Electrophysiology and pharmacology of striatal neuronal dysfunction induced by mitochondrial complex I inhibition.
نویسندگان
چکیده
Reduced activity of the mitochondrial respiratory chain and in particular of complex I is implicated not only in the etiology of Parkinson's disease but also in other forms of parkinsonism in which striatal neurodegeneration occurs, such as progressive supranuclear palsy. The pesticide rotenone inhibits mitochondrial complex I and reproduces features of these basal ganglia neurological disorders in animal models. We have characterized the electrophysiological effects of rotenone in the striatum as well as potential neuroprotective strategies to counteract the detrimental effects of this neurotoxin. We found that rotenone causes a dose-dependent and irreversible loss of the corticostriatal field potential amplitude, which was related to the development of a membrane depolarization/inward current in striatal spiny neurons, coupled to an increased release of both excitatory amino acids and dopamine (DA). In particular, we have investigated whether glutamate, DA, and GABA systems might represent possible targets for neuroprotection against rotenone-induced striatal neuronal dysfunction. Interestingly, whereas modulation of glutamatergic transmission was not neuroprotective, blockade of D(2)-like but not D(1)-like DA receptors significantly reduced the rotenone-induced effects via a GABA-mediated mechanism. In addition, because antiepileptic drugs (AEDs) modulate multiple transmitter systems, we have analyzed the possible neuroprotective effects of some AEDs against rotenone. We found that carbamazepine, unlike other tested AEDs, exerts a potent neuroprotective action against rotenone-induced striatal neuronal dysfunction. This neuroprotection was observed at therapeutically relevant concentrations requiring endogenous GABA. Differential targeting of GABAergic transmission may represent a possible therapeutic strategy against basal ganglia neurodegenerative disorders involving mitochondrial complex I dysfunction.
منابع مشابه
Striatal dopamine levels and changes in mitochondrial function following chronic 3-nitropropionic acid treatment in rats
An irreversible inhibitor of complex II in the mitochondria, 3-nitropropionic acid (3-NP), induces bilateral striatal lesions with many neuropathological features of Huntington’s disease (HD) in rats. It is widely used as a model of HD. Chronic systemic treatment of 3-NP for 4 days in rats (10, 15 and 20 mg/kg) caused a significant dose-dependent reduction in succinate dehydrogenase activity, w...
متن کاملStriatal dopamine levels and changes in mitochondrial function following chronic 3-nitropropionic acid treatment in rats
An irreversible inhibitor of complex II in the mitochondria, 3-nitropropionic acid (3-NP), induces bilateral striatal lesions with many neuropathological features of Huntington’s disease (HD) in rats. It is widely used as a model of HD. Chronic systemic treatment of 3-NP for 4 days in rats (10, 15 and 20 mg/kg) caused a significant dose-dependent reduction in succinate dehydrogenase activity, w...
متن کاملProtective Role of Apigenin Against Aβ 25-35 Toxicity Via Inhibition of Mitochondrial Cytochrome c Release
Introduction: Cognitive dysfunction is the most common problem of patients with Alzheimer disease (AD). The pathological mechanism of cognitive impairment in AD may contribute to neuronal loss, synaptic dysfunction, and alteration in neurotransmitters receptors. Mitochondrial synapses dysfunction due to the accumulation of amyloid beta (Aβ) is one of the earliest pathological features of AD. Th...
متن کاملStriatal cells from mutant huntingtin knock-in mice are selectively vulnerable to mitochondrial complex II inhibitor-induced cell death through a non-apoptotic pathway.
Extensive striatal neuronal loss occurs in Huntington's disease (HD), which is caused by an expanded polyglutamine tract in huntingtin (htt). Evidence suggests that mutant htt directly or indirectly compromises mitochondrial function, contributing to the neuronal loss. To determine the role of compromised mitochondrial function in the neuronal cell death in HD, immortalized striatal cells estab...
متن کاملProbucol Increases Striatal Glutathione Peroxidase Activity and Protects against 3-Nitropropionic Acid-Induced Pro-Oxidative Damage in Rats
Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinat...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- The Journal of neuroscience : the official journal of the Society for Neuroscience
دوره 28 32 شماره
صفحات -
تاریخ انتشار 2008