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The antidepressant-like effect of (2S,6S)-Hydroxynorketamine through adult hippocampal neurogenesis in mouse model of depression

Title
The antidepressant-like effect of (2S,6S)-Hydroxynorketamine through adult hippocampal neurogenesis in mouse model of depression
Other Titles
생쥐 우울증 동물 모델에서 성체 해마 신경생성을 통한 (2S,6S)-Hydroxynorketamine 의 항 우울 효과
Author
손기영
Alternative Author(s)
손기영
Advisor(s)
손 현
Issue Date
2021. 2
Publisher
한양대학교
Degree
Master
Abstract
케타민의 주요 대사체인 (2S,6S)-hydroxynorketamine (HNK) 와 (2R,6R)-HNK 는 설치류 모델에서 케타민에 의해 생성되는 부작용 없이 빠르고 지속되는 항 우울 효과를 낸다고 보고 되었다. 그러나, (2S,6S)-HNK와 (2R,6R)-HNK 의 표적과 작용은 생화학적 수준에서 여전히 불분명하다. 본 연구에서, 케타민 대사체의 항 우울 효과와 성체 해마 신경 생성 사이의 잠재적인 연관성에 대하여 조사하였다. 면역 조직 화학 염색을 통해 신경 줄기 세포 (Neural progenitor cells) 의 증식이 (2S,6S)-HNK 와 (2R,6R)-HNK 모두에 의해 증가되었으나, 신경 줄기 세포의 생존 및 신경 성숙은 (2S,6S)-HNK 에 의해서는 증가하였으나 (2R,6R)-HNK에 의해서는 증가하지 않았다. 이러한 결과는 성체 해마 신경 생성에 있어 (2S,6S)-HNK 의 효과가 (2R,6R)-HNK 보다 더 잠재적이고 지속적인 것임을 시사하였다. 행동 분석을 통해 (2S,6S)-HNK 가 강제 수영 테스트 (Forced swim test) 에서 항 우울 행동 효과를 유도하였으며, 이러한 효과는 성체 해마 신경 생성을 동반하는 것으로 나타났다. 웨스턴 블롯 (Western blots) 을 통해서는 (2S,6S)-HNK 가 성체 마우스 해마에서 인산화된 calcuim/calmodulin-dependent protein kinase II (CaMKII) 와 cAMP response element-binding protein (CREB) 의 발현 및 brain-derived neurotrophic factor (BDNF) 의 발현을 증가시켰다. 이러한 결과는 (2S,6S)-HNK 가 성체 해마 신경 생성의 촉진을 통해 항 우울 효과를 유도하고, CaMKII/CREB/BDNF 신호 경로가 (2S,6S)-HNK 의 항 우울 효과에 있어 관련이 있음을 시사한다.; (2S,6S)-hydroxynorketamine (HNK) and (2R,6R)-HNK, the major metabolites of ketamine, have been reported to produce rapid and sustained antidepressant-like effects in rodent models without the side effects produced by ketamine. However, the targets and actions of (2S,6S)- and (2R,6R)-HNK are unclear at the biochemical level. In the present study, it was investigated that the potential link between antidepressant-like effects of ketamine metabolites and adult hippocampal neurogenesis. Immunohistochemical analysis revealed that proliferation of neural progenitor cells (NPCs) was increased by both (2S,6S)- and (2R,6R)-HNK, whereas neuronal maturation or survival of NPCs in the adult hippocampus was increased by (2S,6S)-HNK but not by (2R,6R)-HNK. These results suggested that the effects of (2S,6S)-HNK on adult hippocampal neurogenesis are more potent and longer-lasting than (2R,6R)-HNK. Behavioral analysis showed that (2S,6S)-HNK induced antidepressant-like behavioral effects in forced swim test (FST), and these effects were accompanied by adult hippocampal neurogenesis. Western blot analysis showed that (2S,6S)-HNK increased phosphorylation of calcuim/calmodulin-dependent protein kinase II (CaMKII) and cAMP response element-binding protein (CREB) and expression of brain-derived neurotrophic factor (BDNF) in the adult mouse hippocampus. Taken together, these results suggest that (2S,6S)-HNK induces antidepressant-like effects via promotion of adult hippocampal neurogenesis, and CaMKII/CREB/BDNF signaling is involved in the antidepressant-like effects of (2S,6S)-HNK.
URI
https://repository.hanyang.ac.kr/handle/20.500.11754/159086http://hanyang.dcollection.net/common/orgView/200000485758
Appears in Collections:
GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > BIOMEDICAL SCIENCE(의생명과학과) > Theses (Master)
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