Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 2 • February 2013

Dietary Help for Stressed Mice and Humans

Antidepressant Effects of Whey Protein Isolate in Mice Under Chronic Unpredictable Stress

A 2011 paper1 reports significant effects of whey protein isolate in significantly reducing depressive behavior in mice subjected to the chronic unpredictable stress (CUS) model, where the mice (except for the controls) were exposed to various types of stress (one per day in random order for 24 days). One group of the mice were treated with the selective serotonin reuptake inhibitor drug fluoxetine (Prozac®) (10 mg/kg po), while four other groups of mice received whey protein isolate (WPI) at dose levels of 75, 150, and 300 mg/kg po. The stress tests included commonly used tests such as the tail suspension test, the forced swimming test, and the open field test. Depression-like behavior included reductions in the activity of the mice (ambulation, rearing and grooming frequencies) and increased latency (“freezing”) in the open field test. Fluoxetine treatment restored the normal value of ambulation in the stressed mice, including the grooming frequency and and rearing frequency. WPI at both 75 mg/kg po and at 150 mg/kg po normalized the ambulation and grooming frequencies. “WPI, on the other hand, normalized all the four parameters and gave results that were comparable to those of fluoxetine (10 mg/kg).”1

Chronic Unpredictable Stress Effects on Brain Serotonin, Norepinephrine, and Dopamine

The CUS model was reported to cause a significant decrease in the neurotransmitters serotonin, norepinephrine, and dopamine in the brains of the mice. There was a significant decrease of 44.83%, 36.13%, and 63.33%, respectively, as compared to the normal control levels. Fluoxetine elevated the levels of serotonin (117.24%), norepinephrine (94.45%), and dopamine (101.33%) compared to the normal controls. WPI (75, 150, and 300 mg/kg) significantly increased serotonin (130.77%, 138.46%, and 146.15%), and increased norepinephrine (146.91%, 156.74%, and 165.45%) and increased dopamine (172%, 172.67%, and 218.67%) compared to the normal control values.1

Protection Against Oxidative Stress in the Brain by Whey Protein Isolate

The 75 and 150 mg/kg dose WPI did not have a significant effect on glutathione compared to the depressed group but both these doses did reduce the malondialdehyde (MDA) levels. The 300 mg/kg dose of WPI resulted in a significant increase in glutathione, with an effect similar to that of fluoxetine; it also significantly decreased the MDA level down to 47.64% as compared to the depressed group.

Alpha-lactalbumin, An Important Constituent of Whey, Benefitted Rats in Earlier Studies

Two earlier studies were reported to show that rats fed am alpha-lactalbumin rich diet showed elevated brain levels of tryptophan and serotonin levels after acute and chronic administration.2,3 In an additional study4 rats on alpha-lactalbumin had enhanced serotonin release and also anxiolytic (reduced anxiety) and rewarding effects. As the authors of paper #1 explained, whey protein is rich in the amino acids tryptophan, glutamine, phenylalanine, and tyrosine. While tryptophan is precursor to the neurotransmitter serotonin, phenylalanine and tyrosine are precursors to both norepinephrine and dopamine.

... And Reduced Pain in Mice

An additional paper5 reported that alpha-lactalbumin derived from bovine milk reduced pain in mice in several commonly used pain models (such as the acetic acid-induced writhing test) and also reduced inflammation in mice by inhibiting COX2 and phospholipase A2. The authors of this paper conclude that “[t]hese results suggest that alpha-lactalbumin can be a safe and useful natural drug for patients with severe pain that requires anti-inflammatory drugs.”


1. Ahmed et al. Pharmacological study of the possible antidepressant activity of whey protein isolate in mice. Aust J Basic Appl Sci. 5(12):2649-59 (2011).
2,3. Choi et al. Meal ingestion, amino acids and brain neurotransmitters: effects of dietary protein source on serotonin and catecholamine synthesis rates, Physiol Behav. 98:156-62 (2009); Choi et al. The chronic ingestion of diets containing different proteins produces marked variations in brain tryptophan and serotonin synthesis in the rat. Neurochem Res. 36:559-65 (2011).
4. Orosco et al. Alphalactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat. Behav Brain Res. 148:1-10 (2004).
5. Yamaguchi et al. Novel functions of bovine milk-derived alpha-lactalbumin: anti-nociceptive and anti-inflammatory activity caused by inhibiting cyclooxygenase-2 and phospholipase A2. Biol Pharm Bull. 32(3):366-71 (2009).

Alpha-Lactalbumin, a Whey Protein With High Tryptophan Content, Improved Coping Ability in Stress-Vulnerable Human Subjects

In the study described above, mice were protected against chronic unpredictable stress by whey protein isolate. Now, in a human study (10 men, 19 women) were subjected to experimental stress and received either a casein based diet or a alpha-lactalbumin-enriched whey protein diet.6 The diets were isoenergetic and contained equal amounts of protein, carbohydrate, and fat.

The human version of experimental stress included 18 successive 1 minute trials in which each subject had to do mental arithmetic under time constraints while at the same time receiving different levels of industrial noise (65, 70, or 80 dB) through headphones. Additional stress was added by changing the “criterion” (the specified number of calculations that had to be solved correctly in order to supposedly have the opportunity to control the noise level) so that all subjects continued to fail each trial and thus lost the “opportunity” to control the noise level. Perhaps they would have preferred the tail suspension test. …

One of the results of the experiment was that there was a significant 48% increase in the plasma ratio of tryptophan to other large neutral amino acids (which compete with tryptophan for transport into the brain) after the alpha-lactalbumin diet as compared to the casein diet. This meant that there was more tryptophan available for entry into the brain (for conversion to serotonin) with the alpha-lactalbumin diet. The latter diet also decreased the increased cortisol released in HS subjects during acute experimental stress.

Concerning mood, “we indeed found that only in HS subjects [high stress vulnerable subjects] did feelings of depression tend to be lower after experimental stress with consumption of the alpha-lactalbumin diet compared with the casein diet. In HS subjects who showed a physiologic stress response, this dietary effect on depression was significant (P=0.007). It is important, however, not to draw strong conclusions concerning the clinical implications of this observation because the dietary effects of mood seem to be small. We also found that HS subjects reported more depressive moods at baseline than did LS subjects. This seems to agree with the observation that experiences of chronic stress may lower mood and reflect a vulnerability to depression.”6

“... the present data show that an alpha-lactalbumin-enriched whey protein diet may reduce in stress-vulnerable subjects the negative consequences of experimental stress on cortisol secretion and mood, probably by enhancing brain serotonin mechanisms that are involved in adaptation to stress.” The authors propose, therefore, that a tryptophan-enriched whey protein diet in healthy but stress vulnerable subjects could improve ability to cope with stress.

6. Markus et al. The bovine protein alpha-lactalbumin increases the plasma ratio of tryptophan to the other large neutral amino acids, and in vulnerable subjects raises brain serotonin activity, reduces cortisol concentration, and improves mood under stress. Am J Clin Nutr. 71:1536-44 (2000).

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