Kanlayaprasit S.Parnich W.Jantheang T.Lertpeerapan P.Panjabud P.Kasitipradit K.Poolcharoen C.Saeliw T.Muangnoi C.Plaingam W.Charoenkiatkul S.Hu V.W.Tencomnao T.Sarachana T.Sukprasansap M.Mahidol University2026-05-162026-05-162026-04-10Nutrients Vol.18 No.8 (2026)https://repository.li.mahidol.ac.th/handle/123456789/116766Background/Objectives: Neuritogenesis and synaptogenesis support learning and cognitive function, and hippocampal neurons play central roles in these processes. Cleistocalyx nervosum var. paniala (CNP), a Southeast Asian berry, has reported neuroprotective activities, but its direct effects on hippocampal neurons remain unclear. We investigated whether CNP extract modulates hippocampal neuronal transcriptomes, neuritogenesis, and synaptogenesis. Methods: Primary hippocampal neurons isolated from male and female Wistar rat pups were treated with CNP extract in vitro. Cytotoxicity was assessed to define non-cytotoxic concentrations. Transcriptomic responses were profiled by RNA sequencing and validated by RT-qPCR. Neuritogenesis was quantified by neurite morphology and Sholl analysis. Synaptogenesis was evaluated by synaptic immunocytochemistry. Molecular docking of cyanidin-3-glucoside (C3G) and resveratrol was used to generate mechanistic hypotheses. Results: At 0.1-10 µg/mL, CNP was non-cytotoxic, whereas a 100 µg/mL dose reduced viability; therefore, 10 µg/mL was used in subsequent experiments. Exploratory RNA-seq profiling identified thousands of differentially expressed genes enriched in synapse- and neurite-related pathways, including synaptogenesis signaling, axon guidance, and neuritogenesis. RT-qPCR showed upregulation of Igf1 in males and Glul in females, with sex-dependent modulation of Bdnf and Cask. CNP increased neurite length, branching, and Sholl complexity in both sexes, with a more pronounced effect in males. A male-biased effect was also observed in synapse-related marker colocalization, with increased Syn1-Psd95 colocalization detected in males. Docking suggested plausible interactions of C3G and resveratrol with regulators such as MYC, TP53, and CREB1. Conclusions: CNP extract alters transcriptional networks and enhances neurite outgrowth in primary hippocampal neurons in a sex-dependent manner, with male-biased effects on Syn1-Psd95 colocalization. These findings support further dose-response, mechanistic, and sex-stratified in vivo studies to evaluate its neurobiological potential.NursingAgricultural and Biological SciencesArticleSCOPUS10.3390/nu180812002-s2.0-1050381259022072664342075012