Effects of St. John’s Wort extract on the release of paracrine markers and neurite outgrowth in mouse hippocampal HT-22 neuronal cells co-cultured with SIM-A9 microglia
- 1Department of Medical Cell Biology, Institute for Anatomy and Cell Biology, Marburg University
- 2Bayer Consumer Health Division, Phytomedicines Supply and Development Center, Steigerwald Arzneimittelwerk GmbH
Abstract
Introduction: Hypericum perforatum L., commonly known as St. John’s wort (SJW), has traditionally been used to treat nervous disorders, including depression. Exposure to chronic stress events can affect neuronal and microglial function and induce depression. However, the molecular mechanisms underlying these processes are not entirely understood. Our investigation aimed to determine the effects of STW3-VI, a special SJW extract, on the paracrine signaling between microglia and neurons in vitro .
Methods: Co-cultures of mouse SIM-A9 microglia (SIM-A9) with mouse hippocampal HT-22 neuronal cells (HT-22) were treated with different concentrations of SJW, hyperoside, an active component of SJW. Escitalopram, or nerve growth factor (NGF) as a positive control. To further elucidate the paracrine signaling, cell viability, ELISA, neurite outgrowth, migration, and ProteomeProfile™ methods were applied.
Results: Incubation HT-22 with SJW, escitalopram, hyperoside, or NGF, co-cultured with SIM-A9, stimulated neurite formation compared to the negative control. Using as screening ProteomeProfiler™ and to validate ELISA analyses, in the presence of mouse SIM-A9, SJW at a concentration 0.50 μg/mL, as well as 0.019 μg/mL hyperoside or 2.10 μg/mL escitalopram, significantly increased the cholinergic differentiation factor (CDF/LIF) release compared to the respective control. After treatment of mouse hippocampal HT-22 with escitalopram, hyperoside, or NGF, the release of the anti-inflammatory cytokine IL-10 was increased. Interestingly, SJW and hyperoside inhibited the release of growth differentiation factor 15 (GDF-15) in co-culture. All experiments were performed under unstimulated co-culture conditions.
Conclusion: Our data show that, under unstimulated co-culture conditions without external stimulation, an increase in CDF/LIF levels in HT-22 cells in the presence of SIM-A9 cells, a reduction in GDF-15 release by SIM-A9 microglia, and stimulation of neurite growth may indicate a possible effect of SJW on paracrine release and neurite outgrowth. Furthermore, the results indicate that hyperoside, escitalopram, and NGF enhance IL-10 release. Since our findings were derived from in vitro experiments, we can only speculate that a similar effect might occur in patients with depressive disorders. Additional in vitro , in vivo , and clinical studies are necessary to confirm this hypothesis.
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BibTeX
@article{bonaterra2026effects,
title = {{Effects of St. John’s Wort extract on the release of paracrine markers and neurite outgrowth in mouse hippocampal HT-22 neuronal cells co-cultured with SIM-A9 microglia}},
author = {Gabriel A. Bonaterra and Laura Much and Josephine Hahn and Heba Aziz-Kalbhenn and Olaf Kelber and Konstanze Bedal and Hans Schwarzbach and Anja Schwarz and Ralf Kinscherf},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1916960},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1916960/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Effects of St. John’s Wort extract on the release of paracrine markers and neurite outgrowth in mouse hippocampal HT-22 neuronal cells co-cultured with SIM-A9 microglia
AU - Gabriel A. Bonaterra
AU - Laura Much
AU - Josephine Hahn
AU - Heba Aziz-Kalbhenn
AU - Olaf Kelber
AU - Konstanze Bedal
AU - Hans Schwarzbach
AU - Anja Schwarz
AU - Ralf Kinscherf
PY - 2026
DA - 2026/10/21
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1916960
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1916960/full
AB - Introduction: Hypericum perforatum L., commonly known as St. John’s wort (SJW), has traditionally been used to treat nervous disorders, including depression. Exposure to chronic stress events can affect neuronal and microglial function and induce depression. However, the molecular mechanisms underlying these processes are not entirely understood. Our investigation aimed to determine the effects of STW3-VI, a special SJW extract, on the paracrine signaling between microglia and neurons in vitro . Methods: Co-cultures of mouse SIM-A9 microglia (SIM-A9) with mouse hippocampal HT-22 neuronal cells (HT-22) were treated with different concentrations of SJW, hyperoside, an active component of SJW. Escitalopram, or nerve growth factor (NGF) as a positive control. To further elucidate the paracrine signaling, cell viability, ELISA, neurite outgrowth, migration, and ProteomeProfile™ methods were applied. Results: Incubation HT-22 with SJW, escitalopram, hyperoside, or NGF, co-cultured with SIM-A9, stimulated neurite formation compared to the negative control. Using as screening ProteomeProfiler™ and to validate ELISA analyses, in the presence of mouse SIM-A9, SJW at a concentration 0.50 μg/mL, as well as 0.019 μg/mL hyperoside or 2.10 μg/mL escitalopram, significantly increased the cholinergic differentiation factor (CDF/LIF) release compared to the respective control. After treatment of mouse hippocampal HT-22 with escitalopram, hyperoside, or NGF, the release of the anti-inflammatory cytokine IL-10 was increased. Interestingly, SJW and hyperoside inhibited the release of growth differentiation factor 15 (GDF-15) in co-culture. All experiments were performed under unstimulated co-culture conditions. Conclusion: Our data show that, under unstimulated co-culture conditions without external stimulation, an increase in CDF/LIF levels in HT-22 cells in the presence of SIM-A9 cells, a reduction in GDF-15 release by SIM-A9 microglia, and stimulation of neurite growth may indicate a possible effect of SJW on paracrine release and neurite outgrowth. Furthermore, the results indicate that hyperoside, escitalopram, and NGF enhance IL-10 release. Since our findings were derived from in vitro experiments, we can only speculate that a similar effect might occur in patients with depressive disorders. Additional in vitro , in vivo , and clinical studies are necessary to confirm this hypothesis.
SN - 1663-9812
ER -