Antioxidants that target the spinal fluid to prevent 'chemo brain'

Chemo-encephalopathy, a chronic side effect that makes it difficult to remember, pay attention and learn new information, affects up to three-quarters of cancer patients undergoing chemotherapy

ANIUpdated: Wednesday, September 14, 2022, 05:33 PM IST
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Representative image | istockphoto

Boston: Chemo brain, a chronic side effect that makes it difficult to recall things, pay attention, and learn new information, affects up to three-quarters of cancer patients getting chemotherapy. When it affects children, whose brains are still developing, it could affect their academic performance and self-esteem.

"One of the most distressing potential side effects we sometimes describe when we meet with parents and talk about the life-saving therapy we are proposing for their child's cancer is cognitive loss," says paediatric oncologist Lisa Diller, MD, chief medical officer for the Dana-Farber/Boston Children's Cancer and Blood Disorders Center.

It would be revolutionary if we could provide preventive treatments during therapy or later on in the survivorship phase of care.

Researchers from the Department of Pathology at Boston Children's Hospital, Maria Lehtinen, PhD, and Naama Kanarek, PhD, take the first step in that direction in a study that was released in the journal Neuron on September 6. Their goal is to treat the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, in order to shield the brain from the damaging side effects of chemotherapy.

According to Kanarek, the brain itself might be able to be treated if the CSF, which is simple to target, can be treated.

Investigating chemo's effects on the brain Lehtinen has carried out ground-breaking investigations demonstrating the role of CSF and the choroid plexus, the little-known brain region that creates CSF, in fostering brain health and growth. Separately, Kanarek has been researching how cancer cells respond to the chemotherapeutic medication methotrexate in terms of metabolism. Children with acute lymphoblastic leukaemia that has spread to the brain, osteosarcoma, and certain brain tumours are treated with methotrexate. Adults with leukaemia, lymphoma, breast cancer, and lung cancer can also receive treatment with it.

The two labs joined forces. They discovered that methotrexate exposure produced oxidative damage to the CSF and the choroid plexus in a preliminary study of rats. Oxidative damage is a metabolic imbalance that results in the generation of harmful oxygen molecules.

The primary learning and memory region of the brain, the hippocampus, also sustained nerve cell loss. Additionally, in behavioural tests, the mice displayed elevated anxiety and impairment in short-term memory and learning tasks.

Lehtinen, Kanarek, and colleagues further demonstrated that methotrexate blocked the choroid plexus from secreting a crucial enzyme, superoxide dismutase 3 (SOD3), into the CSF by using cutting-edge laboratory equipment. SOD3 is an antioxidant that naturally defends the brain and other tissue cells by aiding in the breakdown of potentially harmful oxygen molecules. Scientists believe that brain cells are more vulnerable to harm when SOD3 is not present in the CSF.

Reversing toxic brain effects of methotrexate Do people experience the same effects? First, the researchers looked at human neurons made from stem cells. They found that the neurons produced less SOD and showed signs of oxidative damage after being treated to methotrexate.

Additionally, they looked at CSF samples from 11 adult cancer patients who had undergone methotrexate chemotherapy for central nervous system lymphomas. These patients showed lower levels of SOD3 in their CSF and higher levels of oxidative damage indicators as compared to 12 cancer-free controls who did not take methotrexate.

Could reintroducing SOD3, therefore, shield the brain? The study team increased SOD3 production in the choroid plexus by using a gene therapy method in mice. The CSF and brain tissue of the mice were then virtually free of oxidative damage, and there was less evidence of anxiety and memory loss when they were administered methotrexate.

According to Diller, a researcher who was not involved in the study, "with more research in the future, these discoveries have the potential to prevent or treat one of the most troubling late effects of methotrexate, a cancer treatment we often use." Exploring treatment possibilities
Now, Lehtinen and Kanarek want to investigate how different chemotherapeutic medications affect the CSF and choroid plexus.

Additionally, they aim to examine the effectiveness of antioxidants administered directly, as opposed to through gene therapy, in reducing the symptoms of chemo brain and better understand how methotrexate and antioxidants affect other areas of the brain.

Potential antioxidant therapies include intravenous injections, nasal sprays, and intrathecal spinal tap injections that deliver antioxidants directly to the CSF. These therapies might be administered in addition to chemotherapy. According to Kanarek, individuals taking intrathecal methotrexate for brain cancer, leukaemia, or lymphoma that has brain involvement may present the most urgent chance.

Simply supplying antioxidants through meals or dietary supplements that are high in antioxidants is another potential strategy that has not yet been evaluated.

According to Lehtinen, "This initial investigation is merely the tip of the iceberg." "It would be tremendously thrilling if we could reverse the side effects of chemotherapy and alter the course of the patients' lives even slightly."

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