Publications by authors named "Vipan K Parihar"

30 Publications

  • Page 1 of 1

Detrimental impacts of mixed-ion radiation on nervous system function.

Neurobiol Dis 2021 Apr 5;151:105252. Epub 2021 Jan 5.

Department of Neurosurgery, Stanford University, Palo Alto, CA 94305, United States of America; Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA 94305, United States of America.

Galactic cosmic radiation (GCR), composed of highly energetic and fully ionized atomic nuclei, produces diverse deleterious effects on the body. In researching the neurological risks of GCR exposures, including during human spaceflight, various ground-based single-ion GCR irradiation paradigms induce differential disruptions of cellular activity and overall behavior. However, it remains less clear how irradiation comprising a mix of multiple ions, more accurately recapitulating the space GCR environment, impacts the central nervous system. We therefore examined how mixed-ion GCR irradiation (two similar 5-6 beam combinations of protons, helium, oxygen, silicon and iron ions) influenced neuronal connectivity, functional generation of activity within neural circuits and cognitive behavior in mice. In electrophysiological recordings we find that space-relevant doses of mixed-ion GCR preferentially alter hippocampal inhibitory neurotransmission and produce related disruptions in the local field potentials of hippocampal oscillations. Such underlying perturbation in hippocampal network activity correspond with perturbed learning, memory and anxiety behavior.
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http://dx.doi.org/10.1016/j.nbd.2021.105252DOI Listing
April 2021

Sex-Specific Cognitive Deficits Following Space Radiation Exposure.

Front Behav Neurosci 2020 16;14:535885. Epub 2020 Sep 16.

Department of Radiation Oncology, University of California, Irvine, Irvine, CA, United States.

The radiation fields in space define tangible risks to the health of astronauts, and significant work in rodent models has clearly shown a variety of exposure paradigms to compromise central nervous system (CNS) functionality. Despite our current knowledge, sex differences regarding the risks of space radiation exposure on cognitive function remain poorly understood, which is potentially problematic given that 30% of astronauts are women. While work from us and others have demonstrated pronounced cognitive decrements in male mice exposed to charged particle irradiation, here we show that female mice exhibit significant resistance to adverse neurocognitive effects of space radiation. The present findings indicate that male mice exposed to low doses (≤30 cGy) of energetic (400 MeV/n) helium ions (He) show significantly higher levels of neuroinflammation and more extensive cognitive deficits than females. Twelve weeks following He ion exposure, irradiated male mice demonstrated significant deficits in object and place recognition memory accompanied by activation of microglia, marked upregulation of hippocampal Toll-like receptor 4 (TLR4), and increased expression of the pro-inflammatory marker high mobility group box 1 protein (HMGB1). Additionally, we determined that exposure to He ions caused a significant decline in the number of dendritic branch points and total dendritic length along with the hippocampus neurons in female mice. Interestingly, only male mice showed a significant decline of dendritic spine density following irradiation. These data indicate that fundamental differences in inflammatory cascades between male and female mice may drive divergent CNS radiation responses that differentially impact the structural plasticity of neurons and neurocognitive outcomes following cosmic radiation exposure.
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http://dx.doi.org/10.3389/fnbeh.2020.535885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525092PMC
September 2020

Radiotherapy and Its Impact on the Nervous System of Cancer Survivors.

CNS Neurol Disord Drug Targets 2020 ;19(5):374-385

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.

Radiotherapy is routinely used for the treatment of nearly all brain tumors, but it may lead to progressive and debilitating impairments of cognitive function. The growing evidence supports the fact that radiation exposure to CNS disrupts diverse cognitive functions including learning, memory, processing speed, attention and executive functions. The present review highlights the types of radiotherapy and the possible mechanisms of cognitive deficits and neurotoxicity following radiotherapy. The review summarizes the articles from Scopus, PubMed, and Web of science search engines. Radiation therapy uses high-powered x-rays, particles, or radioactive seeds to kill cancer cells, with minimal damage to healthy cells. While radiotherapy has yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side effects from the treatment, which can lead to dose reduction or even cessation of treatment. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities; however, neuroinflammation is widely considered as one of the major mechanisms responsible for radiotherapy-induced toxicities. The present study reviews the different types of radiotherapy available for the treatment of various types of cancers and their associated neurological complications. It also summarizes the doses of radiations used in the variety of radiotherapy, and their early and delayed side effects. Special emphasis is given to the effects of various types of radiations or late side effects on cognitive impairments.
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http://dx.doi.org/10.2174/1871527319666200708125741DOI Listing
January 2020

An Appraisal of Current Pharmacological Perspectives of Sesamol: A Review.

Mini Rev Med Chem 2020 ;20(11):988-1000

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India.

Sesame (Sesamum indicum L.) seeds have been authenticated for its medicinal value in both Chinese and Indian systems of medicine. Its numerous potential nutritional benefits are attributed to its main bioactive constituents, sesamol. As a result of those studies, several molecular mechanisms are emerging describing the pleiotropic biological effects of sesamol. This review summarized the most interesting in vitro and in vivo studies on the biological effects of sesamol. The present work summarises data available from Pubmed and Scopus database. Several molecular mechanisms have been elucidated describing the pleiotropic biological effects of sesamol. Its major therapeutic effects have been elicited in managing oxidative and inflammatory conditions, metabolic syndrome and mood disorders. Further, compelling evidence reflected the ability of sesamol in inhibiting proliferation of the inflammatory cell, prevention of invasion and angiogenesis via affecting multiple molecular targets and downstream mechanisms. Sesamol is a safe, non-toxic chemical that mediates anti-inflammatory effects by down-regulating the transcription of inflammatory markers such as cytokines, redox status, protein kinases, and enzymes that promote inflammation. In addition, sesamol also induces apoptosis in cancer cells via mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the present review, several pharmacological effects of sesamol are summarised namely, antioxidant, anti-cancer, neuroprotective, cardioprotective, anti-inflammatory, hypolipidemic, radioprotective, anti-aging, anti-ulcer, anti-dementia, anti-depressant, antiplatelet, anticonvulsant, anti-anxiolytic, wound healing, cosmetic (skin whitening), anti-microbial, matrix metalloproteinase (MMPs) inhibition, hepatoprotective activity and other biological effects. Here we have summarized the proposed mechanism behind these pharmacological effects.
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http://dx.doi.org/10.2174/1389557520666200313120419DOI Listing
February 2021

Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy.

Radiat Res 2020 05 5;193(5):407-424. Epub 2020 Mar 5.

Departments of Radiation Oncology.

Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by ∼50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.
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http://dx.doi.org/10.1667/RR15540.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334540PMC
May 2020

Stochastic Modeling of Radiation-induced Dendritic Damage on in silico Mouse Hippocampal Neurons.

Sci Rep 2018 04 3;8(1):5494. Epub 2018 Apr 3.

Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, NV, United States of America.

Cognitive dysfunction associated with radiotherapy for cancer treatment has been correlated to several factors, one of which is changes to the dendritic morphology of neuronal cells. Alterations in dendritic geometry and branching patterns are often accompanied by deficits that impact learning and memory. The purpose of this study is to develop a novel predictive model of neuronal dendritic damages caused by exposure to low linear energy transfer (LET) radiation, such as X-rays, γ-rays and high-energy protons. We established in silico representations of mouse hippocampal dentate granule cell layer (GCL) and CA1 pyramidal neurons, which are frequently examined in radiation-induced cognitive decrements. The in silico representations are used in a stochastic model that describes time dependent dendritic damage induced by exposure to low LET radiation. Changes in morphometric parameters, such as total dendritic length, number of branch points and branch number, including the Sholl analysis for single neurons are described by the model. Our model based predictions for different patterns of morphological changes based on energy deposition in dendritic segments (EDDS) will serve as a useful basis to compare specific patterns of morphological alterations caused by EDDS mechanisms.
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http://dx.doi.org/10.1038/s41598-018-23855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882641PMC
April 2018

Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice.

Exp Neurol 2018 07 11;305:44-55. Epub 2018 Mar 11.

Department of Radiation Oncology, University of California, Irvine, CA 92697-2695, USA. Electronic address:

Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic-radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post-irradiation intervals.
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http://dx.doi.org/10.1016/j.expneurol.2018.03.009DOI Listing
July 2018

Epigenetic determinants of space radiation-induced cognitive dysfunction.

Sci Rep 2017 02 21;7:42885. Epub 2017 Feb 21.

University of California Irvine, CA 92697, USA.

Among the dangers to astronauts engaging in deep space missions such as a Mars expedition is exposure to radiations that put them at risk for severe cognitive dysfunction. These radiation-induced cognitive impairments are accompanied by functional and structural changes including oxidative stress, neuroinflammation, and degradation of neuronal architecture. The molecular mechanisms that dictate CNS function are multifaceted and it is unclear how irradiation induces persistent alterations in the brain. Among those determinants of cognitive function are neuroepigenetic mechanisms that translate radiation responses into altered gene expression and cellular phenotype. In this study, we have demonstrated a correlation between epigenetic aberrations and adverse effects of space relevant irradiation on cognition. In cognitively impaired irradiated mice we observed increased 5-methylcytosine and 5-hydroxymethylcytosine levels in the hippocampus that coincided with increased levels of the DNA methylating enzymes DNMT3a, TET1 and TET3. By inhibiting methylation using 5-iodotubercidin, we demonstrated amelioration of the epigenetic effects of irradiation. In addition to protecting against those molecular effects of irradiation, 5-iodotubercidin restored behavioral performance to that of unirradiated animals. The findings of this study establish the possibility that neuroepigenetic mechanisms significantly contribute to the functional and structural changes that affect the irradiated brain and cognition.
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http://dx.doi.org/10.1038/srep42885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318883PMC
February 2017

Neurophysiology of space travel: energetic solar particles cause cell type-specific plasticity of neurotransmission.

Brain Struct Funct 2017 Jul 30;222(5):2345-2357. Epub 2016 Nov 30.

Department of Neurosurgery, and Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, 94305, USA.

In the not too distant future, humankind will embark on one of its greatest adventures, the travel to distant planets. However, deep space travel is associated with an inevitable exposure to radiation fields. Space-relevant doses of protons elicit persistent disruptions in cognition and neuronal structure. However, whether space-relevant irradiation alters neurotransmission is unknown. Within the hippocampus, a brain region crucial for cognition, perisomatic inhibitory control of pyramidal cells (PCs) is supplied by two distinct cell types, the cannabinoid type 1 receptor (CB)-expressing basket cells (CBBCs) and parvalbumin (PV)-expressing interneurons (PVINs). Mice subjected to low-dose proton irradiation were analyzed using electrophysiological, biochemical and imaging techniques months after exposure. In irradiated mice, GABA release from CBBCs onto PCs was dramatically increased. This effect was abolished by CB blockade, indicating that irradiation decreased CB-dependent tonic inhibition of GABA release. These alterations in GABA release were accompanied by decreased levels of the major CB ligand 2-arachidonoylglycerol. In contrast, GABA release from PVINs was unchanged, and the excitatory connectivity from PCs to the interneurons also underwent cell type-specific alterations. These results demonstrate that energetic charged particles at space-relevant low doses elicit surprisingly selective long-term plasticity of synaptic microcircuits in the hippocampus. The magnitude and persistent nature of these alterations in synaptic function are consistent with the observed perturbations in cognitive performance after irradiation, while the high specificity of these changes indicates that it may be possible to develop targeted therapeutic interventions to decrease the risk of adverse events during interplanetary travel.
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http://dx.doi.org/10.1007/s00429-016-1345-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504243PMC
July 2017

Cosmic radiation exposure and persistent cognitive dysfunction.

Sci Rep 2016 10 10;6:34774. Epub 2016 Oct 10.

Department of Radiation Oncology, University of California, Irvine, CA 92697-2695, USA.

The Mars mission will result in an inevitable exposure to cosmic radiation that has been shown to cause cognitive impairments in rodent models, and possibly in astronauts engaged in deep space travel. Of particular concern is the potential for cosmic radiation exposure to compromise critical decision making during normal operations or under emergency conditions in deep space. Rodents exposed to cosmic radiation exhibit persistent hippocampal and cortical based performance decrements using six independent behavioral tasks administered between separate cohorts 12 and 24 weeks after irradiation. Radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in executive function and reduced rates of fear extinction and elevated anxiety. Irradiation caused significant reductions in dendritic complexity, spine density and altered spine morphology along medial prefrontal cortical neurons known to mediate neurotransmission interrogated by our behavioral tasks. Cosmic radiation also disrupted synaptic integrity and increased neuroinflammation that persisted more than 6 months after exposure. Behavioral deficits for individual animals correlated significantly with reduced spine density and increased synaptic puncta, providing quantitative measures of risk for developing cognitive impairment. Our data provide additional evidence that deep space travel poses a real and unique threat to the integrity of neural circuits in the brain.
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http://dx.doi.org/10.1038/srep34774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056393PMC
October 2016

Elimination of microglia improves cognitive function following cranial irradiation.

Sci Rep 2016 08 12;6:31545. Epub 2016 Aug 12.

Department of Radiation Oncology, University of California Irvine, CA 92697, USA.

Cranial irradiation for the treatment of brain cancer elicits progressive and severe cognitive dysfunction that is associated with significant neuropathology. Radiation injury in the CNS has been linked to persistent microglial activation, and we find upregulation of pro-inflammatory genes even 6 weeks after irradiation. We hypothesize that depletion of microglia in the irradiated brain would have a neuroprotective effect. Adult mice received acute head only irradiation (9 Gy) and were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia post-irradiation. Cohorts of mice maintained on a normal and PLX5662 diet were analyzed for cognitive changes using a battery of behavioral tasks 4-6 weeks later. PLX5622 treatment caused a rapid and near complete elimination of microglia in the brain within 3 days of treatment. Irradiation of animals given a normal diet caused characteristic behavioral deficits designed to test medial pre-frontal cortex (mPFC) and hippocampal learning and memory and caused increased microglial activation. Animals receiving the PLX5622 diet exhibited no radiation-induced cognitive deficits, and exhibited near complete loss of IBA-1 and CD68 positive microglia in the mPFC and hippocampus. Our data demonstrate that elimination of microglia through CSF1R inhibition can ameliorate radiation-induced cognitive deficits in mice.
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http://dx.doi.org/10.1038/srep31545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981848PMC
August 2016

Cranial grafting of stem cell-derived microvesicles improves cognition and reduces neuropathology in the irradiated brain.

Proc Natl Acad Sci U S A 2016 Apr 4;113(17):4836-41. Epub 2016 Apr 4.

Department of Radiation Oncology, University of California, Irvine, CA 92697-2695

Cancer survivors face a variety of challenges as they cope with disease recurrence and a myriad of normal tissue complications brought on by radio- and chemotherapeutic treatment regimens. For patients subjected to cranial irradiation for the control of CNS malignancy, progressive and debilitating cognitive dysfunction remains a pressing unmet medical need. Although this problem has been recognized for decades, few if any satisfactory long-term solutions exist to resolve this serious unintended side effect of radiotherapy. Past work from our laboratory has demonstrated the neurocognitive benefits of human neural stem cell (hNSC) grafting in the irradiated brain, where intrahippocampal transplantation of hNSC ameliorated radiation-induced cognitive deficits. Using a similar strategy, we now provide, to our knowledge, the first evidence that cranial grafting of microvesicles secreted from hNSC affords similar neuroprotective phenotypes after head-only irradiation. Cortical- and hippocampal-based deficits found 1 mo after irradiation were completely resolved in animals cranially grafted with microvesicles. Microvesicle treatment was found to attenuate neuroinflammation and preserve host neuronal morphology in distinct regions of the brain. These data suggest that the neuroprotective properties of microvesicles act through a trophic support mechanism that reduces inflammation and preserves the structural integrity of the irradiated microenvironment.
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http://dx.doi.org/10.1073/pnas.1521668113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855546PMC
April 2016

Contrasting the effects of proton irradiation on dendritic complexity of subiculum neurons in wild type and MCAT mice.

Environ Mol Mutagen 2016 06 20;57(5):364-71. Epub 2016 Mar 20.

Department of Radiation Oncology, University of California, Irvine, California.

Growing evidence suggests that radiation-induced oxidative stress directly affects a wide range of biological changes with an overall negative impact on CNS function. In the past we have demonstrated that transgenic mice over-expressing human catalase targeted to the mitochondria (MCAT) exhibit a range of neuroprotective phenotypes following irradiation that include improved neurogenesis, dendritic complexity, and cognition. To determine the extent of the neuroprotective phenotype afforded by MCAT expression in different hippocampal regions, we analyzed subiculum neurons for changes in neuronal structure and synaptic integrity after exposure to low dose (0.5 Gy) 150 MeV proton irradiation. One month following irradiation of WT and MCAT mice, a range of morphometric parameters were quantified along Golgi-Cox impregnated neurons. Compared with WT mice, subiculum neurons from MCAT mice exhibited increased trends (albeit not statistically significant) toward increased dendritic complexity in both control and irradiated cohorts. However, Sholl analysis of MCAT mice revealed significantly increased arborization of the distal dendritic tree, indicating a protective effect on secondary and tertiary branching. Interestingly, radiation-induced increases in postsynaptic density protein (PSD-95) puncta were not as pronounced in MCAT compared with WT mice, and were significantly lower after the 0.5 Gy dose. As past data has linked radiation exposure to reduced dendritic complexity, elevated PSD-95 and impaired cognition, reductions in mitochondrial oxidative stress have proven useful in ameliorating many of these radiation-induced sequelae. Data presented here shows similar trends, and again points to the potential benefits of reducing oxidative stress in the brain to attenuate radiation injury. Environ. Mol. Mutagen. 57:364-371, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/em.22006DOI Listing
June 2016

Irradiation of Neurons with High-Energy Charged Particles: An In Silico Modeling Approach.

PLoS Comput Biol 2015 Aug 7;11(8):e1004428. Epub 2015 Aug 7.

Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, United States of America.

In this work, a stochastic computational model of microscopic energy deposition events is used to study for the first time damage to irradiated neuronal cells of the mouse hippocampus. An extensive library of radiation tracks for different particle types is created to score energy deposition in small voxels and volume segments describing a neuron's morphology that later are sampled for given particle fluence or dose. Methods included the construction of in silico mouse hippocampal granule cells from neuromorpho.org with spine and filopodia segments stochastically distributed along the dendritic branches. The model is tested with high-energy (56)Fe, (12)C, and (1)H particles and electrons. Results indicate that the tree-like structure of the neuronal morphology and the microscopic dose deposition of distinct particles may lead to different outcomes when cellular injury is assessed, leading to differences in structural damage for the same absorbed dose. The significance of the microscopic dose in neuron components is to introduce specific local and global modes of cellular injury that likely contribute to spine, filopodia, and dendrite pruning, impacting cognition and possibly the collapse of the neuron. Results show that the heterogeneity of heavy particle tracks at low doses, compared to the more uniform dose distribution of electrons, juxtaposed with neuron morphology make it necessary to model the spatial dose painting for specific neuronal components. Going forward, this work can directly support the development of biophysical models of the modifications of spine and dendritic morphology observed after low dose charged particle irradiation by providing accurate descriptions of the underlying physical insults to complex neuron structures at the nano-meter scale.
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http://dx.doi.org/10.1371/journal.pcbi.1004428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529238PMC
August 2015

What happens to your brain on the way to Mars.

Sci Adv 2015 May;1(4)

Department of Radiation Oncology, University of California, Irvine, Irvine, CA 92697-2695, USA.

As NASA prepares for the first manned spaceflight to Mars, questions have surfaced concerning the potential for increased risks associated with exposure to the spectrum of highly energetic nuclei that comprise galactic cosmic rays. Animal models have revealed an unexpected sensitivity of mature neurons in the brain to charged particles found in space. Astronaut autonomy during long-term space travel is particularly critical as is the need to properly manage planned and unanticipated events, activities that could be compromised by accumulating particle traversals through the brain. Using mice subjected to space-relevant fluences of charged particles, we show significant cortical- and hippocampal-based performance decrements 6 weeks after acute exposure. Animals manifesting cognitive decrements exhibited marked and persistent radiation-induced reductions in dendritic complexity and spine density along medial prefrontal cortical neurons known to mediate neurotransmission specifically interrogated by our behavioral tasks. Significant increases in postsynaptic density protein 95 (PSD-95) revealed major radiation-induced alterations in synaptic integrity. Impaired behavioral performance of individual animals correlated significantly with reduced spine density and trended with increased synaptic puncta, thereby providing quantitative measures of risk for developing cognitive decrements. Our data indicate an unexpected and unique susceptibility of the central nervous system to space radiation exposure, and argue that the underlying radiation sensitivity of delicate neuronal structure may well predispose astronauts to unintended mission-critical performance decrements and/or longer-term neurocognitive sequelae.
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http://dx.doi.org/10.1126/sciadv.1400256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500198PMC
May 2015

Consequences of low dose ionizing radiation exposure on the hippocampal microenvironment.

PLoS One 2015 4;10(6):e0128316. Epub 2015 Jun 4.

Department of Radiation Oncology, University of California Irvine, Irvine, CA, 92697-2695, United States of America.

The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (≥ 45 Gy), few studies have been conducted at much lower doses (≤ 2 Gy), where the response of the CNS (like many other tissues) may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT) animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128316PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456101PMC
May 2016

Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction.

Cancer Res 2015 Feb;75(4):676-86

Department of Radiation Oncology, University of California, Irvine, California.

The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as "chemobrain," a condition that can persist long after the cessation of treatment in as many as 75% of survivors. Although cognitive health is a critical determinant of therapeutic outcome, chemobrain remains an unmet medical need that adversely affects quality of life in pediatric and adult cancer survivors. Using a rodent model of chemobrain, we showed that chronic cyclophosphamide treatment induced significant performance-based decrements on behavioral tasks designed to interrogate hippocampal and cortical function. Intrahippocampal transplantation of human neural stem cells resolved all cognitive impairments when animals were tested 1 month after the cessation of chemotherapy. In transplanted animals, grafted cells survived (8%) and differentiated along neuronal and astroglial lineages, where improved cognition was associated with reduced neuroinflammation and enhanced host dendritic arborization. Stem cell transplantation significantly reduced the number of activated microglia after cyclophosphamide treatment in the brain. Granule and pyramidal cell neurons within the dentate gyrus and CA1 subfields of the hippocampus exhibited significant reductions in dendritic complexity, spine density, and immature and mature spine types following chemotherapy, adverse effects that were eradicated by stem cell transplantation. Our findings provide the first evidence that cranial transplantation of stem cells can reverse the deleterious effects of chemobrain, through a trophic support mechanism involving the attenuation of neuroinflammation and the preservation host neuronal architecture.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332567PMC
February 2015

Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation.

Sci Rep 2015 Jan 28;5:8075. Epub 2015 Jan 28.

1] Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine at Scott &White, Temple, Texas, USA [2] Research Service, Olin E. Teague Veterans Affairs Medical Center, Central Texas Veterans Health Care System, Temple, Texas, USA [3] Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, Texas, USA [4] Department of Surgery (Neurosurgery) and Research Service, Duke University and Veterans' Affairs Medical Centers, Durham, North Carolina, USA.

Greatly waned neurogenesis, diminished microvasculature, astrocyte hypertrophy and activated microglia are among the most conspicuous structural changes in the aged hippocampus. Because these alterations can contribute to age-related memory and mood impairments, strategies efficacious for mitigating these changes may preserve cognitive and mood function in old age. Resveratrol, a phytoalexin found in the skin of red grapes having angiogenic and antiinflammatory properties, appears ideal for easing these age-related changes. Hence, we examined the efficacy of resveratrol for counteracting age-related memory and mood impairments and the associated detrimental changes in the hippocampus. Two groups of male F344 rats in late middle-age having similar learning and memory abilities were chosen and treated with resveratrol or vehicle for four weeks. Analyses at ~25 months of age uncovered improved learning, memory and mood function in resveratrol-treated animals but impairments in vehicle-treated animals. Resveratrol-treated animals also displayed increased net neurogenesis and microvasculature, and diminished astrocyte hypertrophy and microglial activation in the hippocampus. These results provide novel evidence that resveratrol treatment in late middle age is efficacious for improving memory and mood function in old age. Modulation of the hippocampus plasticity and suppression of chronic low-level inflammation appear to underlie the functional benefits mediated by resveratrol.
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http://dx.doi.org/10.1038/srep08075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894403PMC
January 2015

Defining the optimal window for cranial transplantation of human induced pluripotent stem cell-derived cells to ameliorate radiation-induced cognitive impairment.

Stem Cells Transl Med 2015 Jan 12;4(1):74-83. Epub 2014 Nov 12.

Department of Radiation Oncology, University of California, Irvine, Irvine, California, USA; Department of Pathology, University of California, San Diego, La Jolla, California, USA

Past preclinical studies have demonstrated the capability of using human stem cell transplantation in the irradiated brain to ameliorate radiation-induced cognitive dysfunction. Intrahippocampal transplantation of human embryonic stem cells and human neural stem cells (hNSCs) was found to functionally restore cognition in rats 1 and 4 months after cranial irradiation. To optimize the potential therapeutic benefits of human stem cell transplantation, we have further defined optimal transplantation windows for maximizing cognitive benefits after irradiation and used induced pluripotent stem cell-derived hNSCs (iPSC-hNSCs) that may eventually help minimize graft rejection in the host brain. For these studies, animals given an acute head-only dose of 10 Gy were grafted with iPSC-hNSCs at 2 days, 2 weeks, or 4 weeks following irradiation. Animals receiving stem cell grafts showed improved hippocampal spatial memory and contextual fear-conditioning performance compared with irradiated sham-surgery controls when analyzed 1 month after transplantation surgery. Importantly, superior performance was evident when stem cell grafting was delayed by 4 weeks following irradiation compared with animals grafted at earlier times. Analysis of the 4-week cohort showed that the surviving grafted cells migrated throughout the CA1 and CA3 subfields of the host hippocampus and differentiated into neuronal (∼39%) and astroglial (∼14%) subtypes. Furthermore, radiation-induced inflammation was significantly attenuated across multiple hippocampal subfields in animals receiving iPSC-hNSCs at 4 weeks after irradiation. These studies expand our prior findings to demonstrate that protracted stem cell grafting provides improved cognitive benefits following irradiation that are associated with reduced neuroinflammation.
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http://dx.doi.org/10.5966/sctm.2014-0063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275007PMC
January 2015

Targeted overexpression of mitochondrial catalase prevents radiation-induced cognitive dysfunction.

Antioxid Redox Signal 2015 Jan;22(1):78-91

1 Department of Radiation Oncology, University of California, Irvine , Irvine, California.

Aims: Radiation-induced disruption of mitochondrial function can elevate oxidative stress and contribute to the metabolic perturbations believed to compromise the functionality of the central nervous system. To clarify the role of mitochondrial oxidative stress in mediating the adverse effects of radiation in the brain, we analyzed transgenic (mitochondrial catalase [MCAT]) mice that overexpress human catalase localized to the mitochondria.

Results: Compared with wild-type (WT) controls, overexpression of the MCAT transgene significantly decreased cognitive dysfunction after proton irradiation. Significant improvements in behavioral performance found on novel object recognition and object recognition in place tasks were associated with a preservation of neuronal morphology. While the architecture of hippocampal CA1 neurons was significantly compromised in irradiated WT mice, the same neurons in MCAT mice did not exhibit extensive and significant radiation-induced reductions in dendritic complexity. Irradiated neurons from MCAT mice maintained dendritic branching and length compared with WT mice. Protected neuronal morphology in irradiated MCAT mice was also associated with a stabilization of radiation-induced variations in long-term potentiation. Stabilized synaptic activity in MCAT mice coincided with an altered composition of the synaptic AMPA receptor subunits GluR1/2.

Innovation: Our findings provide the first evidence that neurocognitive sequelae associated with radiation exposure can be reduced by overexpression of MCAT, operating through a mechanism involving the preservation of neuronal morphology.

Conclusion: Our article documents the neuroprotective properties of reducing mitochondrial reactive oxygen species through the targeted overexpression of catalase and how this ameliorates the adverse effects of proton irradiation in the brain.
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http://dx.doi.org/10.1089/ars.2014.5929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270160PMC
January 2015

Defining functional changes in the brain caused by targeted stereotaxic radiosurgery.

Transl Cancer Res 2014 Apr;3(2):124-137

Department of Radiation Oncology, University of California Irvine, Irvine, CA 92697, USA.

Brain tumor patients routinely undergo cranial radiotherapy, and while beneficial, this treatment often results in debilitating cognitive dysfunction. This serious and unresolved problem has at present, no clinical recourse, and has driven our efforts to more clearly define the consequences of different brain irradiation paradigms on specific indices of cognitive performance and on the underlying cellular mechanisms believed to affect these processes. To accomplish this we have developed the capability to deliver highly focused X-ray beams to small and precisely defined volumes of the athymic rat brain, thereby providing more realistic simulations of clinical irradiation scenarios. Using this technique, termed stereotaxic radiosurgery, we evaluated the cognitive consequences of irradiation targeted to the hippocampus in one or both hemispheres of the brain, and compared that to whole brain irradiation. While whole brain irradiation was found to elicit significant deficits in novel place recognition and fear conditioning, standard platforms for quantifying hippocampal and non-hippocampal decrements, irradiation targeted to both hippocampi was only found to elicit deficits in fear conditioning. Cognitive decrements were more difficult to demonstrate in animals subjected to unilateral hippocampal ablation. Immunohistochemical staining for newly born immature (doublecortin positive) and mature (NeuN positive) neurons confirmed our capability to target irradiation to the neurogenic regions of the hippocampus. Stereotaxic radiosurgery (SRS) of the ipsilateral hemisphere reduced significantly the number of doublecortin and NeuN positive neurons by 80% and 27% respectively. Interestingly, neurogenesis on the contralateral side was upregulated in response to stereotaxic radiosurgery, where the number of doublecortin and NeuN positive neurons increased by 22% and 36% respectively. Neuroinflammation measured by immunostaining for activated microglia (ED1 positive cells) was significantly higher on the ipsilateral versus contralateral sides, as assessed throughout the various subfields of the hippocampus. These data suggest that certain cognitive decrements are linked to changes in neurogenesis, and that the unilaterally irradiated brain exhibits distinct neurogenic responses that may be regulated by regional differences in neuroinflammation. Compensatory upregulation of neurogenesis on the contralateral hemisphere may suffice to maintain cognition under certain dose limits. Our results demonstrate unique cognitive and neurogenic consequences as a result of targeted stereotaxic radiosurgery, and suggest that these irradiation paradigms elicit responses distinct from those found after exposing the whole brain to more uniform radiation fields.
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http://dx.doi.org/10.3978/j.issn.2218-676X.2013.06.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043313PMC
April 2014

Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation.

Brain Struct Funct 2015 Mar 21;220(2):1161-71. Epub 2014 Jan 21.

Department of Radiation Oncology, University of California, Medical Sciences I, Room B-146B, Irvine, CA, 92697-2695, USA.

Cranial radiotherapy is used routinely to control the growth of primary and secondary brain tumors, but often results in serious and debilitating cognitive dysfunction. In part due to the beneficial dose depth distributions that may spare normal tissue damage, the use of protons to treat CNS and other tumor types is rapidly gaining popularity. Astronauts exposed to lower doses of protons in the space radiation environment are also at risk for developing adverse CNS complications. To explore the consequences of whole body proton irradiation, mice were subjected to 0.1 and 1 Gy and analyzed for morphometric changes in hippocampal neurons 10 and 30 days following exposure. Significant dose-dependent reductions (~33 %) in dendritic complexity were found, when dendritic length, branching and area were analyzed 30 days after exposure. At equivalent doses and times, significant reductions in the number (~30 %) and density (50-75 %) of dendritic spines along hippocampal neurons of the dentate gyrus were also observed. Immature spines (filopodia, long) exhibited the greatest sensitivity (1.5- to 3-fold) to irradiation, while more mature spines (mushroom) were more resistant to changes over a 1-month post-irradiation timeframe. Irradiated granule cell neurons spanning the subfields of the dentate gyrus showed significant and dose-responsive reductions in synaptophysin expression, while the expression of postsynaptic density protein (PSD-95) was increased significantly. These findings corroborate our past work using photon irradiation, and demonstrate for the first time, dose-responsive changes in dendritic complexity, spine density and morphology and synaptic protein levels following exposure to low-dose whole body proton irradiation.
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http://dx.doi.org/10.1007/s00429-014-0709-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105336PMC
March 2015

Mood and memory deficits in a model of Gulf War illness are linked with reduced neurogenesis, partial neuron loss, and mild inflammation in the hippocampus.

Neuropsychopharmacology 2013 Nov 28;38(12):2348-62. Epub 2013 Jun 28.

1] Research Service, Durham Veterans Affairs Medical Center, Durham, NC, USA [2] Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, NC, USA.

Impairments in mood and cognitive function are the key brain abnormalities observed in Gulf war illness (GWI), a chronic multisymptom health problem afflicting ∼25% of veterans who served in the Persian Gulf War-1. Although the precise cause of GWI is still unknown, combined exposure to a nerve gas prophylaxis drug pyridostigmine bromide (PB) and pesticides DEET and permethrin during the war has been proposed as one of the foremost causes of GWI. We investigated the effect of 4 weeks of exposure to Gulf war illness-related (GWIR) chemicals in the absence or presence of mild stress on mood and cognitive function, dentate gyrus neurogenesis, and neurons, microglia, and astrocytes in the hippocampus. Combined exposure to low doses of GWIR chemicals PB, DEET, and permethrin induced depressive- and anxiety-like behavior and spatial learning and memory dysfunction. Application of mild stress in the period of exposure to chemicals exacerbated the extent of mood and cognitive dysfunction. Furthermore, these behavioral impairments were associated with reduced hippocampal volume and multiple cellular alterations such as chronic reductions in neural stem cell activity and neurogenesis, partial loss of principal neurons, and mild inflammation comprising sporadic occurrence of activated microglia and significant hypertrophy of astrocytes. The results show the first evidence of an association between mood and cognitive dysfunction and hippocampal pathology epitomized by decreased neurogenesis, partial loss of principal neurons, and mild inflammation in a model of GWI. Hence, treatment strategies that are efficacious for enhancing neurogenesis and suppressing inflammation may be helpful for alleviation of mood and cognitive dysfunction observed in GWI.
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http://dx.doi.org/10.1038/npp.2013.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799073PMC
November 2013

Functional consequences of radiation-induced oxidative stress in cultured neural stem cells and the brain exposed to charged particle irradiation.

Antioxid Redox Signal 2014 Mar 12;20(9):1410-22. Epub 2013 Aug 12.

1 Department of Internal Medicine, Duke University Medical Center , Durham, North Carolina.

Aims: Redox homeostasis is critical in regulating the fate and function of multipotent cells in the central nervous system (CNS). Here, we investigated whether low dose charged particle irradiation could elicit oxidative stress in neural stem and precursor cells and whether radiation-induced changes in redox metabolism would coincide with cognitive impairment.

Results: Low doses (<1 Gy) of charged particles caused an acute and persistent oxidative stress. Early after (<1 week) irradiation, increased levels of reactive oxygen and nitrogen species were generally dose responsive, but were less dependent on dose weeks to months thereafter. Exposure to ion fluences resulting in less than one ion traversal per cell was sufficient to elicit radiation-induced oxidative stress. Whole body irradiation triggered a compensatory response in the rodent brain that led to a significant increase in antioxidant capacity 2 weeks following exposure, before returning to background levels at week 4. Low dose irradiation was also found to significantly impair novel object recognition in mice 2 and 12 weeks following irradiation.

Innovation: Data provide evidence that acute exposure of neural stem cells and the CNS to very low doses and fluences of charged particles can elicit a persisting oxidative stress lasting weeks to months that is associated with impaired cognition.

Conclusions: Exposure to low doses of charged particles causes a persistent oxidative stress and cognitive impairment over protracted times. Data suggest that astronauts subjected to space radiation may develop a heightened risk for mission critical performance decrements in space, along with a risk of developing long-term neurocognitive sequelae.
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http://dx.doi.org/10.1089/ars.2012.5134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936501PMC
March 2014

Mitochondrial-targeted human catalase affords neuroprotection from proton irradiation.

Radiat Res 2013 Jul 14;180(1):1-6. Epub 2013 May 14.

Department of Radiation Oncology, University of California, Irvine, California, USA.

Significant past work has linked radiation exposure of the CNS to elevated levels of oxidative stress and inflammation. These secondary reactive processes are both dynamic and persistent and are believed to compromise the functionality of the CNS, in part, by disrupting endogenous neurogenesis in the hippocampus. While evidence has shown neurogenesis to be sensitive to irradiation and redox state, the mechanistic basis underlying these effects is incompletely understood. To clarify the role of reactive oxygen species (ROS) in mediating radiation-induced changes in neurogenesis we have analyzed transgenic mice that overexpress human catalase localized to the mitochondria. With this model, we investigated the consequences of low dose and clinically relevant proton irradiation on neurogenesis, and how that process is modified in response to genetic disruption of mitochondrial ROS levels. In unirradiated animals, basal neurogenesis was improved significantly by reductions in mitochondrial ROS. In animals subjected to proton exposure, hippocampal progenitor cell proliferation was attenuated significantly by overexpression of human catalase in the mitochondria. Furthermore, expression of the MCAT transgene significantly improved neurogenesis in WT animals after low-dose proton exposure (0.5 Gy), with similar trends observed at higher dose (2 Gy). Our report documents for the first time the impact of proton irradiation on hippocampal neurogenesis, and the neuroprotective properties of reducing mitochondrial ROS through the targeted overexpression of catalase.
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http://dx.doi.org/10.1667/RR3339.1DOI Listing
July 2013

Sesamol treatment reduces plasma cholesterol and triacylglycerol levels in mouse models of acute and chronic hyperlipidemia.

Lipids 2013 Jun 17;48(6):633-8. Epub 2013 Mar 17.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India.

The active constituents of Sesamum indicum, sesamin and sesamolin, have already been explored for hypolipidemic action. In this study we have explored the anti-dyslipidemic activity of another active component and metabolite of sesamolin (sesamol), by using acute models of hyperlipidemia viz., a fat tolerance test, a tyloxapol-induced hyperlipidemia model and a chronic model of hyperlipidemia viz., a high-fat diet-induced hyperlipidemia model in Swiss albino mice. Sesamol (100 and 200 mg/kg) significantly (P < 0.05) decreased triacylglycerol absorption in the fat tolerance test by showing a dose-dependent decrease in triacylglycerol levels. The hypolipidemic effect of sesamol at 200 mg/kg was equivalent to 10 mg/kg of orlistat. In the tyloxapol-induced hyperlipidemia model, Sesamol at 200 mg/kg reversed the elevated levels of cholesterol and triacylglycerol compared with the tyloxapol group at 12 and 24 h, which indicates its probable effect on cholesterol synthesis. Chronic hyperlipidemia in mice was produced by feeding a high-diet, a mixture of cholesterol (2 % w/w), cholic acid (1 % w/w) and coconut oil 30 % (v/w) with standard powdered standard animal chow (up to 100 g). Niacin (100 mg/kg) and sesamol (100 mg/kg) significantly (P < 0.05) reduced the elevated body weight compared with the high fat diet control group. Elevated levels of cholesterol and triacylglycerol were significantly (P < 0.05) reversed by the sesamol (50 and 100 mg/kg), implying that it might reduce the absorption and increase the excretion of cholesterol as well.
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http://dx.doi.org/10.1007/s11745-013-3778-2DOI Listing
June 2013

Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy.

Clin Cancer Res 2012 Apr 14;18(7):1954-65. Epub 2012 Feb 14.

Department of Radiation Oncology, University of California, Irvine, CA 92697, USA.

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 patients with breast cancer, cyclophosphamide and doxorubicin (Adriamycin). Athymic nude rats were given 50 mg/kg cyclophosphamide, 2 mg/kg doxorubicin, or saline injections once per week for 4 weeks. A novel place recognition task and contextual and cued fear conditioning were used 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 with untreated controls, suggesting disrupted hippocampal-based memory function. Chemotherapy-treated animals showed a significant decline in neurogenesis [80%-90% drop in bromodeoxyuridine (BrdUrd)-labeled cells expressing NeuN]. Activated microglia (ED1-positive) were found after cyclophosphamide but not doxorubicin treatment.

Conclusions: Our results show 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-2000DOI Listing
April 2012

Differential susceptibility of interneurons expressing neuropeptide Y or parvalbumin in the aged hippocampus to acute seizure activity.

PLoS One 2011 6;6(9):e24493. Epub 2011 Sep 6.

Medical Research and Surgery Services, Veterans Affairs Medical Center, Durham, North Carolina, United States of America.

Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167860PMC
February 2012

Antitumor and antioxidant activity of Polyalthia longifolia stem bark ethanol extract.

Pharm Biol 2010 Jun;48(6):690-6

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal, India.

In the present study, the ethanol extract of stem bark of Polyalthia longifolia Benth. and Hook (Annonaceae) was screened for its in vitro and in vivo antitumor activity. In vitro cytotoxicity of P. longifolia extract was assessed in murine cancer cells and in human cancer cells by Trypan blue exclusion assay and MTT assay, respectively. P. longifolia extract showed concentration-dependent cytotoxicity in Ehrlich's ascites carcinoma (EAC) and Dalton's ascites lymphoma (DLA) cells with IC50 values of 45.77 and 52.52 microg/mL, respectively. In the MTT assay, the IC50 values of P. longifolia extract against HeLa and MCF-7 cells were 25.24 and 50.49 microg/mL, respectively. In vivo antitumor activity against Ehrlich's ascites tumor and Dalton's solid tumor models was assessed by administering 50 and 100 mg/kg of P. longifolia extract, i.p., for 7 consecutive days. P. longifolia extract, at a dose of 100 mg/kg, significantly enhanced mean survival time (MST) and marginally improved hematological parameters when compared to EAC control mice. And the same dose significantly reduced the tumor volume as compared to control DLA inoculated mice. Positive control, cisplatin (3.5 mg/kg, i.p., single dose), significantly enhanced MST and improved hematological parameters when compared to EAC and significantly reduced the tumor volume when compared to DLA control. In vitro antioxidant potential of P. longifolia extract was also determined owing to the role of reactive oxygen species in tumor initiation and progression. P. longifolia extract scavenged DPPH radicals, reduced ferric ions and inhibited lipid peroxidation with IC50 values of 18.14, 155.41 and 73.33 microg/mL, respectively.
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http://dx.doi.org/10.3109/13880200903257974DOI Listing
June 2010

Identification and evaluation of antioxidant, analgesic/anti-inflammatory activity of the most active ninhydrin-phenol adducts synthesized.

Bioorg Med Chem 2006 Nov 2;14(21):7113-20. Epub 2006 Aug 2.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal 576 104, India.

Treatment of phenols with ninhydrin in acidic medium afforded 2-hydroxy-2-(ortho-hydroxy-phenyl/naphthyl)-1,3-dioxoindanes, which being unstable were isolated in their hemiketal forms. These synthesized compounds were subjected to TLC screening for radical scavenging and in vitro lipoxgenase and cycloxygenase enzyme inhibition assays. The best compound was identified and studied in detail for steady-state and time-resolved free radical kinetics, viz., DPPH, ABTS(-), *OH and rate constants for these reactions were evaluated. The best compound was also subjected to in vivo anti-inflammatory and analgesic activities in which the compound showed good promise for further structural optimization.
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http://dx.doi.org/10.1016/j.bmc.2006.06.068DOI Listing
November 2006