New findings on brain electrodes might improve DBS in Parkinson’s
Implanting electrodes found to trigger inflammation and cell damage
Implanting electrodes into the brain triggers inflammation by activating a group of immune signaling proteins called the inflammasome — which detects infection and, in turn, prompts a strong inflammatory response, a new study shows.
These findings may open new avenues to improve deep brain stimulation, a type of therapy used in Parkinson’s disease and other neurological disorders to ease patients’ symptoms.
“Uncovering multiple mediators that contribute to neuroinflammation will build a greater understanding of the intricate immune response following [electrode] insertion as well as serve to reveal potential therapeutic targets to minimize neuroinflammation,” the researchers wrote.
The study, “Activation of inflammasomes and their effects on neuroinflammation at the microelectrode-tissue interface in intracortical implants,” was published in Biomaterials.
Investigating the mechanisms of electrodes implanted in the brain
The work was led by a team of researchers that included several members of the scientific advisory board at ZyVersa Therapeutics. The U.S.-based company is developing an experimental therapy that aims to block inflammasome activation.
“The research published in Biomaterials provides additional support for the therapeutic potential of ZyVersa’s proprietary monoclonal antibody inflammasome ASC inhibitor, IC 100, in neurological injury and disease,” indicated Stephen C. Glover, co-founder, chairman, CEO and president or ZyVersa, said in a company press release.
Glover added that early studies with the experimental therapy “have demonstrated reduced inflammatory activity and/or improved outcomes in two different models of brain injury, spinal cord injury, age-related inflammation Alzheimer’s disease, and multiple sclerosis.”
Known as DBS, deep brain stimulation is a surgical treatment that involves implanting electrodes into the brain, which can deliver electrical stimulation to specific brain regions. The therapy has been shown to be effective in certain patients for relieving some symptoms of Parkinson’s and other neurological disorders.
“Deep brain stimulation is an important therapeutic option to help maintain quality of life in patients with movement disorders whose symptoms are not effectively controlled by medication,” said Abhishek Prasad, PhD, a professor in biomedical engineering at the University of Miami Miller School of Medicine and a co-author of the study.
While DBS can be an effective treatment option, electrodes implanted in the brain are not able to last very long. This is due, in part, to inflammation caused by the electrodes in the surrounding brain tissue, which damages the electrode’s material.
But the exact molecular mechanisms of how electrodes implanted in the brain trigger inflammation are incompletely understood. Now, a team of scientists conducted a series of experiments in rats to investigate whether the inflammasome might play a role.
Inflammasomes are complexes of proteins that cells use to detect signs of damage or infection. When these danger signals are detected, the inflammasome activates to trigger a powerful inflammatory response.
Results showed that levels of inflammasome proteins increase substantially within a few days after electrode implantation. Several important inflammasome mediators, such as NLRP1 and NLRP3, were still at increased levels by a month after implantation, the latest time point assessed in this study.
“These findings provide strong support that upstream inflammasome sensor molecules are present early following [electrode] implantation and remain elevated to cause sustained inflammasome-mediated neuroinflammation,” the researchers wrote.
Pyroptosis, from the Greek words for “fiery death,” is a form of programmed inflammatory cell death. Specifically, when a cell undergoes pyroptosis, the cell kills itself while simultaneously spewing out pro-inflammatory signaling molecules.
This can be effective for dealing with acute injuries, because a damaged cell can dispatch itself while also sounding the alarm to the rest of the body. However, with an implanted electrode, the process gets continually activated, which could drive a damaging inflammatory response. Indeed, the researchers noted that in this study, more pyroptosis tended to be accompanied by less dense nerve cells, suggesting more damage to brain tissue.
“Inflammasome-mediated neuroinflammation and pyroptosis … could potentially lead to neuronal cell loss,” the researchers wrote. These findings imply that blocking inflammasome activation may help prevent the inflammatory response to implanted electrodes in the brain.
“Our results not only demonstrate that continuous activation of inflammasomes contribute to neuroinflammation at the ME-tissue interface, but also reveal the therapeutic potential of targeting inflammasomes to attenuate the foreign body response to cortical implants,” Prasad said.