Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl- l -carnitine and/or R -α-lipoic acid

Abstract

Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-L-carnitine (ALCAR) [0.5% or 0.2% (wt͞vol) in drinking water], and͞or R-␣-lipoic acid (LA) [0.2% or 0.1% (wt͞wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and͞or LA improved memory, the combination being the most effective for two different tests of spatial memory (P < 0.05; P < 0.01) and for temporal memory (P < 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2 -deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and͞or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and͞or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.

Cloning and functional characterization of a novel up-regulator, cartregulin, of carnitine transporter, OCTN2

“…It has recently been reported in mice that the acetyl group of acetylcarnitine is used mainly for synthesis of neurotransmitters such as glutamate and aspartate in the brain [5]. Thus acetylcarnitine appears to play a role in the brain which is distinct from carnitine: this notion is consistent with the observations that acetylcarnitine but not carnitine possesses therapeutic potentials in the treatment of a wide variety of neurological disorders including chronic fatigue syndrome [27], age-dependent memory loss [6,7] and Alzheimer-type dementia [8,9]. These data strongly indicate that a transporter for acetylcarnitine is present in the brain and plays an important role for brain function.…”

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

“…The complementary effect of LA and ALC on cognitive and mitochondrial dysfunction has been shown in ageing rats [27,28,40]. One reason is that LA+ALC act on different pathways necessary for mitochondria: LA is a mitochondrial antioxidant and cofactor of pyruvate dehydrogenase, while ALC is an energy enhancer [25,41].…”

“…ALC is the acetyl derivative of L-carnitine, which is required for the transport of long-chain fatty acids into the mitochondria for β-oxidation, ATP production and for the removal of excess short-and medium-chain fatty acids [25]. LA and/or ALC improve mitochondrial function in ageing rats and their combination appears more potent owing to complementary effects [25][26][27][28]. LA [29] and ALC [30,31] have been tested in several large clinical trials on prevention or treatment of diabetes and its complications.…”

Increased production of reactive oxygen species contributes to motor neuron death in a compression mouse model of spinal cord injury

“…11 Nucleic acid oxidation The nucleic acid oxidation in the spinal cords was measured by the level of hydroxyguanosine using an 8-hydroxyguanosine (8-OHG) antibody (QED Bioscience, San Diego, CA, USA) as described previously. 17,18 A DAB approach was adopted following the manufacturer's instruction (Vector Laboratories, Burlingame, CA, USA).…”