The role of inflammation on the development of neurodegeneration that results in Parkinson’s disease has been studied more often over the past few years. And researchers are now trying to use target inflammation for developing Parkinson's treatments. One such experimental drug, developed by researchers at Emory University School of Medicine, can protect vulnerable neurons and reduce motor deficits in rat models with Parkinson’s.
The drug, called XPro1595, when administered beneath the skin, enters the brain in sufficient levels to target the inflammation. If the drug can be developed for humans, it would be just like an insulin shot, and much less invasive than previous methods, which involved a direct injection into the brain of animal models. The results of the study were published Thursday in the Journal of Parkinson's Disease.
"This is an important step forward for anti-inflammatory therapies for Parkinson's disease," said Dr. Malu Tansey, associate professor of physiology at Emory University School of Medicine, in a press release. "Our results provide a compelling rationale for moving toward a clinical trial in early Parkinson's disease patients."
For decades, scientists have been trying to understand the cause behind Parkinson’s, a progressive degenerative disease that starts as a tremor in the hand, and sometimes progresses to complete loss of motor abilities. These symptoms have been tied to the loss of neurons that generate dopamine — the chemical messenger that communicates with the part of the brain involved in movement and coordination. What exactly destroys them is still a matter of debate, but the general consensus is that pro-inflammatory mechanisms cause inflammation, and the subsequent death of dopaminergic neurons. As these cells die, neurodegeneration begins.
How XPro1595 Works
XPro1595 targets tumor necrosis factor (TNF), a critical inflammatory signaling molecule. While anti-TNF drugs have been around for some time, and are used to reduce inflammation and stop the progression of rheumatoid arthritis, psoriatic arthritis, and juvenile arthritis, they have been associated with an increased risk for infections like tuberculosis. But XPro1595 targets soluble TNF, and thus avoids affecting immunity to infections.
"Inflammation is probably not the initiating event in Parkinson's disease, but it is important for the neurodegeneration that follows," Tansey said in the press release. "That's why we believe that an anti-inflammatory agent, such as one that counteracts soluble TNF, could substantially slow the progression of the disease."
Researchers studied Parkinson's disease in rats that had the neurotoxin 6-hydroxydopamine (6-OHDA) injected into one side of their brains. This toxin causes the death of dopamine-producing neurons in the injected side of the brain, which led to impaired movement on the opposite side of the body.
Three days after the 6-OHDA injection, the animals were given XPro1595. Five weeks later, only 15 percent of the dopamine-producing neurons were lost. With this reduction, the researchers were also able to reduce motor impairment. Meanwhile, controls saw a 55 percent loss of the same neurons. The researchers found that the loss of dopamine cells was highly correlated to both the degree of motor impairment and immune cell activation. When XPro1595 was given two weeks after injection, however, 44 percent of the vulnerable neurons were lost, suggesting that there is only a small time frame to intervene.
"Recent clinical studies indicate there is a four or five year window between diagnosis of Parkinson's disease and the time when the maximum number of vulnerable neurons are lost," Tansey said. "If this is true, and if inflammation is playing a key role during this window, then we might be able to slow or halt the progression of Parkinson's with a treatment like XPro1595."
The new research, which was funded by the Michael J. Fox Foundation for Parkinson's Research, will be taking another step toward development when testing begins later on with non-human primate models. "A therapy that could slow Parkinson's progression would be a game changer for the millions living with this disease, and this study is a step in that direction," Dr. Marco Baptista, associate director of the Foundation, said in the release.
Source: Tansey M, Barnum C, Tesi R, et al. Peripheral Administration of the Selective Inhibitor of Soluble Tumor Necrosis Factor (TNF) XPro1595 Attenuates Nigral Cell Loss and Glial Activation in 6-OHDA Hemiparkinsonian Rats. Journal of Parkinson's Disease. 2014.