Coenzyme Q₁₀ and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate

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.

Coenzyme Q10 supplementation reverses age-related impairments in spatial learning and lowers protein oxidation

“…Several human studies have suggested that CoQ supplementation ameliorated mitochondria-related abnormalities (Bresolin et al 1990;Morisco et al 1993;Hofman-Bang et al 1995) and age-related symptoms of heart failure and hypertension as well as neurodegenerative diseases including amyotrophic lateral sclerosis, Huntington's disease, and diabetic neuropathy (Baggio et al 1993;Beal et al 1994;Koroshetz et al 1997;Ferrante et al 2002;Rosenfeldt et al 2003Rosenfeldt et al , 2007Hyson et al 2010). Furthermore, several investigations suggest that supplementation of CoQ could have effects similar to caloric restriction or antioxidant-rich foods.…”

Coenzyme Q10 and its effects in the treatment of neurodegenerative diseases

“…Beal et al (1994) injected malonic acid in striatum of laboratory animals, and found that this procedure induced depletion of ATP and an increase in lactic acid. The administration of CoQ 10 in animals was able to mitigate the depletion of ATP induced by malonate while minimizing the increase in concentrations of lactate.…”

“…CoQ 10 significantly attenuates the depletion of ATP and malonate-induced increases of lactate in brain mitochondria of rats (Beal et al, 1994). Supplementation of CoQ 10 in rats increased the endogenous content of CoQ 10 in the brain and provided antioxidant protection against free radical generation (Kwong et al, 2002; Lenaz et al, 1999;Rauscher, Sanders, Watkins, 2001;Somayajulu et al, 2005).…”

“…CoQ 10 has been shown effective in reducing the damage produced by toxins that inhibit complex II, preventing the depletion of ATP and increases in lactate (Beal et al, 1994;Matthews et al, 1998a). CoQ 10 also prolonged survival while delaying the onset of motor impairment in a HD model in transgenic mice (Ferrante et al, 2002).…”

Perioperative Neuroprotection Symposium

“…We studied the effects of administration of CoQ 10 on lesions produced by mitochondrial toxins. Oral administration of C0Q10 produced dose-dependent neuroprotective effects against malonate induced striatal lesions as well as depletions of ATP and increases in lactate concentrations [84]. Administration of CoQ 10 produced significant protection against dopamine depletions induced by MPTP administration [85].…”