Overview of the Biological Role of Zinc

Zinc is the second most abundant trace element in the body and as such any deficiency has serious effects on normal bodily physiology. These effects can include abnormal development, psychological disorders, anorexia, and movement disorders. Interestingly, all of these are reversible with dietary zinc supplementation (1). To date there are no known cases of adult zinc toxicity due to modest over-supplementation, though massive over consumption in infants and pets can have some side effects such as gastrointestinal problems (2). As zinc enters the body primarily through the gastrointestinal tract, careful monitoring for the accidental ingestion of high zinc containing items (e.g. pennies) is necessary with pets and babies.

Normally over consumption of zinc is not a cause for concern. Most bodily zinc is tightly bound to proteins where it plays as a structural or catalytic role. Unbound (or very loosely bound) zinc is present in neurotransmitter vesicles in many glutamatergic presynaptic terminals. As such, release of the neurotransmitter due to neural stimulation will also result in a release of zinc into the synapse (3). Once in the synapse, zinc is able to modulate the activity of postsynaptic glutamate receptors, namely the N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. Zinc binding to the NMDA receptors will result in decreased activity, while binding to AMPA receptors will result in increased activity. This differential activity might be involved in maintaining the integrity of the electrical signal through AMPA receptor activation while decreasing the chemical signaling cascade through NMDA receptor deactivation in the presence of moderate to high frequency stimulation (1). This also results in an overall lower influx of calcium, of which extreme levels can lead to cell death. Thus, the release of zinc normally plays a cell-protective role. However, excess levels of synaptic zinc can cause cell death. Such excess in synaptic zinc occurs most often after an ischemic event.

zinc pathway

Zinc Toxicity Due to Cerebral Ischemia
Cerebral ischemia is the loss of blood flow (and thus oxygen) to an area of the brain, most often caused by either a clot or a hemorrhage (4). The ischemic event can be either local or global depending on the location and duration of the blood flow stoppage. This anoxia will actually result in an extreme overactivation of the cells in that brain area as the membrane potential is disrupted. This disruption causes the fusion of large amounts of neurotransmitter vesicles and the subsequent release of large amounts of neurotransmitter and, if present, zinc. This only occurs in neurons in the cerebral cortex and hippocampus, areas that are especially susceptible to damage from stroke (4). This susceptibility due to zinc release might be due to the large concentrations of post-synaptic NMDA receptors in these two brain areas, thus allowing zinc to have a very pronounced effect.

cerebral ischemia

The actual action of the excess zinc on the postsynaptic cell is still unclear. However, different theories have been proposed. One of the most accepted theories is that excess zinc reduces the genetic transcription of the GluR2 subunit of the AMPA receptor, the subunit responsible for the calcium impermeability of the receptor. Without this receptor subunit, the calcium influx upon glutamate stimulation is drastically increased and cell death ensues (5). Another possible mechanism is actually through the NMDA receptor, which zinc normally inhibits. Zinc’s blockade of the NMDA receptor has been shown to be relatively transient and results in zinc and calcium being taken up into the postsynaptic cell. The increased calcium promotes cell death through the calpain pathway and the increased zinc is toxic to mitochondria through reactive oxide species (1,3). Thus, this toxicity is likely caused by both postsynaptic accumulation of zinc and the zinc-mediated accumulation of calcium.

The possible involvement of zinc in the neuronal death associated with cerebral ischemia raises an entirely new outlook on the prevention of such damage.  As of yet, treatment with calcium chelators has been relatively ineffective in preventing anoxic cell death. As such, the only current method of intervention is the quick removal of the clot or repair of the hemorrhage, something that is not always possible. Recent research has shown that the anoxic death of cultured cortical and hippocampal cells can be prevented with a zinc-free medium. Likewise, extracellular zinc chelators reduce such death in laboratory animals with an induced cerebral ischemia (6,7). However, the problem of getting these chelators into the brain remains unsolved. This preventative mechanism for ischemia induced zinc toxicity will undoubtedly be a large area of research in the upcoming years.


Overview of the Normal Role of Zinc

Zinc Fact Sheet

American Zinc Association

International Zinc Association

Review of the Benefits of Zinc Supplementation

The Pathophysiology of Ischemic Injury


(1) Choi, D. W., & Koh, J. Y. Zinc and brain injury. Annu. Rev. Neurosci. 21, 347-375 (1998).


(3) Konoha, K., Sadakane, Y., & Kawahara, M. Zinc neurotoxicity and its role in neurodegenerative diseases. J. Health Science. 52, 1-8 (2006).

(4) Galasso, S., & Dyck, R. H. The role of zinc in cerebral ischemia. J. Mol. Med. 13, 380-307 (2007).

(5) Weiss, J. H., & Sensi, S. L. Ca2+-Zn2+ permeable AMPA or kainite receptors: possible key factors in selective neurodegeneration. Trends Neurosci. 23, 365-371 (2000).

(6) Koh, J., Suh, S. W.,Gwag, B. J., He, Y. Y., Hsu, C. Y., & Choi, D. W. The role of zinc in selective neuronal death after transient global cerebral ischemia. Science. 272, 1013-1016 (1996).

(7) Fredrickson, C. J., Maret, W., & Cuajungo, M. P. Zinc and excitotoxic brain injury: A new model. The Neuroscientist. 10, 18-25 (2004)

Author: James Corson