Using Ketamine to Find an Undiscovered Pathway in Depression


Summary: Ketamine treatment leads to an increase in IGF-1, which, in turn, produces an antidepressant effect.

Source: Osaka Metropolitan University

For the 280 million people suffering from depression globally, relief cannot come fast enough. Monoaminergic antidepressants, including selective serotonin reuptake inhibitors (SSRIs) take weeks to months to take effect and do not work for more than one in three patients.

For patients diagnosed with treatment-resistant depression, or in immediate crisis, access to safe, effective, rapid-acting antidepressants can improve lives and decrease suicide.

One current possibility being investigated is ketamine, which can improve depression, even in treatment-resistant patients. Ketamine is an anesthetic used for over 50 years, but it has serious side-effects, including dependence, hallucinations, and delusions.

So, while preclinical studies have shown that a single dose of ketamine can have beneficial long-term effects on mental health and is only used to treat depression as a last resort.

There are good reasons to be cautious; in addition to the side-effects, the way ketamine alters brain chemistry is not fully understood. If the biological mechanisms in the brain that ketamine influences are discovered, new drugs could be developed to target the beneficial antidepressant effect specifically.

The study led by Professor Kondo demonstrated ketamine treatment led to an increase in insulin-like growth factor 1 (IGF-1), a known antidepressant brain molecule. However, they did not know if this was linked to previously discovered ketamine related antidepressant molecules like brain-derived neutrophic factor (BDNF).

This shows a depressed looking woman
This discovery indicates that ketamine uses a previously unknown pathway that produces an antidepressant effect.

They confirmed IGF-1 produced an antidepressant effect then demonstrated that they could switch it off by blocking it with an IGF-1 neutralizing antibody.

After demonstrating they could switch off IGF-1, the researchers followed up with a separate experiment. Previous studies have shown that ketamine increases BDNF, a protein that promotes nerve growth, so the researchers wanted to check if IGF-1 and BDNF were working together or separately.

They tested whether IGF-1 and BDNF neutralizing antibodies blocked the other proteins antidepressant effect, they did not, leading the researchers to conclude that IGF-1 and BDNF work through their own independent pathways.

This discovery indicates that ketamine uses a previously unknown pathway that produces an antidepressant effect. The researchers hypothesized that the single dose of ketamine increases the level of IGF-1 in the brain, persistently changing prefrontal cortex nerves and causing them to increase their number of stable connections.

The link between ketamine and IGF-1 presents a brand-new direction for future studies investigating antidepressants that target IGF-1 directly.


IGF-1 release in the medial prefrontal cortex mediates the rapid and sustained antidepressant-like actions of ketamine

Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts rapid and sustained antidepressant actions. Preclinical studies demonstrated that the release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor in the medial prefrontal cortex (mPFC) is essential for the antidepressant-like effects of ketamine.

However, the role of other neurotrophic factors in the antidepressant-like effects of ketamine has not been fully investigated. Since the intra-mPFC infusion of insulin-like growth factor 1 (IGF-1) reportedly produced antidepressant-like effects, the present study examined the role of endogenous intra-mPFC IGF-1 signaling in the antidepressant-like actions of ketamine.

In vivo microdialysis showed that ketamine (10 and 30 mg/kg) significantly increased extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 h. Infusion of an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 min before or 2 h after ketamine injection blocked the antidepressant-like effects of ketamine in three different behavioral paradigms (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively).

The ketamine-like antidepressant-like actions of the intra-mPFC infusion of BDNF (100 ng/side) and IGF-1 (50 ng/side) respectively were not blocked by co-infused IGF-1 nAb and BDNF nAb (200 ng/side).

Moreover, intra-mPFC infusion of IGF-1 nAb 2 h post-ketamine blocked the antidepressant-like effects of ketamine in a murine lipopolysaccharide (LPS)-induced depression model. Intra-mPFC IGF-1 infusion also produced antidepressant-like effects in the LPS-challenged mice via mechanistic target of rapamycin complex 1 activation.

These results suggest that persistent release of IGF-1, independently of BDNF, in the mPFC is essential for the antidepressant-like actions of ketamine.

Low-Protein and Low-Carb Diet May Slow Alzheimer’s Disease


Low-Protein Diet

Story at-a-glance

  • A deficiency of healthy fats, combined with too many carbs may be at the heart of the Alzheimer’s epidemic
  • A growing body of research suggests there may be a powerful connection between the foods you eat and your risk of Alzheimer’s disease and dementia, via similar pathways that cause type 2 diabetes. In one recent animal study, researchers were able to induce dementia by disrupting the proper signaling of insulin in the brain
  • Previous animal research has shown that calorie restriction protects against aging, oxidative stress and neurodegenerative pathologies, and that reduced levels of IGF-1 mediate some of these protective effects.
  • Recent research has also shown that intermittent fasting triggers a variety of health-promoting hormonal and metabolic changes similar to those of constant calorie restriction—including reduced age-related brain shrinkage

Alzheimer’s disease is the sixth leading cause of death in the U.S. This fatal and progressive condition destroys brain cells, resulting in memory loss and severe thinking and behavioral problems (aggression, delusions, and hallucinations) that interfere with daily life and activities.

The cause is conventionally believed to be a mystery. While we know that certain diseases, like type 2 diabetes, are definitively connected to the foods you eat, Alzheimer’s is generally thought to strike without warning or reason.

That is, until recently.

A growing body of research suggests there may be a powerful connection between the foods you eat and your risk of Alzheimer’s disease and dementia, via similar pathways that cause type 2 diabetes. Some have even re-named Alzheimer’s as “type 3 diabetes.”

Top Dietary Factor Now Implicated in Skyrocketing Dementia Rates

Faulty insulin (and leptin), signaling caused by a high non-fiber carb diet is an underlying cause of insulin resistance, which, of course, typically leads to type 2 diabetes. However, while insulin is usually associated with its role in keeping your blood sugar levels in a healthy range, it also plays a role in brain signaling.

In a 2012 animal study,1 researchers were able to induce dementia by disrupting the proper signaling of insulin in the brain.

All in all, it seems clear that your diet plays a tremendous part in Alzheimer’s, and the low-fat craze may have wrought more havoc than anyone could ever have imagined. It was the absolute worst recommendation possible, limiting the nutrient you, and your brain, need the most in your diet.

The disease is currently at epidemic proportions, with 5.4 million Americans — including one in eight people aged 65 and over — living with Alzheimer’s disease. By 2050, this is expected to jump to 16 million, and in the next 20 years it is projected that Alzheimer’s will affect one in four Americans. If that comes to pass, it would then be more prevalent than obesity and diabetes is today!

How Carbohydrates Can Activate Disease Processes

Dr. Ron Rosedale, a prominent expert in the low-carb, high-quality fat approach to improving your health, was possibly the first person to advocate both a moderate protein (and therefore high fat) and low-carb diet. Most low-carb advocates were very accepting of, if not promoting, high protein, and protein was, and still is, often recommended as a replacement for the carbs.

However, a high-fat, low-carb diet is very different than a high-protein, low-carb diet and this is a major source of confusion by both the public and researchers when doing studies and publishing conclusions as if all low-carb diets are the same.

You cannot live without protein, as it’s a main component of your body, including muscles, bones, and many hormones. We also know that protein was instrumental in advancing our intelligence. However, most people today are indulging in hormone laced, antiobiotic loaded meats conveniently available at fast food restaurants and processed meats in grocery stores.

How Much Protein is ‘Enough?’

Dr. Rosedale believes the average amount of protein recommended for most adults is about one gram of protein per kilogram of LEAN body mass, or one-half gram of protein per pound of lean body weight. (As an example, if your body fat mass is 20 percent, your lean mass is 80 percent of your total body weight.

If your total weight is 200 pounds, you would divide 160 by 2.2 to convert pounds to kilograms and come up with 72.7 grams of protein. If you are doing vigorous exercises or are pregnant you can add up to another 25 percent or another 18 grams in this illustration to increase your total to 90 grams per day.)

This is something that makes sense to me and something I seek to apply personally, but this is partly because I foolishly had my amalgam fillings removed 20 years ago by a non-biologically trained dentist that caused serious kidney damage, so I can’t tolerate high levels of protein anyway. However, it seems obvious to me that most people consume too much low-quality protein and carbohydrates, and not enough healthy fat.

So it would make sense that the majority of your diet should be comprised of good fats, followed by good proteins like whey protein concentrate from grass-fed cows, and organic grass-fed beef, pastured organic eggs and chicken, and fish like wild caught salmon.

Your healthiest option is to ensure your carbs come primarily from fresh, organic vegetables, high-quality protein, and eat primary a high fat diet. Depending on the type of carbs (high fiber or not), most people need anywhere between 50-75 percent fat in their diet and sometimes even higher for optimal health.

Another Brain-Boosting Alternative: Intermittent Fasting

Recent research has also shown that intermittent fasting triggers a variety of health-promoting hormonal and metabolic changes similar to those of constant calorie restriction — including reduced age-related brain shrinkage. According to Professor Mark Mattson,2 head of neuroscience at the U.S. National Institute on Ageing:

“Suddenly dropping your food intake dramatically — cutting it by at least half for a day or so — triggers protective processes in the brain.”

He likens the effects to those from exercise, stating intermittent fasting could help protect your brain against degenerative diseases such as Alzheimer’s and Parkinson’s. Constant calorie restriction typically includes restriction of protein, and as discussed above, some of the beneficial effects of calorie restriction may actually be due to the reduction in protein. Likewise, intermittent fasting, where meals are either restricted to a small window of time each day, or calories are restricted on specific days of the week, will also typically lead to a reduction in the amount of protein you consume.

Again, going back to the featured study, the animals were only given a protein-restricted diet every other week for four months — essentially, they were on an intermittent fasting-type diet. So we’re not promoting going vegan here. Just cutting your protein back to what your body really needs, and no more. The science on this is relatively new and there are many different protocols but I personally have evolved to the point where I do it on most days. I will make exceptions a few times a month.

Alzheimer’s Might be ‘Brain Diabetes’

No discussion of brain health can be complete without emphasizing the need to dramatically cut down on the sugars in your diet. It’s becoming increasingly clear that the same pathological process that leads to insulin resistance and type 2 diabetes may also hold true for your brain. As you over-indulge on sugar and grains, your brain becomes overwhelmed by the consistently high levels of sugar and insulin and eventually shuts down its insulin signaling, leading to impairments in your thinking and memory abilities, and eventually causing permanent brain damage.

You may already know I have become passionate about warning of the dangers of fructose. There is NO question in my mind that consuming more than 25 grams of fructose regularly will dramatically increase your risk of dementia and Alzheimer’s disease. Consistently consuming too much fructose will inevitably wreak havoc on your body’s ability to regulate proper insulin levels.

Additionally, fructose has other modes of neurotoxicity, including causing damage to the circulatory system upon which the health of your nervous system depends, as well as profoundly changing your brain’s craving mechanism, often resulting in excessive hunger and subsequent consumption of additional empty carbohydrate-based calories. In one study3 from UCLA, researchers found that rats fed a fructose-rich and omega-3 fat deficient diet (similar to what is consumed by many Americans) developed both insulin resistance and impaired brain function in just six weeks.

More Tips for Avoiding Alzheimer’s Disease

The beauty of following my newly revised Nutrition Plan is that it helps treat and prevent all chronic degenerative diseases, from the common ones like heart disease, cancer, diabetes, obesity and Alzheimer’s to the ones you have never heard of or can’t even pronounce. It is divided into three helpful sections, Beginner, Intermediate and Advanced to help you start at the right level.

The plan is the first step in addressing Alzheimer’s disease. In spite of how common memory loss is among Westerners, it is NOT a “normal” part of aging. While even mild “senior moments” may be caused by the same brain lesions associated with Alzheimer’s disease and other forms of dementia, these cognitive changes are by no means inevitable! People who experience very little decline in their cognitive function up until their deaths have been found (post-mortem) to be free of brain lesions, showing that it’s entirely possible to prevent the damage from occurring in the first place… and one of the best ways to do this is by leading a healthy lifestyle.

  • Limit fructose. Most people will benefit from keeping their total fructose consumed below 25 grams per day.
  • Only use moderate amounts of protein. The featured studies provide compelling evidence that in most cases you will want to limit your protein to the levels discussed in the article. Most people consume 200-300 percent more protein than their body can use and the altered metabolism and metabolic breakdown products can be pernicious to human health.
  • Improve your magnesium levels. There is some exciting preliminary research strongly suggesting a decrease in Alzheimer symptoms with increased levels of magnesium in the brain. Unfortunately most magnesium supplements do not pass the blood brain barrier, but a new one, magnesium threonate, appears to and holds some promise for the future for treating this condition.
  • Optimize your vitamin D levels with safe sun exposure. Strong links between low levels of vitamin D in Alzheimer’s patients and poor outcomes on cognitive tests have been revealed.4 Researchers believe that optimal vitamin D levels may enhance the amount of important chemicals in your brain and protect brain cells by increasing the effectiveness of the glial cells in nursing damaged neurons back to health.Vitamin D may also exert some of its beneficial effects on Alzheimer’s through its anti-inflammatory and immune-boosting properties. Sufficient vitamin D is imperative for proper functioning of your immune system to combat inflammation that is also associated with Alzheimer’s.
  • Keep your fasting insulin levels below 3. This is indirectly related to fructose, as it will clearly lead to insulin resistance. However other sugars (sucrose is 50 percent fructose by weight), grains and lack of exercise are also important factors.
  • Vitamin B12. According to a small Finnish study recently published in the journal Neurology,5 people who consume foods rich in B12 may reduce their risk of Alzheimer’s in their later years. For each unit increase in the marker of vitamin B12 (holotranscobalamin) the risk of developing Alzheimer’s was reduced by 2 percent. Very high doses of B vitamins have also been found to treat Alzheimer’s disease and reduce memory loss.
  • Eat a nutritious diet, rich in folate, such as the one described in my nutrition plan. Vegetables, without question, are your best form of folate, and we should all eat plenty of fresh raw veggies every day.
  • High-quality animal-based omega-3 fats, such as krill oil. (I recommend avoiding regular consumption of most fish because, although fish is naturally high in omega-3, most fish are now severely contaminated with mercury.) High intake of the omega-3 fats EPA and DHA help by preventing cell damage caused by Alzheimer’s disease, thereby slowing down its progression, and lowering your risk of developing the disorder.
  • Coconut Oil may offer profound benefits in the fight against Alzheimer’s disease. One of the primary fuels your brain uses is glucose, which is converted into energy. When your brain becomes insulin resistant, atrophy due to starvation can occur. However, ketone bodies, or ketoacids can also feed your brain, perhaps better, and prevent brain atrophy. It may even restore and renew neuron and nerve function in your brain after damage has set in. In fact, ketones appear to be the preferred source of brain food in patients affected by diabetes or Alzheimer’s.Ketones are what your body produces when it converts fat (as opposed to glucose) into energy, and a primary source of ketone bodies are the medium chain triglycerides (MCT) found in coconut oil.
  • Astaxanthin is a natural pigment with unique properties and many clinical benefits, including some of the most potent antioxidant activity currently known. As a fat-soluble nutrient, astaxanthin readily crosses your blood-brain barrier. One study6 found it may help prevent neurodegeneration associated with oxidative stress, as well as make a potent natural “brain food.”
  • Eat plenty of blueberries. Wild blueberries, which have high anthocyanidin and antioxidant content, are known to guard against Alzheimer’s and other neurological diseases.
  • Gingko biloba: Many scientific studies have found that Ginkgo biloba has positive effects for dementia. Gingko, which is derived from a tree native to Asia, has long been used medicinally in China and other countries. Sixteen years ago, in one of the first issues of my newsletter, I posted the results of a 1997 study from JAMA that showed clear evidence that Ginkgo improves cognitive performance and social functioning for those suffering from dementia. Research since then has been equally promising. One study in 2006 found Gingko as effective as the dementia drug Aricept (donepezil) for treating mild to moderate Alzheimer’s type dementia. A 2010 meta-analysis found Gingko biloba to be effective for a variety of types of dementia.
  • Alpha lipoic acid (ALA) can help stabilize cognitive functions among Alzheimer’s patients and may slow the progression of the disease.
  • Avoid and remove mercury from your body. Dental amalgam fillings, which are 50 percent mercury by weight, are one of the major sources of heavy metal toxicity, however you should be healthy prior to having them removed. Once you have adjusted to following the diet described in my optimized nutrition plan, you can follow the mercury detox protocol and then find a biological dentist to have your amalgams removed.
  • Avoid aluminum, such as antiperspirants, non-stick cookware, vaccine adjuvants, etc.
  • Exercise regularly. It’s been suggested that exercise can trigger a change in the way the amyloid precursor protein is metabolized,7 thus, slowing down the onset and progression of Alzheimer’s. Exercise also increases levels of the protein PGC-1alpha. Research has also shown that people with Alzheimer’s have less PGC-1alpha in their brains8 and cells that contain more of the protein produce less of the toxic amyloid protein associated with Alzheimer’s. I would strongly recommend reviewing the Peak Fitness Technique for my specific recommendations.
  • Avoid flu vaccinations as most contain both mercury and aluminum, well-known neurotoxic and immunotoxic agents.
  • Challenge your mind daily. Mental stimulation, especially learning something new, such as learning to play an instrument or a new language, is associated with a decreased risk of Alzheimer’s. Researchers suspect that mental challenge helps to build up your brain, making it less susceptible to the lesions associated with Alzheimer’s disease.
  • Avoid anticholinergic and statin drugs. Drugs that block acetylcholine, a nervous system neurotransmitter, have been shown to increase your risk of dementia. These drugs include certain nighttime pain relievers, antihistamines, sleep aids, certain antidepressants, medications to control incontinence, and certain narcotic pain relievers.Statin drugs are particularly problematic because they suppress the synthesis of cholesterol, deplete your brain of coenzyme Q10 and neurotransmitter precursors, and prevent adequate delivery of essential fatty acids and fat-soluble antioxidants to your brain by inhibiting the production of the indispensable carrier biomolecule known as low-density lipoprotein.

IGF-1 and Its Receptor in Esophageal Cancer: Association with Adenocarcinoma and Visceral Obesity.


The insulin-like growth factor (IGF) pathway and visceral obesity have been independently linked with esophageal cancer. This study aimed to delineate the differential and interlinked role of visceral obesity and the IGF-1 system in esophageal adenocarcinoma and esophageal squamous-cell carcinoma (SCC).

METHODS:

IGF-1 receptor (IGF-1R) mRNA and protein were examined in esophageal SCC (KYSE 410, OE21) and esophageal adenocarcinoma (OE19, OE33) cell lines by western blotting. Tumor cell proliferation in response to IGF-1 was assessed by bromodeoxyuridine incorporation assay. In esophageal tumor sections, expression of IGF-1R and CD68+ cell numbers were assessed by immunohistochemistry. IGF-1 was measured in serum from esophageal cancer patients, Barrett’s esophagus patients, and healthy controls by enzyme-linked immunosorbent assay.

RESULTS:

Higher IGF-1R protein expressions were observed in SCC cells compared with esophageal adenocarcinoma cells however only adenocarcinoma cell lines significantly increased proliferation in response to IGF-1 (P<0.01). Serum IGF-1 levels were highest in esophageal adenocarcinoma patients (P<0.01) and higher in viscerally obese vs. nonobese (P<0.05) patients. In resected esophageal cancer, increased expression of IGF-1R was observed in the tumor and invasive edge compared with tumor-associated stroma (P<0.05), which coincided with increased CD68+ cells in stromal tissue surrounding invasive tumor edge (P<0.01).

CONCLUSIONS:

 

This novel study examined the differential role of the IGF system in esophageal adenocarcinoma and SCC, and its association with visceral obesity. These results indicate that the IGF-1 axis has a key role in malignant progression of esophageal cancer, and represents a plausible mechanism through which visceral obesity impacts on esophageal adenocarcinoma risk and tumor biology.

Source: American Journal of Gastroenterology.