Browsing by Author "Trinh, Oanh"
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Item Development of a mouse model to study the long-term effects of chemotherapy on brain function(2023) Trinh, Oanh; Vann, Philip; Davis, Delaney; Luedtke, Robert R.; Basha, Riyaz; Singh, Meharvan; Sumien, NathaliePurpose: While remaining an effective life-saving intervention for cancer patients, chemotherapy has been associated with many neurotoxic side effects, including chemotherapy-related cognitive impairments (CRCI). Chemotherapy exposure leads to a decline in learning, memory, processing speed, attention, and executive functions, which may persist for more than 20 years post-treatment, impairing the quality of daily lives of survivors. Childhood cancer survivors are particularly vulnerable to chemotherapy and have been impacted in their educational achievements, employment, social relationships, and even life expectancy. Most common childhood cancers are often treated with the folate-inhibitor methotrexate (MTX). Our study aimed at establishing a tumor-free mouse model of MTX-induced brain impairments. We hypothesized that early exposure to MTX would induce impairment in cognition, as well as motor and affective functions. Methods: Male and female C57BL6/J postnatal day 15 pups received intraperitoneal injections of saline or MTX (2 mg/kg) once a day for 3 days. Pups were weaned on PND21, and subsets were behaviorally characterized at 1 or 7 months after MTX exposure (n=6-8 for 1.5 months old, and n=11-13 for 8 months old) for motor, affective and cognitive functions using a comprehensive behavioral test battery. Results: At 1.5 months, coordination and motor learning was significantly impaired in males and improved in females. All other measures did not reveal any other significant effects, however trends of impaired motor and cognitive functions could be discerned. At 8 months, there were no effects of MTX on motor, affective and some cognitive functions. However, MTX exposure led to an impairment on spatial learning and memory and increased swimming speed. Conclusions: Studies at 1.5 months will need to be repeated to increase power and ascertain conclusions on brain functions. Early exposure to MTX treatment led to long-term impairments in both male and female mice and could be used as a model to test interventions to limit CRCI.Item Hyperbaric Oxygen as Potential Treatment for Chemotherapy-Related Cognitive Impairments(2024-03-21) Trinh, Oanh; Mensah-Kane, Paapa; Shi, Helen; Sumien, NathaliePurpose: “Chemobrain”, characterized by impaired attention, learning and memory retention, is a prevalent condition affecting approximately 75% of patients undergoing cancer treatments. Chemotherapy-related cognitive impairment (CRCI), a subtype of “chemobrain”, can persist for up to 20 years post-treatment, significantly diminishing the daily quality of life for survivors and caretakers. Very few interventions are available to alleviate the effects of chemotherapy on the brain. One potential treatment is hyperbaric oxygen therapy (HBOT), which has shown neuroprotective effects in conditions such as Alzheimer’s disease, traumatic brain injury, and stroke. The current study investigated the effects of HBOT on cognitive impairments induced by commonly used chemotherapeutic agents, and studied the underlying mechanisms with a focus on cellular senescence. Methods: Four-month-old male and female C57BL/6 mice were injected (i.p.) with saline or chemotherapeutic cocktails (Methotrexate (37.5 mg/kg) + 5-Fluorouracil (50 mg/kg)) once a week for three weeks. Simultaneously, half of the mice underwent daily HBOT session (2.4 ATM for 90 min). Morris water maze was used to measure spatial learning and memory. Hippocampus was evaluated for markers of cellular senescence using western blot analyses. Results: Chemotherapy exposure impaired spatial learning and memory, which was attenuated by HBOT in male mice only. The exposure was also associated with increased levels of p16INK4a, ɣH2AX, and b-galactosidase (cellular senescence markers), and increased levels of cleaved-Lamin B1 (a surrogate marker of caspase-6 activity relating to apoptosis) in male hippocampus. HBOT seemed to reduce the effects of chemotherapy on ɣH2AX, b-galactosidase, and cleaved-Lamin B1, but not on p16INK4a in males. Conclusion: HBOT reduced cognitive impairments associated with chemotherapy exposure. Interestingly, females were not impaired by the chosen chemotherapeutic cocktail. Cellular senescence and apoptosis may play a role in the beneficial effects of HBOT.Item Low-dose methotrexate exposure induced long-term cognitive deficits in mice(2022) Trinh, Oanh; Sumien, Nathalie; Vann, Philip; Davis, Delaney; Luedtke, Robert R.; Basha, Riyaz; Singh, MeharvanPurpose: Chemotherapy-related cognitive impairment (CRCI) remains a mysterious morbidity that threatens the quality of life of up to 70% cancer survivors in the United States. Longitudinal studies of CRCI highlighted deficits in memory, learning, attention, motor, and executive functions for up to 20 years after the completion of chemotherapy paradigm. These deficits, especially if happened during childhood, can negatively impact educational achievement, employment, self-independence, and life expectancy of approximately 500,000 adult survivors currently living in the U.S. Given that acute lymphoblastic leukemia (ALL) is the most common diagnosis of childhood cancers worldwide, the folate-inhibitor methotrexate (MTX) has been at the backbone of ALL-treatment with a substantial risk of neurotoxicity. The purpose of this study was to establish a tumor-free mouse model representative of MTX-induced CRCI in childhood ALL survivors and study the long-term effects of chemotherapy treatment on brain function. We hypothesized that MTX administration at a very young age will induce long-term cognitive impairments. Methods: At post-natal day 15, male and female C57BL6/J pups received intraperitoneal injections of either saline (n=12) or MTX (2 mg/kg; n=12) once a day for 3 days. The pups were weaned at post-natal day 21 and allowed to age. At 8-month-old, animals underwent behavioral tests to assess motor, affective and cognitive functions. Results: MTX administration impaired cognitive flexibility in males and impaired spatial learning and memory in females, indicating potential sex- and test-dependent behavioral outcomes. MTX increased performance in coordinated-running test, and increased swimming speed. Anxiety-like behaviors were not affected by the treatment. Conclusions: These preliminary results suggested that low dose MTX-treatment induced sex-dependent cognitive deficits while affective and motor functions were not negatively affected. This study will be repeated, and behaviors will be assessed at other time points to establish complete neurobehavioral profiles of mice affected by MTX chemotherapy.