Samhwangsasim-tang attenuates neuronal apoptosis and cognitive decline through BDNF-mediated activation of tyrosin kinase B and p75-neurotrophin receptors

Malk Eun Pak; Yeo Jin Park; Hye Jin Yang; Youn-Hwan Hwang; Wei Li; Younghoon Go

doi:10.1016/j.phymed.2022.153997

Samhwangsasim-tang attenuates neuronal apoptosis and cognitive decline through BDNF-mediated activation of tyrosin kinase B and p75-neurotrophin receptors

Phytomedicine. 2022 May:99:153997. doi: 10.1016/j.phymed.2022.153997. Epub 2022 Feb 25.

Authors

Malk Eun Pak¹, Yeo Jin Park², Hye Jin Yang¹, Youn-Hwan Hwang³, Wei Li¹, Younghoon Go⁴

Affiliations

¹ Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.
² Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea; Korean Convergence Medicine, University of Science and Technology, Daejeon 34054, Republic of Korea.
³ Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea.
⁴ Korean medicine (KM)-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea. Electronic address: gotra827@kiom.re.kr.

PMID: 35279612
DOI: 10.1016/j.phymed.2022.153997

Abstract

Background: Samhwangsasim-tang (SST) is a traditional medicine used to treat hypertension and arteriosclerosis. Additionally, due to the effects of its constituent herbs, SST is considered effective for memory-related disorders.

Purpose: We investigated the effects of SST on neuronal survival and memory in glutamate-induced hippocampal cells and in a mouse model of scopolamine-induced memory impairment.

Methods: SST components were identified using 3D-ultra performance liquid chromatography (3D-UPLC). In vitro, we induced glutamate-induced excitotoxicity in HT22 cells after SST pretreatment. We used a cell counting kit-8 and cell cytotoxicity assay, flow cytometry, and western blotting to test the protective effects of SST on neuronal death. In vivo, C57BL/6J mice were administered with 150 and 300 mg/kg SST once daily for 7 days and then intraperitoneally injected with 1 mg/kg scopolamine for 7 days to induce cognitive impairment. We then measured cognitive behavior using a novel object recognition test (NORT) and passive avoidance test (PAT) and analyzed the histological and protein changes.

Results: Our results showed that treatment with 50 and 100 μg/ml SST provided significant protection against glutamate-induced cell death. Flow cytometry and western blotting results suggested that 100 μg/ml SST treatment reduced oxidative stress and mitochondrial dysfunction. SST treatment also increased brain-derived neurotrophic factor (BDNF), its receptor, TrkB receptor, and cAMP-response element binding protein (CREB) activation while reducing the P75NTR and JNK signaling activation. Our in vivo results showed that SST administration improved cognitive impairment, similar to donepezil treatment (as a positive control), in NORT and PAT. SST and donepezil decreased neuronal cell death and apoptosis, and acetylcholine levels were increased in the scopolamine-treated hippocampus. Additionally, SST promoted CREB phosphorylation and BDNF maturation while reducing JNK and P75NTR activation; in contrast, donepezil did not alter levels of these proteins in the scopolamine-treated mouse hippocampus.

Conclusion: Our results suggest that SST has neuroprotective effects to attenuate neuronal cell death and oxidative stress through CREB/JNK signaling via BDNF activation. SST may regulate endogenous survival factors in the hippocampus, which may be a safe and potential clinical treatment for cognitive impairment in AD.

Keywords: Apoptosis; BDNF; Neuroprotection; Samhwangsasim-tang; Scopolamine.