Zinc, Depression, and Everything

Today I will review more specific and up-to-date information about the interplay between zinc and depressive disorders and inflammation. Let's summarize the human evidence thus far (1):

1) Depressed patients in studies have a lower serum zinc level than normal controls.
2) The more depressed the patients are, the lower the zinc level.
3) Low zinc levels in pregnant women are associated with pre- and postpartum depression.
4) Treatment with antidepressants normalizes zinc levels (I've been a little loose with the terminology, I admit, and this finding helps us keep in mind that zinc level can be just a biomarker for depression, not necessarily a cause or effect per se.)
5) Zinc supplementation plus antidepressant therapy can work better for depression than antidepressants alone.
6) Zinc supplementation alone can have antidepressant effects.

Now let's try to clarify a bit more about zinc and the brain. As I noted in my last post, the hippocampus seems to be the most vulnerable to zinc deficiency. The hippocampus is a center of memory, and it also plays a big role in nerve plasticity and repair. Recall that nitric oxide and antidepressants seem to work by increasing the production of brain derived neurotrophic factor in the hippocampus. BDNF is one of many nerve growth factors in the hippocampus, and is part of several different neurochemical pathways which help in nerve recovery, adaptation, and repair.

Scientists have been able to cobble together the following pathway in rat brains: Zinc deficiency leads to decreased zinc in the synapse, which results in an increase in the NMDA receptors (these receptors respond to glutamate, an excitatory neurotransmitter that can be responsible for toxic effects in the brain if there is too much). At the same time, the inhibitory (in this case, neuroprotective) neurotransmitter GABA is decreased, along with BDNF and another nerve growth factor, NGF. The glutamate level in the synapse is higher, so calcium mediated stimulation of the nerves is primed. Do this too much, and you get "excitotoxicity." This same mechanism is thought (in acute vs chronic and in differing areas of the brain) to be responsible for seizures, migraines, dementia, anxiety, depression, and bipolar disorder (and is why pharmaceutical GABA receptor modulators can be effective for certain symptoms of any of those conditions).

Getting down to the real nitty-gritty, Zinc works in conjunction with nearly all of the different membrane signaling and second messenger systems you might have learned about in molecular biology classes. Membrane gated ion channels, p53 signaling, g-proteins, zinc-fingers (obviously) - the whole lot. This is why even though a lot of these different nerve chemicals work via different mechanisms, or multiple mechanisms, zinc can have a hand in all of these up regulating and down regulating events. Zinc is a cog in the machine all along the way.

So there are clear mechanisms by which absolute zinc deficiency can have a hand in all sorts of bad brain syndromes, and vegetarians, dieters, the elderly, those with malabsorption or intestinal issues, and the two billion people on the planet who (due to poverty) pretty much subsist on grains alone (rich in zinc-binding phytates) are all at risk for absolute zinc deficiency.

But robust presumably zinc-replete meat-eaters of a Western diet are at risk for depression, diabetes, dementia, and cardiovascular disease along with the whole diaspora of the Western chronic diseases. I contend (along with many others) that inflammation is the primary driving mechanism behind the whole shebang. Could there be a mechanism by which inflammation could affect brain zinc levels (or vice versa) as a part of the pathway leading from inflammation to bad brain disease?

Wanna put some money on it? Did I mention that pancreatic beta cells in particular run on a lot of zinc-dependent pathways too (2)(3)?

It's common knowledge that zinc supplementation can help ameliorate a cold (at least if you take the zinc within the first day of symptoms (4)), and, as I mentioned in the last post, zinc has a lot to do with mediating our body's immune response. We use zinc to activate the immune pathways that zap viruses (like colds), but zinc can influence the activity of 2000 (yeah, two thousand) different immune transcription factors. The baddest of these factors is NFkappaB. NFkappaB hangs around in the nucleus of immune cells and helps them make all sorts of inflammatory cytokines to fight off the perceived bad guys - good old inflammatory frenemies such as IL-6, IL-2, TNFalpha and many, many more. (Yesterday I noted that zinc deficiency is associated with increased IL-6, and on review of several articles, it seems that high and low zinc is associated high IL-6. It is probably a part of what I discuss in the next paragraph, but I'll look into it more, as a lot of the work is done by the Polish group or Maes, and they seem to cite each other all the time). Zinc not only directly promotes the synthesis of NFkappaB, it helps it get into the nucleus where it can work, and it helps it bind to the DNA to promote inflammation.

It isn't so simple as that. Turns out that zinc also has a hand in down regulating inflammation too! It even activates a protein that helps inactivate NFkappaB. And IL-6, an inflammatory cytokine which needs zinc the be born, will then activate a protein in the liver called metallothionein, a protein that holds on to zinc and keeps it in the liver, so that even if you eat a lot of zinc, it won't be available in your blood or brain for other uses. A lot of biochemical systems are like this - too little zinc (such as in people born without the ability to absorb it (5) and you get immune dysfuntion and vulnerability to infection, as your protective inflammatory response won't work. But if inflammation gets high enough, it has its own down regulating systems (sequestering zinc via IL-6 and metallothionein, for example) that cool things off.

Our inflammatory and fight or flight systems were built for acute insults. Viruses, injury, bacterial invasion, angry lion attacking the camp. When the insults are chronic (unalleviated stress, gallons of inflammatory-promoting omega-6 fatty acids, weird glutens and lectins, chronic depression-causing viral infections such as herpes, borna disease, HIV, or Epstein Barr), the whole system becomes dysregulated. What should be up is down. So zinc ought to be in the central nervous system, helping out with nerve repair and plasticity, and instead it is crusading with NFkappaB or stuck with metallothionein in the liver, and your poor hippocampus is shorting out on glutamate and calcium. Extra zinc might help. As might antidepressants, GABA receptor modulators, and other neuroprotective chemicals. But those are bailing buckets. What we really need is to correct the problem causing the boat to sink. We need to reduce the inflammatory insults in the first place.

There's more. Always more!