Chronic exposure to low levels of aluminum alters cerebral cell signaling in response to acute MPTP administration

Abstract

Two-month-old male B/6C3F1 mice were treated for 10 weeks with 100 microM aluminum lactate (Al) in drinking water. This dose of Al did not alter body weight, and there was no evidence of systemic toxicity. The degree of phosphorylation of several kinases which lead to transcription factor activation (reflecting the extent of their activation) was studied. The proportion of extracellular signal-regulated kinase (ERK) that was activated was depressed in cortex but not in the hippocampus following treatment but c-Jun N-terminal kinase (JNK), p38, IkappaB phosphorylation was unaltered in either tissue. Treatment of mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) alone produced no significant changes in the degree of activation of any transcription factor studied. When MPTP dosing had been preceded by extended exposure to low levels of Al in drinking water, ERK activation was profoundly depressed in cortex and hippocampus, whereas JNK in hippocampus and IkappaB in cortex were greatly elevated. These changes consequent to exposure to both Al and MPTP were accompanied by an increase in NF-kappaB in both regions, whereas AP-1 was elevated in the hippocampus alone. Neither agent alone modulated AP-1 or NF-kappaB. Thus a synergistic interaction occurred between the toxicants. This interaction tended to promote the functioning of a kinase largely associated with inflammation and to depress that of ERK, which is associated with maintenance of cell survival. It is concluded that exposure to levels of Al with no evident toxicity can worsen the response to an acute challenge with MPTP. Al treatment alone was able to increase striatal 3,4-dihydroxyphenylacetic acid levels, suggesting an elevation of the rate of dopamine turnover in the striatum. However, no interaction in alteration of monoamine levels was found between Al and MPTP.

The neurotoxicity of environmental aluminum is still an issue

“…Extended exposure to 100μM Al lactate increased striatal levels of the dopamine metabolite, DOPAC (Li et al, 2008). This was accompanied by a non-significant trend toward depressed levels of dopamine, suggesting that exposure to Al may cause increased turnover of dopamine.…”

“…1). Thus, aluminum and MPTP interact synergistically in enhancing dopamine turnover, levels of GFAP and activation of NF-| B (Li et al, 2008). There are reports of potentiation of MPTP effects by other neurotoxicants including 3-niroproprionic acid (Ahuja et al, 2008).…”

Melatonin Alters Age-Related Changes in Transcription Factors and Kinase Activation

“…The competitor reactions also contained 50 μg of nuclear fraction derived from Al-treated mouse brains. This treatment has been shown not to alter the extent of NF-kB or AP-1 activation [14]. X-ray films were manually developed and the intensity of each band was measured and quantitated using the image analyzer, Eagle Eye, from Strategene (San Diego, CA).…”

Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

“…Monoamine oxidase B is able to promote alpha-synuclein fibril formation and this may account for the observed association between neurotoxic metals and PD (Uversky et al, 2001). The initiation of inflammatory processes by activation of the transcription factor NF-kB was found to occur after simultaneous treatment of experimental animals with the dopaminergic neurotoxin, MPTP and low levels of Al in drinking water (Li et al, 2008), in a synergistic manner.…”