IGF-1 May Be Involved in Parkinson’s Development, Review Suggests

Margarida Azevedo, MSc avatar

by Margarida Azevedo, MSc |

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alpha-synuclein, therapeutic strategy

Increasing evidence links insulin-like growth factor 1 (IGF-1) deficiency to the development and progression of Parkinson’s disease, a review study said.

Estrogen, the female sex hormone thought to hold potential beneficial effects against Parkinson’s, or PD, may exert its protective actions via IGF-1, the researchers said.

The data may open new avenues to develop combined therapies for brain preservation and against the toxic protein buildup seen in Parkinson’s patients.

The review study, “Is insulin-like growth factor-1 involved in Parkinson’s disease development?” was published in the Journal of Translational Medicine.

Despite decades of research, the definitive cause of Parkinson’s is unknown. It is known, however, that genetic and environmental factors are at play.

Age is an established risk factor for Parkinson’s, as studies have shown a marked prevalence of the disease in those between the ages of 65 and 79. Previous research has also shown that the condition is more prevalent in men than in women.

Scientists have attributed the lower prevalence, later onset, and milder clinical presentation of Parkinson’s in women to a potential protective effect of estrogen. This hormone can cross the blood-brain barrier, a semipermeable membrane that protects the brain and spinal cord.

The brain can also produce estrogen from cholesterol.

Although estrogen is mainly known as the hormone that promotes female sex characteristics, research has increasingly highlighted its effects in protecting against chronic and degenerative diseases.

“In this manner, women with PD typically have a more benign phenotype with slower progression of the disease than men, and the incidence and prevalence of PD is higher in postmenopausal than in premenopausal women of similar age,” the researchers wrote.

That could be due to “higher estrogen activity, which increases dopamine levels in the brain’s striatum, thus promoting neuron survival and neuroprotective actions,” Ethey said. Estrogen may also prevent the formation of Lewy bodies inside nerve cells, a key hallmark of Parkinson’s.

Studies have suggested that the molecular mechanism by which estrogen exerts its protective effects involves phosphatidyl inositol-3-kinase (PI3K) signaling pathway activation, which is activated by insulin and IGF-1  in the brain.

IGF-1 is a hormone with important roles in embryonic and post-natal development, tissue growth, insulin-like activity. It also has anti-aging, antioxidant and neuroprotective effects. Although it is mainly produced by the liver, nearly every tissue is able to secrete this hormone.

In humans, IGF-1 deficiency is mostly associated with growth hormone insensitivity (GHI), liver cirrhosis, cardiovascular and neurological diseases associated with aging, intrauterine growth restriction and metabolic syndrome.

The hormone is produced throughout the central nervous system (CNS), albeit in higher levels in the brain stem, cerebellum, cerebral cortex,and striatum. IGF-1 is also important for CNS development and production of nerve cells.

Studies have shown that IGF-1 increases following CNS injury, acting as a protective and recovery mechanism. Higher IGF-1 levels have been observed at the initial stages of PD, then even out as symptoms progress. This suggests “an ongoing compensatory or ‘fight-to-injury’ mechanism, since as the disease progresses such elevation dissipates,” the researchers said. It also means that patients whose IGF-1 concentrations do not rise enough “will present a worst outcome,” they said.

Studies have also shown that IGF-1 concentrations inversely correlate with motor function (lower UPDRS-III scores), verbal memory, visual and perception abilities and cognitive function. However, “IGF-1 correlation with the disease onset, duration, severity, etc., still remains a hot topic,” the researchers wrote.

Obesity has been considered as a risk factor for PD. IGF-1 and insulin functioning are known to be dysregulated under metabolic disorders such as obesity, suggesting that “insulin/IGF-1 signaling deficit could decrease neuroprotection and render the brain vulnerable to oxidative damage,” the researchers said.

Exposure to toxins has also been connected to the development of Parkinson’s. Toxins can interfere with IGF-1 signaling, thus lowering the hormone’s protective effect against PD and rendering the body more vulnerable to its development.

In a preclinical study, IGF-1 deficiency in a mouse model increased brain oxidative damage, inflammation, swelling, nerve cell death, learning and memory. These effects were rescued by IGF-1 replacement therapy. “More experimental studies need to be performed to better understand the molecular mechanisms from IGF-1 cascade involved in PD,” the researchers wrote.

Overall “it could be reasonable to think in a combined therapy with estrogens and IGF-1, since both molecules can cross the blood–brain barrier activating the IGF-1 signaling pathway to exert its favorable actions in brain and also to prevent [alpha]-synuclein aggregation (Lewy body deposition), thus avoiding PD development,” the researchers said.

“However, in order to solve this question, more experimental and clinical studies need to be done,” they added.