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

Abstract

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.

Aluminum, NO, and nerve growth factor neurotoxicity in cholinergic neurons

“…It is also unclear why considerable loss of cholinergic neurons takes place in AD and other encephalopathies (Szutowicz et al, 1996;Pappas et al, 2000). Our studies indicate that neurotoxic factors involved in pathogenesis of neurodegeneration, such as Al, NO, ␤-A, as well as NGF, are implicated in impairment of acetyl-CoA and energy metabolism in neuronal cells (Bielarczyk et al, 1998;Tomaszewicz et al, 1998;Szutowicz et al, 2000).…”

“…The AlPO 4 (OH) Ϫ was proposed to be a biologically active form of Al because its inhibitory effects on acetyl-CoA and ACh metabolism in nerve terminals were observed only in the medium containing phosphate. Al inhibited oxidation of glucose and pyruvate both in isolated nerve terminals and whole brain mitochondria as well as in cultured SN56 cholinergic neuroblastoma cells (Table I) (Bielarczyk et al, 1998;Szutowicz et al, 1998aSzutowicz et al, ,b, 2000Jankowska et al, 2000). It had, however, no direct inhibitory effect on PDH and KDH activities in disintegrated brain preparations (Zatta et al, 2000).…”

“…Several discrepancies concerning Al effects on cholinergic transmission may result from the differential interferences of extracellular and intracellular Al with cholinergic metabolism (Bielarczyk et al, 1998;Szutowicz et al, 1998b). Extracellular Al was found to inhibit Ca 2ϩ entry through voltage-gated Ca-channels (Koenig and Jope, 1987).…”

Phytoconstituents Profile of Clitoria Ternatea by Gc-MS and Its Age-Related Anticholinergic Activity Against Aluminum and Restraint Stress

“…The cholinotoxic effects of Al are exerted by blocking Acetyl CoA-which is responsible for ACh synthesis 28 . In the present study ACh levels were decreased in AlM and RS of both the age groups compared to control.…”

Aluminium Binding Amount of Dietary Fiber Extracted from 14 Kinds of Food.

“…Aluminium (Al) is known to accumulate in the brain and may cause neurotoxic injury by long-term exposure (Sarin et al, 1997;Oshiro et al, 1998;Gonda & Lehotzky, 1996;Bielarczyk et al, 1998;Gandolfi et al, 1998).…”