The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'.

The neurobiology of zinc in health and disease

A beta 1-40, a major component of Alzheimer's disease cerebral amyloid, is present in the cerebrospinal fluid and remains relatively soluble at high concentrations (less than or equal to 3.7 mM). Thus, physiological factors which induce A beta amyloid formation could provide clues to the pathogenesis of the disease. It has been shown that human A beta specifically and saturably binds zinc. Here, concentrations of zinc above 300 nM rapidly destabilized human A beta 1-40 solutions, inducing tinctorial amyloid formation. However, rat A beta 1-40 binds zinc less avidly and is immune to these effects, perhaps explaining the scarcity with which these animals form cerebral A beta amyloid. These data suggest a role for cerebral zinc metabolism in the neuropathogenesis of Alzheimer's disease.

http://science.sciencemag.org/content/sci/265/5177/1464.full.pdf

Rapid induction of Alzheimer A beta amyloid formation by zinc.

The role of divalent transition metal ions in neural function is poorly understood. In excess, these ions are associated with neurological disorders such as Wilson's disease1, Pick's disease2 and epileptic seizures3,4. We suggest that zinc ions, which are contained in nerve terminals, are extruded into the extracellular space during neuronal activity. Excessive levels of zinc may be released during intense neuronal activation, and contribute to the paroxysm and toxic damage observed. Zinc ions are contained in high concentrations in mossy fibres of the hippocampal formation5, and it is the postsynaptic neurones of these fibres which are most susceptible to the toxic effects of kainic acid6, a potent convulsant, or to chronic exposure to organometallic compounds7. Here we demonstrate for the first time that Zn2+ is released into the extracellular space during excitation of hippocampal slices.

Release of endogenous Zn2+ from brain tissue during activity.

Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Hence, many of its toxic effects are in fact due to copper deficiency. While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells. Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families. One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. Rather than being a toxic metal ion, zinc is an essential trace element. Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal. Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.

https://www.mdpi.com/1660-4601/7/4/1342/pdf

The Essential Toxin: Impact of Zinc on Human Health

Publisher Summary This chapter discusses separate pools of CNS zinc, which are, vesicular zinc, free zinc, and protein-bound zinc Vesicular zinc is the one which is sequestered in the presynaptic vesicles of a special class of neurons, the zinc-containing neurons, which are found primarily in limbic, cerebrocortical, and corticofugal systems This vesicular zinc can be selectively stained by several histochemical procedures and is, therefore, accessible to histological and histoanalytical studies The second pool, free zinc, is an entirely hypothetical pool of ionic Zn +2 in the cytosol or interstitial fluid that may or may not be present in normal, healthy brain tissue The third pool of zinc is that which is bound firmly into the structure of the many zinc-containing enzymes in the brain The enzymatic zinc is, therefore, a stable pool, involved only in the specific function of the zinc-containing enzymes Zinc metalloenzymes are essential to the normal biology of brain cells, and any experimental treatment that is extreme enough to affect the metalloenzymes, such as prolonged zinc undernutrition or administration of chelators, can disrupt brain function through metalloenzymatic effects

Mark A. Klitenick

Papers

Cytoarchitectonic distribution of zinc in the hippocampus of man and the rat