Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy

Dey, Deblina; Parihar, Vipan K.; Szabó, Gergely; Klein, Peter; Tran, Jenny; Moayyad, Jonathan; Ahmed, Faizy; Nguyen, Quynh-Anh; Murry, Alexandria; Merriott, David J.; Nguyen, Brandon; Goldman, J.W.; Angulo, Marı́a Cecilia; Piomelli, Daniele; Soltész, Iván; Baulch, Janet E.; Limoli, Charles L.

doi:10.1667/rr15540.1

Cited by 17 publications

(16 citation statements)

References 85 publications

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“…Furthermore, a single dose of whole brain radiotherapy was used in current studies to follow-up on the significant body of work from our laboratory implementing such a dosing scheme. While previous studies (59,60) have shown that fractionated irradiation causes RICD, follow-up studies aimed at determining how EVs might mitigate RICD after dose fractionation and in female mice are clearly warranted.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicle–Derived miR-124 Resolves Radiation-Induced Brain Injury

et al. 2020

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Radiation-induced cognitive dysfunction (RICD) is a progressive and debilitating health issue facing patients following cranial radiotherapy to control central nervous system cancers. There has been some success treating RICD in rodents using human neural stem cell (hNSC) transplantation, but the procedure is invasive, requires immunosuppression, and could cause other complications such as teratoma formation. Extracellular vesicles (EV) are nanoscale membrane-bound structures that contain biological contents including mRNA, miRNA, proteins, and lipids that can be readily isolated from conditioned culture media. It has been previously shown that hNSC-derived EV resolves RICD following cranial irradiation using an immunocompromised rodent model. Here, we use immunocompetent wild-type mice to show that hNSC-derived EV treatment administered either intravenously via retro-orbital vein injection or via intracranial transplantation can ameliorate cognitive deficits following 9 Gy head-only irradiation. Cognitive function assessed on the novel place recognition, novel object recognition, and temporal order tasks was not only improved at early (5 weeks) but also at delayed (6 months) postirradiation times with just a single EV treatment. Improved behavioral outcomes were also associated with reduced neuroinflammation as measured by a reduction in activated microglia. To identify the mechanism of action, analysis of EV cargo implicated miRNA (miR-124) as a potential candidate in the mitigation of RICD. Furthermore, viral vector-mediated overexpression of miR-124 in the irradiated brain ameliorated RICD and reduced microglial activation. Our findings demonstrate for the first time that systemic administration of hNSC-derived EV abrogates RICD and neuroinflammation in cranially irradiated wild-type rodents through a mechanism involving miR-124.Significance: Radiation-induced neurocognitive decrements in immunocompetent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124.

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Section: Discussionmentioning

confidence: 99%

Extracellular Vesicle–Derived miR-124 Resolves Radiation-Induced Brain Injury

et al. 2020

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“…The effect of TMZ on various cognitive functions has been investigated previously in clinical studies (memory, attention, and overall life quality of patients) [15,16] and in animal models (parameters related to depression and anxiety) [17,18]. However, the effect of the drug on locomotor activity has not been studied enough, with research mainly focused on young animals [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…Data on long-term TMZ effects on health-related quality of life and cognitive function are quite controversial and demonstrate both no negative side effects during the chemotherapy [14,15] and significant depression starting at the third month after adjuvant TMZ therapy [16]. It was shown that mice treated with a regimen of TMZ similar to humans demonstrate anxiety-and depression-like behaviour [17] and behavioural and biochemical changes that have relevance to the development of depression [18]. Another important parameter of a high life quality after TMZ treatment is physical activity that might be compromised by TMZ chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Exposure to Temozolomide Affects Locomotor Activity and Cartilage Structure of Elderly Experimental Rats

et al. 2020

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Chemotherapy with temozolomide (TMZ) is an essential part of anticancer therapy of various malignant tumours; however, its long-term effects on patients’ health and life quality need to be further investigated. Here, we studied the effects of TMZ and/or companion drug dexamethasone (DXM) on the locomotor activity and cartilage structure of elderly Wistar rats (n = 40). Long-term TMZ treatment selectively inhibited the horizontal, but not vertical locomotor activity of the rats (6.7-fold, p < 0.01) and resulted in delamination of the superficial epiphyseal cartilage of the femoral epiphysis of knee joints, a 2-fold decrease in mean thickness of epiphyseal cartilage (p < 0.001), and changes in the proliferative and maturation cartilage zones ratio. The simultaneous use of DXM attenuated TMZ-induced changes in cartilage thickness and integrity and compensated the decrease in horizontal locomotor activity of experimental animals. Nevertheless, combined TMZ/DXM treatment still significantly affected the structure of proximal tibial, but not distal femoral epiphysis of knee joints of the rats. These changes were accompanied by the increased content of total glycosaminoglycans (GAGs) and their partial re-localisation from chondrocytes into tissue matrix, as well as the decrease in sulfated GAGs content in both compartments. Taken together, the results demonstrate that long-term treatment with TMZ results in a significant decrease in locomotor activity of elderly Wistar rats and the reorganisation of their knee joint cartilage structure, while DXM treatment attenuates those effects. So, use of DXM or chondroprotective drugs might be beneficial to maintain quality of life for TMZ-treated cancer patients.

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“…Open Field Test (OFT) was performed in a fully lit behavior room, mice were placed in an empty white arena with no habituation or prior extensive handling. Exploration and distance traveled was measured over 5 minutes using Ethovision XT (Noldus) software as described previously [60]. Light Dark Box (LDB) was performed in a fully lit behavior room, mice were placed in an arena with an open white 'light' portion connected to a closed black 'dark' compartment.…”

Section: Methodsmentioning

confidence: 99%

Sex-Specific Differences in Toxicity Following Systemic Paclitaxel Treatment and Localized Cardiac Radiotherapy

Stivers¹,

Petit²,

Ollivier³

et al. 2021

Preprint

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The impact of sex in the development of long-term toxicities affecting the quality of life of cancer survivors has not been investigated experimentally. To address this issue, a series of neurologic and cardiologic endpoints were used to investigate sex-based differences triggered by paclitaxel treatment and radiotherapy exposure. Male and female WT mice were treated with Paclitaxel (150 and 300 mg/kg) administered weekly over 6 weeks or exposed to 19 Gy cardiac irradiation. Cohorts were analyzed for behavioral and neurobiologic endpoints to assess systemic toxicity of paclitaxel or cardiovascular endpoints to assess radiotherapy toxicity. Interestingly, female WT mice exhibited enhanced tolerance compared to male WT mice regardless of the treatment regimen. To provide insight into the possible sex-specific protective mechanisms, rhoB deficient animals and elderly mice (22 months) were used with a focus on the possible contribution of sex hormones including estrogen. RhoB deficiency and advanced age had no impact on neurocognitive impairment induced by Paclitaxel but reversed the cardioprotection was observed in females after radiotherapy. Conversely, rhoB deficiency protected males from radiation toxicity. In sum, rhoB was identified as a molecular determinant driving estrogen dependent cardioprotection in female mice, whereas neuroprotection was not sex-hormone dependent. To our knowledge, this study revealed for the first time sex- and organ-specific responses to paclitaxel and radiotherapy.

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Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy

Cited by 17 publications

References 85 publications

Extracellular Vesicle–Derived miR-124 Resolves Radiation-Induced Brain Injury

Extracellular Vesicle–Derived miR-124 Resolves Radiation-Induced Brain Injury

Long-Term Exposure to Temozolomide Affects Locomotor Activity and Cartilage Structure of Elderly Experimental Rats

Sex-Specific Differences in Toxicity Following Systemic Paclitaxel Treatment and Localized Cardiac Radiotherapy

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