Additive aluminum as a cause of induced immunoexcitoxicity resulting in neurodevelopmental and neurodegenerative disorders: A biochemical, pathophysiological, and pharmacological analysis

Abstract

Much has been learned about the neurotoxicity of aluminum over the past several decades in terms of its ability to disrupt cellular function, result in slow accumulation, and the difficulty of its removal from cells. Newer evidence suggests a central pathophysiological mechanism may be responsible for much of the toxicity of aluminum and aluminofluoride compounds on the brain and spinal cord. This mechanism involves activation of the brain's innate immune system, primarily the microglia, astrocytes, and macrophages, with a release of neurotoxic concentrations of excitotoxins and proinflammatory cytokines, chemokines, and immune mediators. Many studies suggest that excitotoxicity plays a significant role in the neurotoxic action of several metals, including aluminum. Recently, researchers have found that while most of the chronic pathology involved in the observed neurodegenerative effects of these metals are secondary to prolonged inflammation, it is the enhancement of excitotoxicity by the immune mediators that are responsible for most of the metal's toxicity. This enhancement occurs through a crosstalk between cytokines and glutamate-related mechanisms. The author coined the name immunoexcitotoxicity to describe this process. This paper reviews the evidence linking immunoexcitotoxicity to aluminum's neurotoxic effects and that a slow accumulation of aluminum may be the cause of neurodevelopmental defects as well as neurodegeneration in the adult.

Keywords: Accumulation in neurons and glia; Aluminofluoride complex; Aluminum; Excitotoxicity; Immunoexcitotoxicity; Microglial activation; Nanoscaled aluminum; Neurodegeneration; Sickness behavior.

Figure 1:

Synaptic illustration showing trafficking of AMPAR initiated by activation of tumor necrosis factor (TNF) R1 by high levels of TNF-alpha, which then releases GluR 2-lacking AMPA receptors from the endoplasmic reticulum. This AMPA type of receptor allows calcium entry into the neuron, thus making it much stronger and potentially more destructive. Internalization of the gamma-aminobutyric acid inhibitory receptor is not shown but occurs when stimulated by inflammation. Na+: Sodium, Ca2+: Calcium, AMPA:α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA:N-methyl-D-aspartate,Mg 2+: Magnesium, TNFR: Tumor necrosis factor receptor, AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, MAPK: Mitogen-activated protein kinase, CREB: cAMP-response element binding protein, CaMK:Calmodulin-dependent protein kinase, PKC: Protein kinase C.

Figure 2:

An activated, primed microglial cell initiating both an inflammatory reaction (inflammatory cytokine and inflammatory prostaglandin release) and excitotoxicity (Immunoexcitoxicity). IL: Interleukin, TNF: Tumor necrosis factor, ROS: Reactive oxygen species, RNS: Reactive nitrogen species.

Figure 3:

Activation of tumor necrosis factor-alpha mechanisms that enhance excitotoxicity. TNF: Tumor necrosis factor, EAATs: Excitatory amino acid transporters, TNFR: Tumor necrosis factor receptor, GABA: γ-aminobutyric acid, AMPAr: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor