In Mice, COVID-19 Leaves Nerve Cells Vulnerable to Further Injury
A prior COVID-19 infection in mice increased their susceptibility to nerve cell loss caused by MPTP, a neurotoxin known to cause symptoms of Parkinson’s disease, according to a recent study.
The findings suggest that while COVID-19 alone likely does not cause Parkinson’s, it may make nerve cells more sensitive to the effects of other Parkinson’s risk factors, like toxins or genetic mutations, to possibly raise a person’s overall risk.
“Parkinson’s is a rare disease that affects 2% of the population above 55 years, so the increase in risk is not necessarily a cause for panic,” Richard Smeyne, PhD, the study’s first author and director of the Jefferson Comprehensive Parkinson’s Disease and Movement Disorder Center at the Farber Institute for Neuroscience, said in a press release.
“But understanding how coronavirus impacts the brain can help us prepare for the long-term consequences of this pandemic,” Smeyne added.
The study, “COVID-19 infection enhances susceptibility to oxidative-stress induced parkinsonism,” was published in Movement Disorders.
Viral infections have long been considered a risk factor for neurodegenerative disorders like Parkinson’s. COVID-19 is a respiratory infection caused by the SARS-CoV2 virus that also affects “a number of other organ systems, including the nervous system,” its researchers wrote. As a result, the ongoing pandemic raises concerns about the risks of neurological consequences in the years following infection.
An estimated 35% to 40% of COVID-19 cases have been associated with the later development of neurological symptoms like smell loss, headache, brain fog, numbness, seizures, or stroke. Signs of Parkinson’s or parkinsonism have also been reported in a few cases, but whether COVID-19 truly increases the risk of developing Parkinson’s remains unknown.
To explore the potential relationship, a research team in the U.S. examined whether mice infected with SARS-CoV2 and allowed to recover would later be more susceptible to the effects of MPTP, relative to mice without induced COVID 19. Both male and female mice were used.
A strain of mice genetically engineered to be susceptible to SARS-CoV-2 were infected with a viral dose associated with a moderate infection in people.
About five weeks later (38 days), some of these mice — and some of the non-infected group — were injected with a low dose of the MPTP toxin. Normally, this dose would cause low levels of inflammation, but not nerve cell death, in mice.
After seven days, researchers examined a brain region called the substantia nigra pars compacta (SNpc) in all the mice for signs of Parkinson’s. This is the main region where dopamine-producing neurons are affected by the disease.
Mice given the neurotoxin after or without SARS-CoV2 infection showed no signs of dopamine neuron loss.
But mice that recovered from COVID 19 before MPTP exposure had a significant 23% greater loss of neurons compared with mice with COVID but not MPTP, and a significant 19% greater loss than mice never infected with SARS-CoV2 and given MPTP, indicating an increased susceptibility to the toxin after infection.
In addition to neurons, the SNpc region contains a high number of microglia, brain cells involved in immune responses. When in an activated state, these cells are associated with a strong — and sometimes damaging — neuroinflammatory response.
SARS-CoV2 infected and recovered mice given MPTP showed a significant reduction in the number of resting microglia in this brain region compared with all other mice, but marked elevations in the number of activated microglia. Specifically, activated microglia levels were 308% higher in these mice compared with animals left alone (neither COVID nor MPTP), and 232% higher in those infected with SARS-CoV2 alone, altogether indicating a heightened inflammatory state.
The observed link between a prior COVID-19 infection and nerve cell loss is likely related to this increase in inflammation, the researchers noted. Viruses play a known role in promoting inflammation which can make nerve cells more susceptible to injury.
Since SARS-CoV2 alone did not cause nerve cell loss, but required the addition of the neurotoxin MPTP to do so, the virus by itself apparently doesn’t cause Parkinson’s, the researchers noted.
“We think about a ‘multi-hit’ hypothesis for Parkinson’s – the virus itself does not kill the neurons, but it does makes them more susceptible to a ‘second hit’, such as a toxin or bacteria or even an underlying genetic mutation,” Smeyne said.
The team noted that while the findings support a link between COVID-19 and a Parkinson’s risk, more work is needed to understand how these findings translate to people.
“This is preclinical work. It is too soon to say whether we would see the same thing in humans, given that there seems to [be] a 5–10 year lag between any changes in clinical manifestation of Parkinson’s in humans,” Smeyne said.
“If it does turn out that COVID-19 increases the risk of Parkinson’s, it will be a major burden on our society and healthcare system,” he added. “But we can anticipate that challenge by advancing our knowledge of potential ‘second hits’ and mitigating strategies.”
Future research should focus on how COVID-19 influences the effects of other Parkinson’s risk factors, the varying effects of different COVID-19 variants, and whether vaccination or antiviral treatments may mitigate these effects, the researchers noted.