Effects of Dietary Supplementation with N-Acetyl Cysteine, Acetyl-l-Carnitine and S-Adenosyl Methionine on Cognitive Performance and Aggression in Normal Mice and Mice Expressing Human ApoE4

Abstract

In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.

Cytoprotective Effect of Acetyl-l-Carnitine Evidenced by Analysis of Gene Expression in the Rat Brain

“…Acetyl-L-carnitine (ALC) is the acetyl ester of the trimethylated amino acid L-carnitine (LA) that plays an essential role in energy production as "shuttles" of long-chain fatty acids between the cytosol and the mitochondria for subsequent β oxidation [1][2][3]. Together with LA, ALC is involved in the control of mitochondrial acyl-CoA/CoA ratio and peroxisomal oxidation of fatty acids [4].…”

Nitrones for understanding and ameliorating the oxidative stress associated with aging

“…There is evidence that carnitine supplementation may reverse the age-associated decline of brain function (Lohninger et al 2005;Shea 2007). The combination in CarnDOD-7C of carnitine and a nitrone moiety may provide double benefit because acyclic nitrones themselves have shown promise for the treatment of agerelated diseases (Floyd et al 2008).…”

Transcription and protein synthesis inhibitors influence long-term effects of acetyl-l-carnitine on non-associative learning in the leech

“…Several studies carried out in vertebrate models and humans illustrate the effects of ALC in the nervous system including its effect in improving the cognitive capability likely due to its protective actions against several physiological and pathological brain modifications induced by aging (Calabrese et al, 2012;Tolu et al, 2002), diseases (Shea, 2007;Torrioli et al, 2008;Traina et al, 2006Traina et al, , 2008aTraina et al, , 2008bTraina et al, , 2009Traina et al, , 2011 and drug abuse (Coccurello et al, 2007;Scheggi et al, 2004) rather than to its actual action on the mechanisms underlying learning processes. Recently, a role of ALC in the modulation of pain perception has been demonstrated mostly in the treatment of neuropathies of various origins (Chiechio et al, 2010;Sima, 2007).…”

“…A relevant action ascribed to ALC is its anti-nociceptive effect observed in the treatment of painful neuropathies of various origins (Chiechio et al, 2010;Di Cesare Mannelli et al, 2009;Janiri et al, 2009;Memeo and Loiero, 2008;Sima, 2007;Sima et al, 2005). In addition, there is evidence that ALC improves cognitive capabilities (Adriani et al, 2004;Ando et al, 2001;Marini et al, 2006;Shea, 2007).…”