Current neuropharmacology · 2026
Behavioral and Molecular Effects of Kamikihito and Mesenchymal Stem Cells in a Two-hit Model of Treatment-resistant Depression.
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Deriha Kenta, Marchesin Alessia, Nishimura Emi, Inoue Yuito, Shimazu Haruto, Kihara Kano, Tateno Masaru, Furuse Kengo, Isoyama Kyoko, Morimoto Takafumi, Sato Tatsuya, Nakachi Yutaka, Bundo Miki, Iwamoto Kazuya, Nagaishi Kanna, Hashimoto Eri, Ishii Takao, Ukai Wataru, Riva Marco Andrea, Kawanishi Chiaki
Аннотация
BACKGROUND: Treatment-Resistant Depression (TRD) features persistent socio-affective deficits poorly responsive to monoaminergic antidepressants. We investigated Kamikihito, mesenchymal stem cells, or their combination in a two-hit rat model recapitulating TRD-like social withdrawal and empathic impairment (prenatal ethanol exposure + adolescent corticosterone) Methods: Pregnant Wistar rats were exposed to ethanol from D10 to D14 twice a day. Offspring received corticosterone from weaning to PND 42. In late adolescence, they were treated with the traditional Japanese herbal formula Kamikihito (KMK), intravenous Mesenchymal Stem Cells (MSCs), or a combination of both, as compared to a vehicle-treated control. At nine weeks of age, we assessed social interaction and rescue‑task performance, followed by rt-qPCR to measure the gene expression of VGLUT1 and VGAT in the Anterior Cingulate Cortex (ACC) and OXTR and Cd38 in the paraventricular nucleus (PVN).
RESULTS: The stressed saline-treated rats showed significant reductions in social and empathic behaviours. MSCs alone produced modest improvements, whereas KMK (alone or combined with MSCs) significantly restored rescue‑task performance, with the highest composite behavioural scores in the combination group. All active treatments tended to normalize the ACC excitatory/ inhibitory balance (as reflected in the VGLUT1/VGAT ratio) and significantly upregulated OXTR and Cd38 expression in the PVN compared with stressed controls.
DISCUSSION: Developmental stress induces persistent socio-affective dysfunction linked to alterations in cortical excitatory/inhibitory balance and oxytocinergic signaling. The greater efficacy of KMK, particularly in combination with MSCs, supports complementary neuromodulatory and neuroimmune mechanisms relevant to TRD.
CONCLUSION: KMK, especially combined with MSCs, partially reverses stress-induced socio-affective deficits and modulates key molecular pathways, supporting a promising strategy for targeting socio-affective dysfunction in TRD.
RESULTS: The stressed saline-treated rats showed significant reductions in social and empathic behaviours. MSCs alone produced modest improvements, whereas KMK (alone or combined with MSCs) significantly restored rescue‑task performance, with the highest composite behavioural scores in the combination group. All active treatments tended to normalize the ACC excitatory/ inhibitory balance (as reflected in the VGLUT1/VGAT ratio) and significantly upregulated OXTR and Cd38 expression in the PVN compared with stressed controls.
DISCUSSION: Developmental stress induces persistent socio-affective dysfunction linked to alterations in cortical excitatory/inhibitory balance and oxytocinergic signaling. The greater efficacy of KMK, particularly in combination with MSCs, supports complementary neuromodulatory and neuroimmune mechanisms relevant to TRD.
CONCLUSION: KMK, especially combined with MSCs, partially reverses stress-induced socio-affective deficits and modulates key molecular pathways, supporting a promising strategy for targeting socio-affective dysfunction in TRD.