Pipecolic acid induces apoptosis in neuronal cells.
Pipecolic acid, a lysine metabolite, is thought to be a factor responsible for hepatic encephalopathy; however, the underlying mechanism is far from understood. Twenty minutes treatment with D-, L-, and DL-pipecolic acid at concentrations ranging from 1 to 100 microM, except for 1 microM L-pipecolic acid, had no inhibitory effect on excitatory postsynaptic responses in the dentate gyrus of rat hippocampal slices. In a whole-cell voltage-clamp configuration, DL-pipecolic acid (10 and 100 microM) did not affect voltage-sensitive Na(+) channel currents and K(+) channel currents, but it potentiated voltage-sensitive Ca(2+) channel currents, but to a lesser extent, in cultured rat cortical neurons and Neuro-2A cells, a mouse neuroblastoma cell line. Notably, 72-h treatment with D-, L-, and DL-pipecolic acid reduced Neuro-2A cell viability in a dose-dependent manner at concentrations ranging from 1 to 100 microM in a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, in parallel with reactions to propidium iodide, a marker of cell death, and Hoechst 33,342, a marker of apoptosis in a fluorescent microscopic study, with DL-pipecolic acid being the most potent. The results of the present study suggest that pipecolic acid could cause hepatic encephalopathy by inducing neuronal cell death, perhaps apoptosis, rather than by depressing neurotransmissions.
Matsumoto
Shinji
S
Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.
Yamamoto
Satoshi
S
Sai
Katsunari
K
Maruo
Keishi
K
Adachi
Masaru
M
Saitoh
Masaru
M
Nishizaki
Tomoyuki
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010875:Pipecolic Acids / Q000494:pharmacology*; D051381:Rats
D010875:Pipecolic Acids; C031345:pipecolic acid