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Protective role of hydrogen peroxide in oxygen‐deprived dopaminergic neurones of the rat substantia nigra
Author(s) -
Geracitano Raffaella,
Tozzi Alessandro,
Berretta Nicola,
Florenzano Fulvio,
Guatteo Ezia,
Viscomi Maria Teresa,
Chiolo Barbara,
Molinari Marco,
Bernardi Giorgio,
Mercuri Nicola B.
Publication year - 2005
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2005.092510
Subject(s) - substantia nigra , hyperpolarization (physics) , chemistry , hypoxia (environmental) , membrane potential , pars compacta , biophysics , hydrogen peroxide , dopamine , dopaminergic , reactive oxygen species , depolarization , endocrinology , medicine , biochemistry , pharmacology , oxygen , biology , stereochemistry , organic chemistry , nuclear magnetic resonance spectroscopy
Hydrogen peroxide (H 2 O 2 ) is a reactive oxygen species, responsible for cytotoxic damage through the formation of hydroxyl radicals. Dopamine (DA) neurones of the substantia nigra pars compacta (SNc) are highly sensitive to metabolic stress, and they typically respond to energy deprivation with membrane hyperpolarization, mainly through opening of ATP‐dependent K + channels. Accordingly, H 2 O 2 (3 m m ) induced a tolbutamide‐sensitive outward current in DA neurones. Conversely, in a hypoxic medium, H 2 O 2 reverted membrane hyperpolarization, which is associated with oxygen deprivation in DA neurones, restored their action potential firing, and reduced the hypoxia‐mediated outward current in a concentration‐dependent manner, between 0.1 and 3 m m (IC 50 0.6 ± 0.1 m m ). Notably, H 2 O 2 did not counteract membrane hyperpolarization associated with hypoglycaemia, moreover, when catalase was inhibited with 3‐amino‐1,2,4‐triazole (3‐AT; 30 m m ), H 2 O 2 did not reduce hypoxia‐mediated outward current. The counteracting action of H 2 O 2 on hypoxia‐mediated effects was further confirmed by single‐unit extracellular recordings of presumed DA neurones in acute midbrain slices preparations, using a planar multi‐electrode array device. Whilst a prolonged period of hypoxia (40 min) caused firing suppression, which did not recover after perfusion in normoxic conditions, the presence of H 2 O 2 (3 m m ) during this prolonged hypoxic period rescued most of the neurones from irreversible firing inhibition. Accordingly, morphological studies showed that H 2 O 2 counteracts the cytochrome c release provoked by prolonged hypoxic treatment. Taken together, our data suggest that H 2 O 2 prevents the metabolic stress of DA neurones induced by hypoxia by serving as a supplementary source of molecular oxygen, through its degradation by catalase.