Blue Velvet

A little nubbin of a post tonight, mostly to get my brain churning about a topic that I need to do a bit more reading on. The Journal of Affective Disorders has a number of intriguing papers this month and next, one of them being "Association between inducible and neuronal nitric oxide synthase polymorphisms and recurrent depressive disorder."

What? Doesn't sound intriguing to you? I keep an eye out for nitric oxide in the literature. See, my pet (and as far as I know completely unproven) theory is that the strong link between insulin resistance and depression is not just in the inflammation of hyperglycemia, but also due to insulin resistance making the endothelium (inner cell layer) of blood vessels less responsive to nitric oxide. This can make one hypertensive and prevent men from getting erections (if that doesn't make men want to go low-carb, I'm not sure what would). But endothelial nitric oxide synthase (an enzyme that is part of the pathway that makes nitric oxide in the blood) is thought to be part of a larger neuroprotective and regenerative pathway that (in part) could explain the anti-depressant effects of exercise and meditation. This would imply that high blood sugar would be rather like anti-exercise (sloth) and anti-meditation (stress) neurochemically. Again, speculative but not entirely off the wall.

But of course it is never that simple. Anyone reading up on nitric oxide will figure out that in certain areas of the brain, too much nitric oxide is Bad News. It's pro-oxidant and pro-inflammatory. The authors of today's paper state, "we may conclude that NO may have beneficial and detrimental effects depending on its concentrations, location, source, and duration of exposure."

But don't despair. There are three different types (or isoforms) of the enzyme that churns out nitric oxide. They are inducible nitric oxide synthase, neuronal nitric oxide synthase, and endothelial nitric oxide synthase. We'll call them iNOS, nNOS, and eNOS. For the purposes of understanding a healthy brain, iNOS and nNOS are bad, while eNOS is good.

Just to add more excruciating detail to a familiar Evolutionary Psychiatry theme, glutamate binds the NMDA receptor, leading to a flux of calcium into the cell, activating nNOS (via calmodulin, biochem geeks!). In addition, inflammatory cytokines cause brain cells called astrocytes and microglia to make NO via iNOS. This increases glutamate release. So both iNOS and nNOS are part of the glutamate/NMDA/calcium excitotoxic neuron-killing inflammatory cycle of brain badness.  This pathway is linked to depression, anxiety, parkinson's dementia, schizophrenia, and even non-psychiatric illnesses such as migraines and rheumatoid arthritis.

So the interesting thing from this paper is that the researchers checked the genetic make-up of 181 (caucasian european) people with recurrent depression (around 4 episodes on average over 8 years) and 149 non-depressed controls. They found that carriers of certain types of nitric oxide synthase genes were more likely to have resistant depression, and other types of nitric oxide synthase genes were protective against having depression. A similar but smaller study was done in Asians and didn't show a linkage.

I have more reading to do to see how this information falls into the overall evo-med scheme, especially the exercise and mindfulness side of things. And I'll link the paper and some of my pertinent previous posts sometime tomorrow - if you are reading Sunday night I'm on the iPad.

And I know it was nitrous oxide (N2O) not nitric oxide (NO) in Blue Velvet, but hey, I've got to get the random googlers somehow. And N2O might act by mimicking NO in the central nervous system. So chew on that for a bit. Time for bed!