Effect of l‐Carnitine Pretreatment on 3‐Nitropropionic Acid‐Induced Inhibition of Rat Brain Succinate Dehydrogenase Activity

Abstract

l‐Carnitine (LC) plays an important regulatory role in the mitochondrial transport of long chain free fatty acids (FFA). 3‐Nitropropionic acid (3‐NPA) is known to induce cellular energy deficit and oxidative stress‐related neurotoxicity via an irreversible inhibition of mitochondrial succinate dehydrogenase (SDH). In the present study, activity of SDH was measured in order to evaluate neuroprotective effects of LC against the 3‐NPA‐induced neurotoxicity. Male, CD Sprague‐Dawley rats, three months old, were injected with either 50 or 100 mg/kg of LC, i.p., 30 min prior to 3‐NPA (30 mg/kg, s.c.) or with 3‐NPA alone. The activity of brain SDH was quantified spectrophotometrically in caudate nucleus (CN), frontal cortex (FC), and hippocampus (HIP) 60 min after the 3‐NPA injection. The SDH activity in the animals treated with 3‐NPA alone was 38% (CN), 50% (FC), and 36% (HIP) that of saline controls. Pretreatment with LC prior to 3‐NPA injection attenuated decreases of SDH activity by approximately 15 and 29% (LC low and high dose, respectively). Despite the attenuation of SDH inhibition, the activity of SDH in these regions remained significantly lower in treated than in control rats (p < 0.05). It appears that the protective effect of LC against 3‐NPA‐induced oxidative stress cannot be explained by the direct action of LC to interfere with the SDH inhibition but are rather achieved by LC actions downstream of the SDH inhibition.

Mechanism of 3‐nitropropionic acid‐induced membrane permeability transition of isolated mitochondria and its suppression by L‐carnitine

“…19 Furthermore, it is known that LC plays a protective role against various mitochondrial toxins in animal model and tissues. 45,46 In agreement with these findings, we showed that LC suppressed 3NP-induced Ca 2þ release from mitochondria, swelling, and cytochrome c release. These results suggest that 3NP increases free fatty acids in mitochondria through the activation of Ca 2þ -dependent PLA 2 , and thus LC suppresses mitochondrial MPT by consuming the fatty acids through b-oxidation which requires ATP or an ATP generation system.…”

“…20,[43][44][45] LC also protects against the toxic action of 3NP in animal models, HD, and cultured cells. 19 Furthermore, it is known that LC plays a protective role against various mitochondrial toxins in animal model and tissues.…”

Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects ofl‐carnitine

“…In contrast, those animals receiving the l ‐CAR pre‐treatment and infused with 3‐NP exhibited horizontal, vertical and ambulatory patterns close to control animals, thereby suggesting an ameliorative effect of l ‐CAR on 3‐NP‐induced hypokinesia, that was confirmed when the total cumulative activities were represented. Given the positive effects reported for l ‐CAR against 3‐NP‐induced neurotoxicity (Binienda et al. 2001, 2004) and our own findings, it is likely that its neuroprotective properties might achieve a considerable level of nerve tissue preservation, thus allowing major integrative behavioral tasks to be preserved.…”

“…Whether l ‐CAR is acting by this pathway in the toxic models tested in this work will be subject of further studies. For final consideration, the neuroprotective effects of l ‐CAR on 3‐NP‐induced oxidative damage have been suggested to be because of several factors (such as mitochondrial energy enhancement by alternative energy sources like ketone bodies, enhancement of oxidative metabolism by preventing lactate accumulation, and preservation of membrane phospholipids by prevented accumulation of fatty acyl‐CoAs), but not to direct interference with succinate dehydrogenase (Binienda et al. 2001).…”

“…For this second model, we choose a long period of exposure of rats to the toxin for two reasons: (a) the chronic infusion of 3‐NP to rats mimics in a better fashion the patterns of behavioral changes and neurodegeneration seen in HD (Borlongan et al. 1995); and (b) previous reports in literature (Binienda and Ali 2001; Binienda et al. 2001) have already described the protective properties of l ‐CAR on the acute markers of toxicity evoked by 3‐NP, but until now, whether such positive properties might be lasting for longer periods in rats chronically exposed to 3‐NP, still remains untested.…”