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In JoVE (2)
- Stem Cell Transplantation Strategies for the Restoration of Cognitive Dysfunction Caused by Cranial Radiotherapy
- Quantifying Cognitive Decrements Caused by Cranial Radiotherapy
Other Publications (9)
- Indian Journal of Experimental Biology
- Zeitschrift Für Naturforschung. C, Journal of Biosciences
- Experimental Neurology
- Neuroscience Letters
- Progress in Neurobiology
- Proceedings of the National Academy of Sciences of the United States of America
- Free Radical Biology & Medicine
- Cancer Research
- Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Articles by Munjal M. Acharya in JoVE
Stem Cell Transplantation Strategies for the Restoration of Cognitive Dysfunction Caused by Cranial Radiotherapy
Munjal M. Acharya*, Dante E. Roa*, Omar Bosch, Mary L. Lan*, Charles L. Limoli
Department of Radiation Oncology, University of California Irvine
Brain tumor patients routinely undergo cranial radiotherapy, and while beneficial, this treatment often results in debilitating cognitive dysfunction. This serious unresolved problem has at present, no clinical recourse, and has driven our efforts to devise stem cell based therapies for the recovery of radiation-induced cognitive decrements.
Quantifying Cognitive Decrements Caused by Cranial Radiotherapy
Lori- Ann Christie, Munjal M. Acharya, Charles L. Limoli
Department of Radiation Oncology, University of California Irvine
Cognitive impairment resulting from the radiotherapeutic management of brain tumors represents a clinically intractable condition that adversely impacts quality of life. The capability to critically evaluate potential interventions for ameliorating radiation-induced cognitive decrements ultimately depends on the capability to undertake rigorous quantitative assessments of cognition.
Other articles by Munjal M. Acharya on PubMed
Indian Journal of Experimental Biology. Aug, 2004 | Pubmed ID: 15573532
Effect of repeated (20 days) exposure to picrotoxin (PTX) on rat liver lysosomal function was evaluated by measuring the free and total activities of acid phosphatase, cathepsin D, ribonuclease II (RNAse II) and deoxyribonuclease II (DNAse II). The free activities of the nucleases (both RNAse II and DNAse II) were increased following PTX exposure. The total DNAse II activity was increased by 2.2-fold whereas the total acid phosphatase activity was decreased by 28%. Consequently, the ratios of total activity / free activity were low in the PTX exposed groups, implying loss of membrane integrity. Cathepsin D activity was completely abolished. The results show that repeated exposure to PTX can lead to lysosomal dysfunction in liver.
Zeitschrift Für Naturforschung. C, Journal of Biosciences. Nov-Dec, 2004 | Pubmed ID: 15666553
A modified and improved micromethod for tyrosine determination has been developed. The method is sensitive, economic and applicable for estimation of tyrosine released in enzymatic reactions and in tissue. A range of Folin-Ciocalteu (FC) reagent was used to optimize the conditions for the development of blue color. Thus in 1.5 ml of the assay system, the suitably diluted FC reagent at the final concentration of 0.2 N gave a rapid optimum color development with an absorption maximum at 750 nm. Color development showed a linear relationship in the range of 2 to 16 microg tyrosine for a described assay system under optimized conditions. Thus, the method is 3-fold more sensitive in terms of its estimation range than a conventional method. The blue color formed was stable up to 24 h. The applicability of the method for tyrosine determination in the assay of lysosomal cathepsin D and in tissue was checked by comparison to the conventional procedure. Under both systems the results obtained by the micromethod were identical to those obtained by the conventional method. In general the method that produces quantitatively a blue color, not only is rapid and economical in terms of chemical usage but also has application for routine biochemical analysis.
Structural and Functional Alterations in Mitochondrial Membrane in Picrotoxin-induced Epileptic Rat Brain
Experimental Neurology. Mar, 2005 | Pubmed ID: 15698621
Mitochondrial function is a key determinant of both excitability and viability of neurons. Present studies were carried out to decipher cerebral mitochondrial oxidative energy metabolism and membrane function in the chronic condition of generalized seizures induced by picrotoxin (PTX) in rats. PTX-induced convulsions resulted in decreased respiration rates (14-41%) with glutamate, pyruvate + malate, and succinate as substrate. The ADP phosphorylation rates were drastically reduced by 44-65%. An opposite trend was observed with ascorbate + N,N,N',N'-tetramethyl-p-phenylenediamine [corrected] (TMPD) as substrate. In general, uncoupling of the mitochondrial electron transport was observed after PTX treatment. Malate dehydrogenase (MDH) and succinate dehydrogenase (SDH) activities were decreased by 20-80%; also, there was significant reduction in cytochrome b content after PTX treatment, while the F(o)F(1) ATPase (complex V) activity increased in basal and 2,4-dinitrophenol (DNP)-stimulated condition, indicating increased membrane fragility. The substrate kinetics analysis had shown that K(m) and V(max) of the higher affinity kinetic component of ATPase increased significantly by 1.2- to 1.4-fold in epileptic condition. Temperature kinetic analysis revealed 1.2-fold increase in energies of activation with decreased transition temperature. The total phospholipid (TPL) and cholesterol (CHL) contents decreased significantly with lowering of diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidylserine (PS), while lysophospholipid (lyso), sphingomyelin (SPM), and phosphatidylcholine components were found to be elevated. Brain mitochondrial membrane was somewhat more fluidized in epileptic animals. Possible consequences of mitochondrial respiratory chain (MRC) dysfunction are discussed. In conclusion, impairment of MRC function along with structural alterations suggests novel pathophysiological mechanisms important for chronic epileptic condition.
Neuroscience Letters. Feb, 2006 | Pubmed ID: 16368191
Cerebral microsomal membrane properties were assessed in the chronic condition of generalized seizure induced by picrotoxin (PTX) in rats. PTX-induced seizures resulted in increased lysophosphatidyl glycerol, phosphatidylcholine and phosphatidic acid components, while phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol were significantly reduced by 19-73%. The cholesterol (CHL) content increased considerably by 25% without alteration in total phospholipids content. Microsomal membrane was more fluidized in the epileptic condition. Possible consequences of microsomal membrane alterations are discussed in terms of deregulation of Ca2+ homeostasis. In conclusion, alterations in the microsomal membrane properties may have a significant influence on the cerebral function in the chronic epileptic condition.
Progress in Neurobiology. Apr, 2008 | Pubmed ID: 18207302
Neuroprotection is increasingly considered as a promising therapy for preventing and treating temporal lobe epilepsy (TLE). The development of chronic TLE, also termed as epileptogenesis, is a dynamic process. An initial precipitating injury (IPI) such as the status epilepticus (SE) leads to neurodegeneration, abnormal reorganization of the brain circuitry and a significant loss of functional inhibition. All of these changes likely contribute to the development of chronic epilepsy, characterized by spontaneous recurrent motor seizures (SRMS) and learning and memory deficits. The purpose of this review is to discuss the current state of knowledge pertaining to neuroprotection in epileptic conditions, and to highlight the efficacy of distinct neuroprotective strategies for preventing or treating chronic TLE. Although the administration of certain conventional and new generation anti-epileptic drugs is effective for primary neuroprotection such as reduced neurodegeneration after acute seizures or the SE, their competence for preventing the development of chronic epilepsy after an IPI is either unknown or not promising. On the other hand, alternative strategies such as the ketogenic diet therapy, administration of distinct neurotrophic factors, hormones or antioxidants seem useful for preventing and treating chronic TLE. However, long-term studies on the efficacy of these approaches introduced at different time-points after the SE or an IPI are lacking. Additionally, grafting of fetal hippocampal cells at early time-points after an IPI holds considerable promise for preventing TLE, though issues regarding availability of donor cells, ethical concerns, timing of grafting after SE, and durability of graft-mediated seizure suppression need to be resolved for further advances with this approach. Overall, from the studies performed so far, there is consensus that neuroprotective strategies need to be employed as quickly as possible after the onset of the SE or an IPI for considerable beneficial effects. Nevertheless, ideal strategies that are capable of facilitating repair and functional recovery of the brain after an IPI and preventing the evolution of IPI into chronic epilepsy are still hard to pin down.
Rescue of Radiation-induced Cognitive Impairment Through Cranial Transplantation of Human Embryonic Stem Cells
Proceedings of the National Academy of Sciences of the United States of America. Nov, 2009 | Pubmed ID: 19901336
Cranial irradiation remains a frontline treatment for the control of tumor growth, and individuals surviving such treatments often manifest various degrees of cognitive dysfunction. Radiation-induced depletion of stem/precursor cell pools in the brain, particularly those residing in the neurogenic region of the hippocampus, is believed, in part, to be responsible for these often-unavoidable cognitive deficits. To explore the possibility of ameliorating radiation-induced cognitive impairment, athymic nude rats subjected to head only irradiation (10 Gy) were transplanted 2 days afterward with human embryonic stem cells (hESC) into the hippocampal formation and analyzed for stem cell survival, differentiation, and cognitive function. Animals receiving hESC transplantation exhibited superior performance on a hippocampal-dependent cognitive task 4 months postirradiation, compared to their irradiated surgical counterparts that did not receive hESCs. Significant stem cell survival was found at 1 and 4 months postirradiation, and transplanted cells showed robust migration to the subgranular zone throughout the dentate gyrus, exhibiting signs of neuron morphology within this neurogenic niche. These results demonstrate the capability to ameliorate radiation-induced normal tissue injury using hESCs, and suggest that such strategies may provide useful interventions for reducing the adverse effects of irradiation on cognition.
Free Radical Biology & Medicine. Dec, 2010 | Pubmed ID: 20826207
Cranial irradiation remains a frontline treatment for brain cancer, but also leads to normal tissue damage. Although low-dose irradiation (≤10 Gy) causes minimal histopathologic change, it can elicit variable degrees of cognitive dysfunction that are associated with the depletion of neural stem cells. To decipher the mechanisms underlying radiation-induced stem cell dysfunction, human neural stem cells (hNSCs) subjected to clinically relevant irradiation (0-5 Gy) were analyzed for survival parameters, cell-cycle alterations, DNA damage and repair, and oxidative stress. hNSCs showed a marked sensitivity to low-dose irradiation that was in part due to elevated apoptosis and the inhibition of cell-cycle progression that manifested as a G2/M checkpoint delay. Efficient removal of DNA double-strand breaks was indicated by the disappearance of γ-H2AX nuclear foci. A dose-responsive and persistent increase in oxidative and nitrosative stress was found in irradiated hNSCs, possibly the result of a higher metabolic activity in the fraction of surviving cells. These data highlight the marked sensitivity of hNSCs to low-dose irradiation and suggest that long-lasting perturbations in the CNS microenvironment due to radiation-induced oxidative stress can compromise the functionality of neural stem cells.
Cancer Research. Jul, 2011 | Pubmed ID: 21757460
Cranial radiotherapy induces progressive and debilitating declines in cognition that may, in part, be caused by the depletion of neural stem cells. The potential of using stem cell replacement as a strategy to combat radiation-induced cognitive decline was addressed by irradiating athymic nude rats followed 2 days later by intrahippocampal transplantation with human neural stem cells (hNSC). Measures of cognitive performance, hNSC survival, and phenotypic fate were assessed at 1 and 4 months after irradiation. Irradiated animals engrafted with hNSCs showed significantly less decline in cognitive function than irradiated, sham-engrafted animals and acted indistinguishably from unirradiated controls. Unbiased stereology revealed that 23% and 12% of the engrafted cells survived 1 and 4 months after transplantation, respectively. Engrafted cells migrated extensively, differentiated along glial and neuronal lineages, and expressed the activity-regulated cytoskeleton-associated protein (Arc), suggesting their capability to functionally integrate into the hippocampus. These data show that hNSCs afford a promising strategy for functionally restoring cognition in irradiated animals.
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Feb, 2012 | Pubmed ID: 22338017
PURPOSE: A substantial proportion of breast cancer survivors report significant, long-lasting impairments in cognitive function, often referred to as "chemobrain." Advances in detection and treatment mean that many more patients are surviving long-term following diagnosis of invasive breast cancer. Thus, it is important to define the types, extent and persistence of cognitive impairments following treatment with cytotoxic cancer drugs. EXPERIMENTAL DESIGN: We examined the effects of chronic treatment with two agents commonly used in breast cancer patients, cyclophosphamide and doxorubicin (Adriamycin). Athymic nude rats were given 50mg/kg cyclophosphamide, 2mg/kg doxorubicin or saline injections once per week for 4 weeks. A novel place recognition task and contextual and cued fear conditioning were employed to characterize learning and memory ability. Immunofluorescence staining for immature and mature neurons and activated microglia was used to assess changes in neurogenesis and neuroinflammation.RESULTS: Cyclophosphamide- and doxorubicin-treated rats showed significantly impaired performance on the novel place recognition task and the contextual fear conditioning task compared to untreated controls, suggesting disrupted hippocampal-based memory function. Chemotherapy-treated animals showed a significant decline in neurogenesis (80 to 90% drop in BrdU labeled cells expressing NeuN). Activated microglia (ED1 positive) were found after cyclophosphamide, but not doxorubicin treatment.CONCLUSIONS: Our results demonstrate that chronic treatment with either of two commonly-used chemotherapeutic agents impairs cognitive ability, and suggest that strategies to prevent or repair disrupted hippocampal neurogenesis may be effective in ameliorating this serious side effect in cancer survivors.