Behavioral, Metabolic Changes Linked to Sleep Restriction Could Foretell Parkinson’s, Animal Study Suggests

José Lopes, PhD avatar

by José Lopes, PhD |

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Chronic sleep restriction alters movement, worsens cognitive dysfunction and induces changes in the levels of several amino acids — the building blocks of proteins — and other markers in rats with Parkinson’s, according to a new study.

According to researchers, these findings could enable the use of biomarkers to identify those at risk of developing the disease.

The study, “Chronic sleep restriction in the rotenone Parkinson’s disease model in rats reveals peripheral early-phase biomarkers,” was published in the journal Scientific Reports.

Non-motor symptoms of Parkinson’s typically appear years before significant loss of dopamine-producing neurons in the substantia nigra, an area of the brain key to motor control. One such symptom is impaired sleep. Both sleep disturbances and lifestyle-imposed sleep restrictions may contribute to cognitive decline and produce detectable alterations in the body.

However, it remains unclear whether sleep disturbances constitute a risk factor for developing Parkinson’s disease.

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An international team of researchers from Brazil, the U.K. and the Netherlands used the rotenone-induced rat model of Parkinson’s disease to evaluate if chronic sleep restriction triggers metabolic changes, cognitive impairment, and changes in the circadian rhythm (the body’s internal clock).

When injected into the substantia nigra, rotenone, an agrochemical, induces similar changes to those seen in early Parkinson’s, including excessive daytime sleepiness, rapid eye movement (REM) sleep behavior disorder, insomnia, and disruption of spontaneous sleep.

The results revealed that, unlike rotenone, sleep restriction for 21 days (six hours per day) — by soft tapping or gently shaking the cage, or gently disturbing rats’ sleeping nest — did not induce loss of dopamine-producing nerve cells.

Animals subjected to sleep restriction did not show the decreased levels of locomotor activity (movement) observed in  rats injected with rotenone, as assessed using the open field test, which is an experimental test used to evaluate animals’ general locomotor activity levels, anxiety, and willingness to explore.

The object recognition task, which evaluates memory by measuring the time animals spend on a new object, revealed that sleep restriction aggravated rotenone-induced cognitive dysfunction. Sleep recovery for 15 days reversed rats’ memory deficits.

Sleep restriction also impaired the animals’ circadian rhythm, as they showed reduced activity during the first 75 minutes after lights-off (the night period  when rodents become more active) at weeks 2 and 3.

The investigators subsequently looked at biochemical alterations in blood plasma using two metabolic profiling approaches called global 1H nuclear magnetic resonance (NMR) spectroscopy and targeted liquid chromatography/mass spectrometry (LC/MS).

Sleep restriction increased plasma levels of amino acids leucine, isoleucine, valine, ornithine (reportedly increased in Parkinson’s), arginine, lysine, alanine, proline, phenylalanine (a precursor of dopamine) and carnitine, as well as 15 different phospholipids, which is a type of fat that is a key component of cellular membranes.

In contrast, sleep restriction lowered the levels of creatinine (a product of muscle metabolism), acetylcarnitine (a form of the amino acid L-carnitine), and kynurenine (a byproduct of the amino acid L-tryptophan and previously implicated in Parkinson’s), among other molecules.

When combined with rotenone, sleep restriction increased plasma concentrations of most of the same amino acids and also of 54 phospholipids, while decreasing creatinine and forms of amino acids such as acetylcarnitine. Sleep recovery completely eliminated the changes induced by sleep restriction and rotenone regarding these molecules.

A statistical analysis then revealed that the concentrations of isoleucine, leucine and kynerunine were different when comparing animals on sleep restriction to controls. Concentration of the amino acid methionine correlated with rats’ activities.

NMR data additionally showed rotenone alone induced higher levels of circulating triglycerides and lipoproteins as well as LDL cholesterol (the “bad” cholesterol). In contrast, sleep restriction alone did not alter biochemical parameters.

Combined with rotenone, sleep restriction led to a more pronounced increase in amino acids levels, including phenylalanine and tryptophan, whose metabolism has been found altered in early-stage Parkinson’s patients. Sleep recovery again eliminated these changes.

“If combined, our results bring a plethora of parameters that represents reliable early-phase [Parkinson’s] biomarkers which can easily be measured and could be translated to human studies,” researchers wrote. Identifying who is at risk of developing the disease “has the potential to improve therapeutic strategies and possibly delay or attenuate the onset of symptoms,” they added.