Neuroprotective Nootropics: A Brief Primer

Since suffering a concussion a few years ago, I've been captivated by neuroprotective compounds.

Wouldn’t it be nice to protect your brain from the daily “scrapes and bruises” that everyone inevitably encounters?

Let's step back for a moment. What does “neuroprotective” mean?

Put simply:

Neuroprotective compounds shield your brain from a neurological insult.

Here are some examples of "neurological insults":

• radiation
• exposure to neurotoxins (e.g., mercury)
• a head injury
• a depressive episode
• substance abuse
• living next to a freeway
• high sugar diet plus sedentary lifestyle
• nutritional deficiencies (e.g., insufficient dietary iodine)

Anything that’s “bad” for your brain can be codified as a neurological insult.

The human brain tends to deteriorate with age (though this is not universally the case). Given this fact of life, it is in our collective interest to explore neuroprotective strategies and prevent brain aging.

Many nootropic enthusiasts may be more drawn to cognitive enhancing nootropics that promise to propel functioning above baseline.

Neuroprotection doesn't sound quite as sexy as cognitive enhancement. But since humans live in a messy environment, we’re constantly accruing neurological microdamage.

In principle, neuroprotective substances could enhance ability if everyone is at baseline exposed to neurotoxins. What if we could protect ourselves from neurotoxic events - wouldn’t that be pretty cool?

What Drugs or Supplements Are “Neuroprotective”?

Although diverse, neuroprotective substances "work" via a small number of mechanisms. Neuroprotective compounds prevent at least one of the following:

Excitotoxicity

Excitotoxicity usually refers to glutamate excitoxocity.

Too much glutamate overactivates neurons, leading to unchecked calcium entry and cell death.

Oxidative damage

Oxidative damage (aka oxidative stress) is a catch-call phrase for damage to cellular components induced by free radicals.

I'm personally skeptical of the free radical theory of aging. It's reductionistic and overly simplistic - kind of like the monoamine hypothesis of depression.

Inflammation

There are some interesting tradeoffs with inflammation.

If your immune response is too weak, you're more likely to suffer infections and face an increased risk of cancer. The immune response is critical for for fighting cancerous cells.

On the other hand, overzealous immune encourages autoimmune diseases like narcolepsy and multiple sclerosis.

Immune system hypersensitivity is also linked to depression and Alzheimer's disease. Depressives have markedly increased TNFalpha, a pro-inflammatory cytokine. It's unclear whether immune markers are a consequence of depression, a causal factor, or both.

In general, putting a damper on the immune system is good for cognitive health. It's no coincidence that minocycline is both a powerful immunosuppressive drug and a neuroprotectant.

Insulin Resistance

Consuming too much sugar over a period of time results in insulin resistance.

Insulin is needed for glucose (sugar) to enter cells.

After eating, there's an insulin spike. Most of the glucose in your bloodstream is taken up into cells to generate ATP, which lowers blood sugar.

But over time eating lots of carbohydrates leads to sustained increases in blood sugar. Insulin receptors become less sensitive, resulting in insulin resistance.

Paradoxically, high blood sugar starves cells of sugar.

Dietary flavonoids have a protective effect against hyperglycemia (elevated blood sugar). This means that dietary flavonoids also have a neuroprotective effect.

Apoptosis/necrosis

Apoptosis and necrosis are mechanisms of cell death.

Nutritional deficiencies

Nutritional deficiencies can have a big impact on cognitive function, particularly during development.

Some deficiencies to watch out for include:

• Iodine deficiency (largest cause of preventable intellectual disability worldwide)
• Magnesium deficiency (magnesium is an endogenous neuroprotectant)
• Vitamin D deficiency
• Iron deficiency (iron is needed to form heme groups in hemoglobin which delivers oxygen to the brain)

A Classic Neuroprotectant

Magnesium is a classic neuroprotective agent.

It sits in the pore of NMDA-type glutamate receptors. NMDA-type glutamate receptors act as a kind of “coincidence detector” (http://www.cell.com/neuron/abstract/S0896-6273(12)00440-0) that underpins the encoding of long-term memories. Hence, blocking NMDARs outright with DXM or high-dose ketamine results in amnesia.

But on the other hand, excessive activation of NMDARs entails excitoxicity and cell death. Magnesium is an essential mineral that protects neurons from excess activation.

Melatonin

Melatonin is another neuroprotectant. It’s endogenous, meaning that it’s naturally present in your body.

Melatonin plays a well-known role in circadian rhythm. But it’s also one of the most robust antioxidants. Both the antioxidant effects of melatonin coupled with its beneficial effects on sleep hygiene make it a strong neuroprotectant.

Curcumin

There are a staggering number of studies published on the neuroprotective effects of curcumin.

Like melatonin, curcumin’s neuroprotective effects are likely mediated by bolstering antioxidant defense.

Modafinil

Modafinil is, surprisingly, neuroprotective.

I say surprising because modafinil is known to enhance cortical glutamate release while suppressing GABA release.

In addition to modafinil showing potent effects on the sleep/wake system, it is clear that modafinil has noteworthy neuroprotective effects as well that involve some sort of antioxidative process. While these effects may be coincidental to modafinil’s wake-promoting effects, the role of the ATP breakdown product adenosine in homeostatic sleep regulation is at least suggestive that modafinil’s neuroprotective effects are not irrelevant to the consideration of modafinil’s wake-promoting effects. Because the primary site of action of modafinil’s antioxidant effects remains elusive, we discuss some possible targets for future investigation here.

Excerpted from Mechanisms of modafinil: A review of current research.

Melatonin

Minocycline is a broad-spectrum tetracycline antibiotic originally introduced in 1971. It’s synthetic, though it’s derived from natural antibiotics. Minocycline is indicated for the treatment of acne and a host of other diseases.

Minocycline has robust neuroprotective and neurorestorative effects that are unrelated to its antibiotic activity.

• Inhibition of nitric oxide synthase (NOS)
• Inhibition of 5-lipoxygenase
• Reduction of TNFalpha

But minocycline is an extremely potent drug and should not be used lightly.

Some adverse effects to watch out for are photosensitivity (the sun will burn you!). Minocycline is also rarely associated with liver toxicity and "benign" intracranial hypertension (hint: it's not really benign). Intracranial hypertension presents with intractable headaches.