Researchers glimpse Parkinson’s in rats’ eyes

Retinal changes may serve as a marker for Parkinson’s disease, an experiment in mice suggests. And the therapy also points to a potential treatment.

“We show that rosiglitazone can efficiently protect retinal neurons from the rotenone insult, and that systemic administration of liposome-encapsulated rosiglitazone has an enhanced neuroprotective effect on the retina and central nervous system,” wrote Eduardo Maria Normando of Imperial College London, UK, and colleagues.

They published their finding in Acta Neuropathologica Communications.

Their line of inquiry began with the observation that intracytoplasmic inclusions called Lewy bodies characteristic of Parkinson’s disease appear not just in the brain, where they damage cells that produce dopamine, but throughout the central nervous system, including the retina.

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Patients often experience reduced visual acuity, low contrast sensitivity, and disturbed colour vision. The inner retinal layer thins as the disease progresses. Studies are underway to see whether such changes can serve as biomarkers in treatment trials.

In other trials, investigators have created conditions similar to Parkinson’s in animals. One approach is to administer rotenone, which selectively damages dopaminergic cells, creating cytoplasmic inclusions similar to Lewy bodies. Rats poisoned this way show signs of Parkinson’s, such as parkinsonian bradykinesia and rigidity.

On the other hand, rosiglitazone, a member of the thiazolidinedione drug family, has shown promise in protecting against the effects of rotenone in these animals. It appears to promote an anti-inflammatory response and to reverse inhibition of monoamine oxidase, a crucial enzyme for dopamine metabolism.

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Originally used to counter insulin resistance in type 2 diabetes, thiazolidinedione reduced the incidence of Parkinson’s in patients with diabetes by 28% in one study. But in another, it failed to slow disease progression in patients already diagnosed with Parkinson’s. Some investigators theorise that it can protect cells but not restore their function.

Dr Normando and colleagues wanted to see whether they could measure signs of retinal change in rats treated with rotenone, and whether they could also measure the effects of rosiglitazone in these eyes.

They treated eight different groups of rats with rotenone, rosiglitazone, the vehicles for these drugs, or various combinations.

Study results

The investigators used optical coherence tomography and a fluorescently labelled annexin A5 in a technique called detection of apoptosing retinal cells (DARC) to quantify the extent of damage to retinal ganglion cells. They then killed the rats to analyse their retinas and brains.  

They found that those rats treated with rotenone had more dead retinal ganglion cells compared with those treated only with a vehicle for this drug, peaking at 20 days after the administration of the rotenone. The difference then levelled off.

The researchers also found that whole retinal thickness increased significantly in rats treated with rotenone compared with those treated with the vehicle for the drug at 10 and 20 days. But this difference disappeared after that. The researchers speculated that this thickening could result from inflammation.

The retinal nerve fibre layers also thickened in the rotenone-treated rats, with a peak at 20 days. Their outer nuclear layers did not thicken up to the 60 days during which it was measured. But their photoreceptor layers thickened at 10 and 20 days, then thinned at 60 days.

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 In the substantia nigras of the brains of the rotenone-treated rats, the investigators found a significant reduction in the number of neurons positive for tyrosine hydroxylase, a finding also found in people with Parkinson’s disease.

The investigators also found a significant increase in the expression of alpha synuclein, a major constituent of Lewy bodies 60 days after rotenone administration.

Together with the observations of the rats’ retinas “this [finding] highlights the fact that significant changes in the retina occur before the classical [Parkinson’s] changes in the brain,” the researchers wrote.

Culturing rat retinal cells in the laboratory, the researchers found that rotenone damaged them when applied by itself. But giving rosiglitazone at the same time seemed to protect the cells from this damage.

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So they tried giving the rosiglitazone at the same time as the rotenone to the living rats. They found that it significantly reduced the death of retinal ganglion cells. Also, they found that liposomal rosiglitazone was more effective than unencapsulated rosiglitazone.

Likewise, they found that the rosiglitazone reduced the rotenone-induced thickening of the retinal nerve fibre and photoreceptor layers.

And in the rats’ brains they found that the animals treated with rosiglitazone had a greater number of neurons positive for tyrosine hydroxylase. Rosiglitazone appeared to have a protective effect on the substantia nigra as well, but this did not reach statistical significance.

 “In conclusion,” the researchers wrote, “this study provides evidence of the rotenone model as a valuable tool in [Parkinson’s] research…the results advocate use of the retinal as an endpoint for the evaluation of possible therapeutic strategies.”