Mitochondrial calcium, oxidative stress and apoptosis in a neurodegenerative disease model induced by 3-nitropropionic acid.
Intracellular calcium homeostasis is important for cell survival. However, increase in mitochondrial calcium (Ca2+m) induces opening of permeability transition pore (PTP), mitochondrial dysfunction and apoptosis. Since alterations of intracellular Ca2+ and reactive oxygen species (ROS) generation are involved in cell death, they might be involved in neurodegenerative processes such as Huntington's disease (HD). HD is characterized by the inhibition of complex II of respiratory chain and increase in ROS production. In this report, we studied the correlation between the inhibitor of the complex II, 3-nitropropionic acid (3NP), Ca2+ metabolism, apoptosis and behavioural alterations. We showed that 3NP (1 mm) is able to release Ca2+m, as neither Thapsigargin (TAP, 2 microm) nor free-calcium medium affected its effect. PTP inhibitors and antioxidants inhibited this process, suggesting an increase in ROS generation and PTP opening. In addition, 3NP (0.1 mm) also induces apoptotic cell death. Behavioural changes in animals treated with 3NP (20 mg/kg/day for 4 days) were also attenuated by pre- and co-treatment with vitamin E (VE, 20 mg/kg/day). Taken together, our results show that complex II inhibition could involve Ca2+m release, oxidative stress and cell death that may precede motor alterations in neurodegenerative processes such as HD.
Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, Brazil.
T R
TR
Rosenstock
A C P
AC
Carvalho
A
A
Jurkiewicz
R
R
Frussa-Filho
S S
SS
Smaili
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009574:Nitro Compounds; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates; D014475:Uncoupling Agents / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D009574:Nitro Compounds; D011422:Propionates; D014475:Uncoupling Agents; D014810:Vitamin E; D042963:Electron Transport Complex II; C015392:3-nitropropionic acid; D002118:Calcium