Phytochemical Profiling of Berberis crataegina DC. Plant Parts: Antidiabetic Potential and Cytoprotection in High-Glucose-Exposed SH-SY5Y Cells

Background/Objectives: Berberis species are recognized for their ethnomedicinal importance and phytochemical richness associated with antidiabetic activity. Although B. crataegina is widely distributed in the Turkish flora and has a history of traditional use, its phytochemical properties and biological activities remain less extensively investigated than those of other Berberis species. This study aimed to comparatively evaluate the phytochemical profiles, in vitro antidiabetic potential, and cytoprotective effects of extracts prepared from different parts of B. crataegina in a high-glucose-induced SH-SY5Y cell-based model of diabetic neuropathy. Methods: Crude hydroethanolic extracts (70% ethanol) were prepared from the leaves, flowers, shoots, roots, and fresh fruits of B. crataegina collected from Kızılcahamam, Ankara, Türkiye. The total phenolic and flavonoid contents, antioxidant capacities and α-glucosidase inhibitory activities of leaf, flower, shoot, root, and fruit extracts were determined. The cytoprotective effects of the crude extracts were evaluated in a high-glucose-induced SH-SY5Y cell model. The metabolomic profiles of the extracts were comparatively analyzed using liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). The most active fruit extract was fractionated by reversed-phase vacuum liquid chromatography (RP-VLC), and the phytochemical contents and α-glucosidase inhibitory activities of the fractions were evaluated. The major phenolic compounds in the most active fruit extract were quantitatively determined using high-performance liquid chromatography–diode array detection (HPLC-DAD). The relationships between metabolites and biological activities were investigated through correlation analysis. Results: The fruit extract was distinguished by its α-glucosidase inhibitory activity, total phenolic content, antioxidant capacity, and cytoprotective effect in the high-glucose-induced SH-SY5Y cell model. It showed no marked cytotoxicity at concentrations ranging from 25 to 400 µg/mL and, at 25 µg/mL, attenuated the high-glucose-induced reduction in cell viability, restoring viability to a level close to that of the normal control. Untargeted metabolomic analysis identified 191 metabolites detected in at least two crude extracts, while the metabolites detected exclusively in the fruit extract were predominantly flavonoids and flavonoid glycosides. Fractionation showed that α-glucosidase inhibitory activity was mainly concentrated in the medium-polarity fractions; however, none of the fractions reached the activity level of the crude extract. Chlorogenic acid, rutin, caffeic acid, protocatechuic acid, quercetin, and quercetin-3-O-glucoside were detected and quantified in the fruit extract by HPLC-DAD. Correlation analysis indicated that the observed biological activities may be associated with phenolic acids, flavonoids, and other polyphenolic metabolites. Conclusions: The fruit extract of B. crataegina showed promising α-glucosidase inhibitory activity and cytoprotective effects in the high-glucose-induced SH-SY5Y cell model. The findings suggest that these effects may arise from the combined contribution of multiple constituents within a polyphenolic matrix rather than from a single compound; however, synergistic interactions were not experimentally demonstrated. These results support further evaluation of the fruit extract through mechanistic, in vivo, and standardization studies.