Changes in Fatty Acid Metabolism May be Linked to Parkinson’s Severity, Rat Study Finds

The metabolism of certain types of fats, namely palmitic acid and stearic acid commonly found in animal and vegetable fats and oils, may be altered in Parkinson’s disease, according to a study in rats.

The study, “Palmitate and Stearate are Increased in the Plasma in a 6-OHDA Model of Parkinson’s Disease,” was published in the journal Metabolites.

Studying small molecules produced by metabolism — commonly known as metabolites — within cells, biofluids, tissues, or organisms holds promise for the discovery of potential diagnostic biomarkers, which may shed light on susceptibility to Parkinson’s, disease prognosis, and therapeutic response to treatment.

In fact, an increase in metabolites of fatty acid-related molecular pathways has been reported in the plasma and cerebrospinal fluid of Parkinson’s patients, which correlated with disease progression. An increase in amino acid (protein’s building blocks) metabolism in urine samples of Parkinson’s patients has also been reported.

Evidence also suggests that metabolic profiling of cerebrospinal fluid is useful for distinguishing between newly diagnosed Parkinson’s patients and healthy individuals.

Although studies indicate that an array of molecular changes have the potential to become disease biomarkers, there is still no consensus on which markers are more informative from a diagnostic, prognostic, or even therapeutic point of view.

King’s College London researchers set out to investigate changes in brain, plasma, and liver metabolism of a rat model of Parkinson’s to discover small molecules that are associated with dopaminergic cell loss — a hallmark of the disease.

Thirteen rats were injected on one side of the brain only (unilaterally) with 6-hydroxydopamine (6-OHDA), a neurotoxin that causes the death of dopamine-producing (dopaminergic) neurons. Another 13 animals were injected with saline into the same brain region and used as a control sample.

Two weeks after injection, the animals were given two behavioral tests for researchers to assess their motor function.

“Unilateral lesions of 6-OHDA successfully resulted in the manifestation of motor symptoms, as observed by [behavioral tests] indicating the intensity of the lesions,” the researchers wrote.

Tissue analysis of the animals’ substantia nigra — a midbrain area important for muscle control that is commonly damaged in Parkinson’s disease — revealed that rats injected with 6-OHDA only had 28% of dopaminergic neurons on the injection side, compared with the other side that was not injected. Control samples had similar dopaminergic neuronal cell count on both brain sides.

Scientists then performed a metabolic analysis on the animals’ plasma, midbrain, cerebellum, and liver samples.

Results showed significantly high plasma levels of palmitic acid and stearic acid, both saturated fatty acids, within the Parkinson’s disease modeling group, which were found to be associated with motor dysfunction.

Lipid metabolism involves the degradation of triglycerides, a type of fat, into smaller chain fatty acids and subsequently into monoglycerides (glycerol molecule combined with a fatty acid) by specific enzymes.

Monoglyceride forms of palmitic acid and stearic acid, also known as monopalmitin and monostearin, respectively, were reduced in the midbrain of animals injected with 6-OHDA. Low levels of myo-inositol, a sugar alcohol molecule that has been used to decrease hormonal changes in polycystic ovary syndrome, were also found in the midbrain.

Compared with the control group, 6-OHDA rats showed a tendency toward lower levels of monopalmitin, monostearin, and myo-inositol in the cerebellum, but statistical significance was not reached.

No fatty acid-related molecular changes were observed in the animals’ livers.

“Our results show that saturated free fatty acids, their monoglycerides and myo-inositol metabolism in the midbrain and enteric circulation are associated with 6-OHDA-induced [Parkinson’s disease] pathology,” the researchers wrote.

“Changes of the midbrain metabolites may be associated with neuronal loss elicited by 6-OHDA while palmitic acid and stearic acid showed a high correlation with behaviour tests, indicating a possible association with disease severity,” they said.