Isorhynchophylline Attenuates MPP ⁺ -Induced Apoptosis Through Endoplasmic Reticulum Stress- and Mitochondria-Dependent Pathways in PC12 Cells: Involvement of Antioxidant Activity.

Publisher: Humana Press Country of Publication: United States NLM ID: 101135365 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1174 (Electronic) Linking ISSN: 15351084 NLM ISO Abbreviation: Neuromolecular Med Subsets: MEDLINE

Original Publication: Totowa, NJ : Humana Press, c2002-

1-Methyl-4-phenylpyridinium/*antagonists & inhibitors ; Antioxidants/*pharmacology ; Apoptosis/*drug effects ; Endoplasmic Reticulum Stress/*drug effects ; Indole Alkaloids/*pharmacology ; Mitochondria/*drug effects ; Neurotoxins/*antagonists & inhibitors; 1-Methyl-4-phenylpyridinium/pharmacology ; Animals ; Dopamine/metabolism ; Drug Evaluation, Preclinical ; Mitochondria/metabolism ; Neuroprotective Agents/pharmacology ; Neurotoxins/pharmacology ; Oxidation-Reduction ; Oxidative Stress/drug effects ; Oxindoles ; PC12 Cells ; Phosphorylation ; Protein Kinases/metabolism ; Protein Processing, Post-Translational/drug effects ; Rats ; Reactive Oxygen Species/metabolism ; Signal Transduction/drug effects

Endoplasmic reticulum stress (ERS) and mitochondrial dysfunctions are thought to be involved in the dopaminergic neuronal death in Parkinson's disease (PD). In this study, we found that isorhynchophylline (IRN) significantly attenuated 1-methyl-4-phenylpyridinium (MPP ⁺ )-induced apoptotic cell death and oxidative stress in PC12 cells. IRN markedly reduced MPP ⁺ -induced-ERS responses, indicative of inositol-requiring enzyme 1 (IRE1) phosphorylation and caspase-12 activation. Furthermore, IRN inhibits MPP ⁺ -triggered apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal Kinase (JNK) signaling-mediated mitochondria-dependent apoptosis pathway. IRN-mediated attenuation of endoplasmic reticulum modulator caspase-12 activation was abolished by diphenyleneiodonium (DPI) or IRE-1α shRNA, but not by SP600125 or pifithrin-α in MPP ⁺ -treated PC12 cells. Inhibitions of MPP ⁺ -induced both cytochrome c release and caspase-9 activation by IRN were blocked by pre-treatment with DPI or pifithrin-α, but not by IRE-1α shRNA. IRN blocks the generation of reactive oxygen species upstream of both ASK1/JNK pathway and IRE1/caspase-12 pathway. Altogether, our in vitro findings suggest that IRN possesses potent neuroprotective activity and may be a potential candidate for the treatment of PD.

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Keywords: Apoptosis; Endoplasmic reticulum stress; Isorhynchophylline; Mitochondria dysfunction; Parkinson’s disease

0 (Antioxidants)
0 (Indole Alkaloids)
0 (Neuroprotective Agents)
0 (Neurotoxins)
0 (Oxindoles)
0 (Reactive Oxygen Species)
46BQ79VJ8D (rhyncophylline)
EC 2.7.- (Protein Kinases)
R865A5OY8J (1-Methyl-4-phenylpyridinium)
VTD58H1Z2X (Dopamine)

Date Created: 20170820 Date Completed: 20180718 Latest Revision: 20181202

20240628

10.1007/s12017-017-8462-x

28822073