Functional vitamin B ₁₂ deficiency and Alzheimer disease

Abstract

Moderately elevated total serum homocysteine is associated with an increased risk of atherothrombotic vascular events. Accordingly, serum homocysteine is increased in patients with vascular dementia but is also increased in clinically diagnosed and histologically confirmed AD. It is generally considered that homocysteine potentiates endothelial and neuronal oxidative injury in these diseases. A complementary model of oxidative stress-induced hyperhomocystinemia is proposed by the authors. The hypothesis accounts for several unusual features relating to single-carbon metabolism and AD, including the absence of macrocytic anemia in these patients. It is suggested that cerebral oxidative stress augments the oxidation of an intermediate form of vitamin B(12) (cob[I]alamin) generated in the methionine synthase reaction, thereby impairing the metabolism of homocysteine. Oxidative stress also compromises the intraneuronal reduction of the vitamin to its metabolically active state. Currently available pharmaceutic forms of vitamin B(12) are unlikely to be utilized by neurons under these conditions. Glutathionylcobalamin might be preferential for the treatment of such patients.

Methionine metabolism in an animal model of sepsis

“…Sepsis-induced inhibition of these methyltransferases may lead to impaired SAM utilization and contribute to the increase in SAM levels. Increased Hcy remethylation to methionine and finally SAM during sepsis is unlikely, as oxidative stress leads to lower methionine synthase and betaine-Hcy S-methyltransferase activity (19)(20)(21). In addition, we would expect Hcy levels to be lower in septic animals if increased remethylation occurred during sepsis.…”

“…Thus, our results indicate that higher levels of SAM lead to a higher transsulfuration rate to allow GSX synthesis for defense of oxidative stress induced by sepsis. In addition, oxidative stress leads to an increased Hcy flux through the transsulfuration pathway by up-regulation of CBS activity (35) and decreased activity of methionine synthase and betaine-Hcy S-methyltransferase (19)(20)(21). Increased transsulfuration rates during experimentally induced sepsis were also shown by injection of radiolabeled cysteine and methionine in rats (36,37).…”

A simple, convenient method to synthesize cobalamins: synthesis of homocysteinylcobalamin, N-acetylcysteinylcobalamin, 2-N-acetylamino-2-carbomethoxyethanethiolatocobalamin, sulfitocobalamin and nitrocobalamin

“…24 Finally, McCaddon and coworkers suggested that GSCbl and related thiolatocobalamins might be more effective than currently available pharmaceutical B 12 forms (CNCbl and H 2 OCbl + ) in treating B 12 -related conditions associated with oxidative stress such as Alzheimer's disease. 34,35 However, the apparent clinical benefit of combining N-acetyl-L-cysteine with H 2 OCbl + in patients with Alzheimer's disease or mild cognitive impairment requires formal clinical trials to prove or refute such observations. 34,46 In this paper we describe the synthesis of three novel thiolatocobalamins: D,Lhomocysteinylcobalamin (HcyCbl), the sodium salt of N-acetyl-L-cysteinylcobalamin (Na [NACCbl]), and 2-N-acetylamino-2-carbomethoxy-L-ethanethiolatocobalamin (NACMECbl).…”

“…34,35 However, the apparent clinical benefit of combining N-acetyl-L-cysteine with H 2 OCbl + in patients with Alzheimer's disease or mild cognitive impairment requires formal clinical trials to prove or refute such observations. 34,46 In this paper we describe the synthesis of three novel thiolatocobalamins: D,Lhomocysteinylcobalamin (HcyCbl), the sodium salt of N-acetyl-L-cysteinylcobalamin (Na [NACCbl]), and 2-N-acetylamino-2-carbomethoxy-L-ethanethiolatocobalamin (NACMECbl). The thiol ligand structures are shown in Fig.…”

“…[47][48][49][50][51][52] In addition, moderately raised serum homocysteine levels are more prevalent in patients suffering from neurological diseases such as Alzheimer's disease, [53][54][55][56] and appear to predict cognitive decline. 57,58 Na [NACCbl] is also of interest, given the benefits of co-administrating H 2 OCbl + and N-acetyl-L-cysteine to Alzheimer's patients, 34,46 and the possibility that NACCbl − , rather than the individual components themselves, is responsible for the beneficial effects of this approach. The X-ray structure and XAS spectrum of Na[NACCbl]·18H 2 O are also reported.…”