Metabolism of Acetyl-CoA and Cholinergic Neuropathies

Szutowicz, Andrzej; Bielarczyk, Hanna; Tomaszewicz, Maria

doi:10.1007/978-1-4615-5405-9_135

Cited by 5 publications

(8 citation statements)

References 23 publications

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“…It is consistent with the appearance of functional and behavioral cholinergic deficits in Al-treated animals, at no apparent loss of cholinergic neurons in the brain (Connor et al, 1988;Meiri et al, 1993;Platt et al, 1995). This theory is also supported because, in various animal models of brain pathologies, changes in Ca-evoked ACh release correlated positively with shifts in concentrations of synaptoplasmic acetyl-C0A but not with those in synaptosomal mitochondria (Szutowicz et al, 1997).…”

Section: Discussionsupporting

confidence: 80%

Effect of Aluminum on Acetyl‐CoA and Acetylcholine Metabolism in Nerve Terminals

Bielarczyk

Tomaszewicz

Szutowicz

1998

Journal of Neurochemistry

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The potential ability of Al to affect cholinergic transmission was studied on synaptosomal fractions of rat brain incubated with pyruvate in depolarizing medium containing 30 mM K+. Addition of 1 mM Ca caused a 266% increase in the acetylcholine (ACh) release despite decreased pyruvate oxidation. Under these conditions, 0.25 mM Al did not affect pyruvate oxidation but raised mitochondrial and decreased synaptoplasmic acetyl‐CoA. Simultaneously, a 61% inhibition of Ca‐evoked ACh release was observed. Verapamil (0.1 and 0.5 mM) decreased the acetyl‐CoA concentration in synaptoplasm and inhibited ACh release. Al (0.012 mM) partially reversed these inhibitory effects. Omission of Pi from the medium abolished suppressive effects of Al on acetyl‐CoA content and Ca‐evoked transmitter release. We conclude that the Al(PO4)OH− complex may be the active form of Al, which, by interaction with the verapamil binding sites of Ca channels, is likely to restrict the Ca influx to the synaptoplasm. This may inhibit the provision of acetyl‐CoA to the synaptoplasm as well as the Ca‐evoked ACh release. One may suppose that excessive accumulation of Al in some encephalopathic brains may, by this mechanism, suppress still‐surviving cholinergic neurons and exacerbate cognitive deficits caused by already‐existing structural losses in the cholinergic system.

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Section: Discussionsupporting

confidence: 80%

Effect of Aluminum on Acetyl‐CoA and Acetylcholine Metabolism in Nerve Terminals

Bielarczyk

Tomaszewicz

Szutowicz

1998

Journal of Neurochemistry

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“…2B). This activity was inhibited by the MAO-B-specific inhibitor deprenyl at a concentration of 10 M; other studies have used deprenyl in this same approximate range (55,56). Based on time course of induction, we observed that deprenyl-sensitive activity in the desired range occurred by 4 -6 h post-dox addition (40 g/ml) and remained stable for more than 24 h (Fig.…”

Section: Dox-inducible Mao-b Expression In Dopaminergic Pc12mentioning

confidence: 63%

Oxidative α-Ketoglutarate Dehydrogenase Inhibition via Subtle Elevations in Monoamine Oxidase B Levels Results in Loss of Spare Respiratory Capacity

Kumar

Nicholls

Andersen

2003

Journal of Biological Chemistry

114

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Age-related increases in brain monoamine oxidase B (MAO-B) and its ability to produce reactive oxygen species as a by-product of catalysis could contribute to neurodegeneration associated with Parkinson's disease. This may be via increased oxidative stress and/or mitochondrial dysfunction either on its own or through its interaction with endogenous or exogenous neurotoxic species. We have created genetically engineered dopaminergic PC12 cell lines with subtly increased levels of MAO-B mimicking those observed during normal aging. In our cells, increased MAO-B activity was found to result in increased H 2 O 2 production. This was found to correlate with a decrease in mitochondrial complex I activity which may involve both direct oxidative damage to the complex itself as well as oxidative effects on the tricarboxylic acid cycle enzyme ␣-ketoglutarate dehydrogenase (KGDH) which provides substrate for the complex. Both complex I and KGDH activities have been reported to be decreased in the Parkinsonian brain. These in vitro events are reversible by catalase addition. Importantly, MAO-B elevation was found to abolish the spare KGDH threshold capacity, which can normally be significantly inhibited before it affects maximal mitochondrial oxygen consumption rates. Our data suggest that H 2 O 2 production via subtle elevations in MAO-B levels can result in oxidative effects on KGDH that can compromise the ability of dopaminergic neurons to cope with increased energetic stress.

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“…A complexity that remains to be explained is the report of Szutowicz et al [52] that MAO-A, or a component tightly bound to it, can modify the behaviour of MAO-B. These authors reported that preincubation of platelet MAO-B with purified human placental MAO-A resulted in a modification of the MAO-B to yield a form of the enzyme with both MAO-A and MAO-B substrate and inhibitor affinities whilst retaining MAO-B immunospecificity.…”

Section: Are There Oddities Out There?mentioning

confidence: 94%

Monoamine Oxidases: Certainties and Uncertainties

Tipton

Boyce²,

O'Sullivan³

et al. 2004

Current Medicinal Chemistry

179

117

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A great deal has been learned about the behaviour of monoamine oxidase in the 75 years since it was first discovered, but there is still a great deal left to understand. This review concentrates on the dynamic aspects of our knowledge of the interactions of MAO with substrates and inhibitors and how it may collaborate with other enzymes, with particular emphasis on aspects that remain to be clarified.

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Metabolism of Acetyl-CoA and Cholinergic Neuropathies

Cited by 5 publications

References 23 publications

Effect of Aluminum on Acetyl‐CoA and Acetylcholine Metabolism in Nerve Terminals

Effect of Aluminum on Acetyl‐CoA and Acetylcholine Metabolism in Nerve Terminals

Oxidative α-Ketoglutarate Dehydrogenase Inhibition via Subtle Elevations in Monoamine Oxidase B Levels Results in Loss of Spare Respiratory Capacity

Monoamine Oxidases: Certainties and Uncertainties

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