Kamikihito and Mesenchymal Stem Cells synergistically reverse stress-induced socio-affective deficits in a rat TRD model

Patients with Treatment-Resistant Depression (TRD) experience persistent socio-affective deficits, including social withdrawal and empathic impairment, which respond poorly to conventional monoaminergic antidepressants. This clinical gap highlights the need for novel therapeutic strategies targeting underlying mechanisms beyond monoamines. Emerging evidence points to altered immune signaling, synaptic plasticity, and oxytocinergic dysfunction in TRD pathogenesis. This study investigates the potential of Kamikihito (KMK) and Mesenchymal Stem Cells (MSCs) to modulate these pathways and alleviate TRD-like symptoms.

Researchers utilized a two-hit rat model of TRD, involving prenatal ethanol exposure (D10-D14) followed by adolescent corticosterone administration (weaning to PND 42). In late adolescence, rats were treated with either the traditional Japanese herbal formula Kamikihito (KMK), intravenous Mesenchymal Stem Cells (MSCs), or a combination of both, compared to a vehicle-treated control group. At nine weeks of age, primary endpoints included assessments of social interaction and rescue-task performance. Molecular analyses involved rt-qPCR to measure gene expression of VGLUT1 and VGAT in the Anterior Cingulate Cortex (ACC), and OXTR and Cd38 in the paraventricular nucleus (PVN).

Stressed saline-treated rats exhibited significant reductions in both social and empathic behaviors, confirming the TRD-like phenotype. While MSCs alone produced modest improvements in these deficits, Kamikihito (KMK), whether administered alone or in combination with MSCs, significantly restored rescue-task performance. The combination group demonstrated the highest composite behavioral scores, suggesting synergistic effects. > All active treatments, including KMK, MSCs, and their combination, tended to normalize the ACC excitatory/inhibitory balance, as reflected by the VGLUT1/VGAT ratio, compared to stressed controls. Furthermore, these treatments significantly upregulated the expression of OXTR and Cd38 in the PVN, indicating modulation of oxytocinergic signaling and neuroimmune responses.