title: The anti-hypertensive drug reserpine induces neuronal cell death through inhibition of autophagic flux.
abstract: Reserpine is a well-known medicine for the treatment of hypertension and schizophrenia, but its administration can induce Parkinson's disease (PD)-like symptoms in humans and animals. Reserpine inhibits the vesicular transporter of monoamines and depletes the brain of monoamines such as dopamine. However, the cellular function of reserpine is not fully understood. In this report, we present one possible mechanism by which reserpine may contribute to PD-like symptoms. Reserpine treatment induced the formation of enlarged autophagosomes by inhibiting the autophagic flux and led to accumulation of p62, an autophagy adapter molecule. In particular, reserpine treatment increased the level of α-synuclein protein and led to accumulation of α-synuclein in autophagosomes. Treatment with rapamycin enhanced the effect of reserpine by further increasing the level of α-synuclein and neuronal cell death. Drosophila raised on media containing reserpine showed loss of dopaminergic neurons. Furthermore, cotreatment with reserpine and rapamycin aggravated the loss of dopaminergic neurons. Our results suggest that reserpine contributes to the loss of dopaminergic neurons by interfering with autophagic flux.
authors.affiliation: Division of Biological Science and Technology, Yonsei University, Wonju 220-100, Republic of Korea.
authors.forename: Kang Il
authors.initials: KI
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Mitochondria Hub Regulation Center (MHRC), Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Min Ju
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Mitochondria Hub Regulation Center (MHRC), Dong-A University College of Medicine, Busan 602-714, Republic of Korea.
authors.forename: Hyongjong
authors.initials: H
authors.lastname: Koh
authors.affiliation: Division of Biological Science and Technology, Yonsei University, Wonju 220-100, Republic of Korea.
authors.forename: Jin I
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Division of Biological Science and Technology, Yonsei University, Wonju 220-100, Republic of Korea.
authors.forename: Sim
authors.initials: S
authors.lastname: Namkoong
authors.affiliation: Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Won Keun
authors.initials: WK
authors.lastname: Oh
authors.affiliation: Division of Biological Science and Technology, Yonsei University, Wonju 220-100, Republic of Korea. Electronic address: junsoo@yonsei.ac.kr.
authors.forename: Junsoo
authors.initials: J
authors.lastname: Park
mesh_terms: D000959:Antihypertensive Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D012110:Reserpine
keywords: Autophagic flux; Autophagy; Parkinson's disease; Reserpine; α-Synuclein