RESUMEN
Breast cancer (BC) is the most common cancer among women. Fortunately, BC survival rates have increased because the implementation of adjuvant chemotherapy leading to a growing population of survivors. However, chemotherapy-induced cognitive impairments (CICIs) affect up to 75% of BC survivors and may be driven by inflammation and oxidative stress. Chemotherapy-induced cognitive impairments can persist 20 years and hinder survivors' quality of life. To identify early effects of CMF administration in mice, we chose to evaluate adult female mice at 2-week postchemotherapy. Mice received weekly IP administration of CMF (or saline) for 4 weeks, completed behavioral testing, and were sacrificed 2 weeks following their final CMF injection. Behavioral results indicated long-term memory (LTM) impairments postchemotherapy, but did not reveal short-term memory deficits. Dendritic morphology and spine data found increases in overall spine density within CA1 basal and CA3 basal dendrites, but no changes in DG, CA1 apical, or CA3 apical dendrites. Further analysis revealed decreases in arborization across the hippocampus (DG, CA1 apical and basal, CA3 apical and basal). These physiological changes within the hippocampus correlate with our behavioral data indicating LTM impairments following CMF administration in female mice 2-week postchemotherapy. Hippocampal cytokine analysis identified decreases in IL-1α, IL-1ß, IL-3, IL-10, and TNF-α levels.
Asunto(s)
Ciclofosfamida/toxicidad , Fluorouracilo/toxicidad , Hipocampo/efectos de los fármacos , Metotrexato/toxicidad , Neuronas/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Región CA1 Hipocampal , Quimioterapia Adyuvante , Dendritas , Espinas Dendríticas , Modelos Animales de Enfermedad , Femenino , Ratones , Calidad de VidaRESUMEN
The radiation environment in space remains a major concern for manned space exploration, as there is currently no shielding material capable of fully protecting flight crews. Additionally, there is growing concern for the social and cognitive welfare of astronauts, due to prolonged radiation exposure and confinement they will experience on a mission to Mars. In this artice, we report on the late effects of 16O-particle radiation on social and cognitive behavior and neuronal morphology in the hippocampus of adult female mice. Six-month-old mice received 16O-particle whole-body irradiation at doses of either 0.25 or 0.1 Gy (600 MeV/n; 18-33 cGy/min) at the NASA's Space Radiation Laboratory in Upton, NY. At nine months postirradiation, the animals underwent behavioral testing in the three-chamber sociability, novel object recognition and Y-maze paradigms. Exposure to 0.1 or 0.25 Gy 16O significantly impaired object memory, a 0.25 Gy dose impaired social novelty learning, but neither dosage impaired short-term spatial memory. We observed significant decreases in mushroom spine density and dendrite morphology in the dentate gyrus, cornu ammonis 3, 2 and 1 of the hippocampus, which are critical areas for object novelty and sociability processing. Our data suggest exposure to 16O modulates hippocampal pyramidal and granular neurons and induces behavioral deficits at a time point of nine months after exposure in females.
Asunto(s)
Conducta Animal/efectos de la radiación , Cognición/efectos de la radiación , Hipocampo/fisiología , Hipocampo/efectos de la radiación , Oxígeno/efectos adversos , Conducta Social , Animales , Espinas Dendríticas/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Medio Ambiente Extraterrestre , Femenino , Hipocampo/citología , Ratones , Ratones Endogámicos C57BL , Factores de TiempoRESUMEN
NASA's Missions to Mars and beyond will expose flight crews to potentially dangerous levels of charged-particle radiation. Of all charged nuclei, 1H is the most abundant charged particle in both the galactic cosmic ray (GCR) and solar particle event (SPE) spectra. There are currently no functional spacecraft shielding materials that are able to mitigate the charged-particle radiation encountered in space. Recent studies have demonstrated cognitive injuries due to high-dose 1H exposures in rodents. Our study investigated the effects of 1H irradiation on neuronal morphology in the hippocampus of adult male mice. 6-month-old mice received whole-body exposure to 1H at 0.5 and 1 Gy (150 MeV/n; 0.35-0.55 Gy/min) at NASA's Space Radiation Laboratory in Upton, NY. At 9-months post-irradiation, we tested each animal's open-field exploratory performance. After sacrifice, we dissected the brains along the midsagittal plane, and then either fixed or dissected further and snap-froze them. Our data showed that exposure to 0.5 Gy or 1 Gy 1H significantly increased animals' anxiety behavior in open-field testing. Our micromorphometric analyses revealed significant decreases in mushroom spine density and dendrite morphology in the Dentate Gyrus, Cornu Ammonis 3 and 1 of the hippocampus, and lowered expression of synaptic markers. Our data suggest 1H radiation significantly increased exploration anxiety and modulated the dendritic spine and dendrite morphology of hippocampal neurons at a dose of 0.5 or 1 Gy.
Asunto(s)
Radiación Cósmica/efectos adversos , Hipocampo/fisiología , Hidrógeno/efectos adversos , Neuronas/fisiología , Actividad Solar , Animales , Biomarcadores/metabolismo , Relación Dosis-Respuesta en la Radiación , Perfilación de la Expresión Génica/métodos , Hipocampo/efectos de la radiación , Masculino , Ratones , Neuronas/efectos de la radiaciónRESUMEN
Postchemotherapy cognitive impairment, or PCCI, is a common complaint, particularly among breast cancer patients. However, the exact nature of PCCI appears complex. To model the human condition, ovariectomized C57BL/6J mice were treated intravenous weekly for 4 weeks with saline, 2 mg/kg doxorubicin (DOX), 50 mg/kg cyclophosphamide (CYP), or DOX + CYP. For the subsequent 10 weeks, mice were assessed on several behavioral tests, including those measuring spatial learning and memory. After sacrifice, hippocampal spine density and morphology in the dentate gyrus, CA1, and CA3 regions were measured. Additionally, hippocampal levels of total glutathione, glutathione disulfide, MnSOD, CuZnSOD, and cytokines were measured. Body weight decreased in all groups during treatment, but recovered post-treatment. Most behaviors were unaffected by drug treatment: Open field activity, motor coordination, grip strength, water maze and Barnes maze performance, buried food test performance, and novel object and object location recognition tests. There were some significant effects of CYP and DOX + CYP treatment during the initial test of home cage behavior, but these did not persist into the second and third test times. Density of stubby spines, but not mushroom or thin spines, in the dentate gyrus was significantly decreased in the DOX, CYP, and DOX + CYP treatment groups. There were no significant effects in the CA1 or CA3 regions. CuZnSOD levels were significantly increased in DOX + CYP-treated mice; other hippocampal antioxidant levels were unaffected. Most cytokines showed no treatment-related effects, but IL-1ß, IL-6, and IL-12 were slightly reduced in mice treated with DOX + CYP. Although the animal model, route of exposure, and DOX and CYP doses used here were reflective of human exposure, there were only sporadic effects due to chemotherapeutic treatment.
Asunto(s)
Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Ciclofosfamida/toxicidad , Modelos Animales de Enfermedad , Doxorrubicina/toxicidad , Animales , Antioxidantes/metabolismo , Disfunción Cognitiva/metabolismo , Ciclofosfamida/administración & dosificación , Giro Dentado/efectos de los fármacos , Giro Dentado/enzimología , Doxorrubicina/administración & dosificación , Sinergismo Farmacológico , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Inyecciones Intravenosas , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , OvariectomíaRESUMEN
Radiation from galactic cosmic rays (GCR) poses a significant health risk for deep-space flight crews. GCR are unique in their extremely high-energy particles. With current spacecraft shielding technology, some of the predominant particles astronauts would be exposed to are 1H + 16O. Radiation has been shown to cause cognitive deficits in mice. The hippocampus plays a key role in memory and cognitive tasks; it receives information from the cortex, undergoes dendritic-dependent processing and then relays information back to the cortex. In this study, we investigated the effects of combined 1H + 16O irradiation on cognition and dendritic structures in the hippocampus of adult male mice three months postirradiation. Six-month-old male C57BL/6 mice were irradiated first with 1H (0.5 Gy, 150 MeV/n) and 1 h later with 16O (0.1 Gy, 600 MeV/n) at the NASA Space Radiation Laboratory (Upton, NY). Three months after irradiation, animals were tested for hippocampus-dependent cognitive performance using the Y-maze. Upon sacrifice, molecular and morphological assessments were performed on hippocampal tissues. During Y-maze testing, the irradiated mice failed to distinguish the novel arm, spending approximately the same amount of time in all three arms during the retention trial relative to sham-treated controls. Irradiated animals also showed changes in expression of glutamate receptor subunits and synaptic density-associated proteins. 1H + 16O radiation compromised dendritic morphology in the cornu ammonis 1 and dentate gyrus within the hippocampus. These data indicate cognitive injuries due to 1H + 16O at three months postirradiation.
Asunto(s)
Hipocampo/fisiología , Hipocampo/efectos de la radiación , Hidrógeno/efectos adversos , Memoria a Corto Plazo/efectos de la radiación , Oxígeno/efectos adversos , Animales , Conducta Animal/efectos de los fármacos , Radiación Cósmica/efectos adversos , Regulación de la Expresión Génica/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/fisiología , Sinapsis/efectos de la radiaciónRESUMEN
5-Fluorouracil (5-Fu) is commonly used chemotherapy drug, but it can lead to the impairment of cognitive function. The pathogenesis of this injury is unknown but may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology. Dendritic spines are sites of excitatory synaptic transmission and changes in spine structure and dendrite morphology are thought to represent a morphological correlate of altered brain functions associated with hippocampal dependent learning and memory. A total of 28 one-year-old C57BL6/J male mice were used in this study; 14 mice received 5-Fu treatment and 14 were given saline injections. One month post treatment, 14 cytokines were measured at the same time Golgi samples were taken. 8 analytes were significantly elevated in mice treated with 5-Fu. 5-Fu significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal tri-synaptic network. The present data provide the evidence that 5-Fu has deleterious effects on mature neurons associated with hippocampal learning and memory.
Asunto(s)
Envejecimiento , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Fluorouracilo/farmacología , Hipocampo/citología , Inmunosupresores/farmacología , Regulación hacia Arriba/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Animales , Dendritas/ultraestructura , Espinas Dendríticas/ultraestructura , Masculino , Ratones , Ratones Endogámicos C57BL , Tinción con Nitrato de PlataRESUMEN
PURPOSE: PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu. EXPERIMENTAL DESIGN: Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138(+) multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti-multiple myeloma immune response and tumor cell growth. RESULTS: Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression. CONCLUSIONS: Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti-multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy.