Chemo brain is a persistent side effect that causes difficulty recalling things, paying attention, and learning new information in up to three-quarters of cancer patients receiving chemotherapy. When it affects youngsters, whose brains are still growing, it may have an impact on their academic achievement as well as their 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.
If we could deliver preventative therapies during therapy or later in the survivorship phase of care, that would be revolutionary. Researchers from Boston Children’s Hospital’s Department of Pathology, Maria Lehtinen, PhD, and Naama Kanarek, PhD, take the first step in that direction in a paper published on September 6 in the journal Neuron. Their objective is to treat the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, in order to protect the brain from the potentially harmful effects of chemotherapy.
Kanarek believes that if the CSF, which is easy to target, can be treated, the brain itself may be able to be treated.
Investigating chemo’s effects on the brain
Lehtinen has conducted groundbreaking research establishing the function of CSF and the choroid plexus, a little-known brain area that produces CSF, in brain health and growth. Kanarek has also been studying how cancer cells respond metabolically to the chemotherapy drug methotrexate. Methotrexate is used to treat children with acute lymphoblastic leukaemia that has progressed to the brain, osteosarcoma, and certain brain tumours. Adults with leukaemia, lymphoma, breast cancer, and lung cancer can all benefit from 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 have the same reactions? First, the researchers examined human neurons derived from stem cells. After being treated with methotrexate, the neurons generated less SOD and exhibited symptoms of oxidative damage.
They also studied CSF samples from 11 adult cancer patients who had had methotrexate treatment for central nervous system lymphomas. When compared to 12 cancer-free controls who did not use methotrexate, these patients had lower levels of SOD3 in their CSF and greater levels of oxidative damage markers.
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
Lehtinen and Kanarek now aim to look at how various chemotherapy medicines influence the CSF and choroid plexus. They also hope to investigate the efficacy of antioxidants provided directly rather than through gene therapy in lowering chemo brain symptoms and better understand how methotrexate and antioxidants influence other parts of the brain.
Intravenous injections, nasal sprays, and intrathecal spinal tap injections that give antioxidants directly to the CSF are also potential antioxidant therapy. These treatments might be used in addition to chemotherapy. Individuals receiving intrathecal methotrexate for brain cancer, leukaemia, or lymphoma with brain involvement, according to Kanarek, may provide the most immediate risk.
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.”