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Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate
M F Beal1, D R Henshaw, B G Jenkins
1Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
Abstract:
A potential mechanism of neuronal injury in neurodegenerative diseases is a defect in energy metabolism that may lead to slow excitotoxic neuronal death. Consistent with this possibility, we showed that specific inhibitors of the electron transport chain produce excitotoxic lesions in vivo. In the present study we examined whether agents that improve energy metabolism can block lesions produced by the mitochondrial toxin malonate. Striatal lesions produced by the complex II inhibitor malonate were blocked in a dose-dependent manner by oral pretreatment with coenzyme Q10. Administration of nicotinamide by Alzet pump for 1 week attenuated malonate-induced lesions, but riboflavin had no effect. Administration of nicotinamide intraperitoneally just prior to and following induction of the lesions produced dose-dependent neuroprotection. A combination of coenzyme Q10 with nicotinamide was more effective than either compound alone, as shown by both lesion size and magnetic resonance imaging in vivo. Both coenzyme Q10 and nicotinamide blocked adenosine triphosphate depletions and lactate increases. These results confirm that mitochondrial toxins produce striatal excitotoxic lesions by a mechanism involving energy depletion in vivo. Furthermore, they suggest novel neuroprotective strategies that may be useful in the treatment of both mitochondrial encephalopathies and neurodegenerative diseases.
Insights
Agents that enhance cellular energy metabolism, like coenzyme Q10 and nicotinamide, can protect against excitotoxic neuronal injury caused by mitochondrial dysfunction. These findings offer new neuroprotective strategies for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Neuroprotection
Background:
- Neurodegenerative diseases may involve neuronal injury due to impaired energy metabolism.
- Electron transport chain inhibitors can induce excitotoxic lesions in vivo.
- Mitochondrial toxins, such as malonate, are implicated in neuronal damage.
Purpose of the Study:
- To investigate if agents improving energy metabolism can prevent lesions caused by the mitochondrial toxin malonate.
- To evaluate the neuroprotective effects of coenzyme Q10, nicotinamide, and riboflavin against malonate-induced striatal lesions.
Main Methods:
- Administered malonate, a complex II inhibitor, to induce striatal lesions in vivo.
- Pretreated animals with coenzyme Q10 (oral) and nicotinamide (Alzet pump or intraperitoneal).
- Assessed lesion size, used magnetic resonance imaging, and measured adenosine triphosphate (ATP) levels and lactate accumulation.
Main Results:
- Coenzyme Q10 dose-dependently blocked malonate-induced lesions.
- Nicotinamide attenuated lesions when administered via pump or intraperitoneally, showing dose-dependent neuroprotection.
- A combination of coenzyme Q10 and nicotinamide was more effective than either agent alone.
- Both coenzyme Q10 and nicotinamide prevented ATP depletions and lactate increases.
Conclusions:
- Mitochondrial toxins induce striatal excitotoxic lesions via energy depletion.
- Coenzyme Q10 and nicotinamide show significant neuroprotective potential against mitochondrial toxins.
- These compounds offer promising therapeutic strategies for mitochondrial encephalopathies and neurodegenerative diseases.