Attenuating Effect of Geijigadaehwang-tang in Aggression Animal Model by Isolation Rearing Based on Experimental Study and Network Pharmacology

Background: Social isolation reportedly induces excessive aggression and impairs hippocampal neurogenesis. In this study, we investigated whether Geijigadaehwang-tang (GDT), a traditional herbal formulation containing Rhei Radix et Rhizoma and Cinnamomi Ramulus, could ameliorate such behavioral and neurogenic deficits. Methods and Results: We assessed aggressive behaviors in socially isolated mice. Isolation markedly increased aggressive responses compared to sham controls. GDT treatment significantly reduced the number of attacks on days 3 and 7 and lowered both the attack duration and biting frequency. Immunohistochemical analysis of the dentate gyrus revealed that the isolation substantially reduced DCX-positive immature neuron numbers, whereas GDT administration partially restored these counts. Network pharmacology profiling has identified numerous GDT-associated compounds that interact with neuroendocrine and neurotransmission-related targets, including the dopaminergic, adrenergic, GABAergic, and CRH receptor pathways. Enrichment analysis high-lighted neuroactive ligand-receptor interaction, PI3K-Akt signaling, calcium signaling, apoptosis regulation, and steroid hormone biosynthesis as major functional clusters, supporting the role of GDT in neural plasticity and stress-related behavior. Conclusions: GDT attenuated isolation-induced aggression and partially rescued impaired hippocampal neurogenesis. Integrated network analysis suggests that its multimodal actions might involve the modulation of neurotransmitter systems, neuroendocrine pathways, and pro-survival signaling cascades. GDT represents a promising multitarget therapeutic candidate for stress-related behavioral dysregulation and neurogenic impairment.