Neuroprotective Action of Selected Natural Drugs Against Neurological Diseases and Mental Disorders: Potential Use Against Radiation Damage.

Exposure to radiation, ionizing and non-ionizing radiation, is a significant concern in modern society. The brain is the organ that is most sensitive to radiation exposure. This review describes how exposure to radiation can affect neurotransmitters in different brain regions, affecting brain function. This review covers neurodegenerative diseases such as Alzheimer's, Parkinson's, and neuroinflammation due to changes in neurons in the central nervous system, and the effects thereon of medicinal plants such as Allium cepa, Allium sativum, Centella asiatica, Coriandrum sativum, and Crocus sativus plants, used for centuries in traditional medicine. These herbal medicines exert free radical scavenging, and antioxidant as well as anti-inflammatory properties which can be beneficial in managing neurological diseases. The present review compiles the neuroprotective effects of selected natural plants against neurological damage, as well as highlights the different mechanisms of action elicited to induce and produce beneficial effects. The current review describes recent studies on the pharmacological effects of neuroprotective herbs on various neurological and mental illnesses, and shows the way further studies can impact this field, including potential effects on radiation-induced damage.

Antimicrobial Potential of Polyphenols: An Update on Alternative for Combating Antimicrobial Resistance.

The last decade has encountered an increasing demand for plant-based natural antibiotics. This demand has led to more research-based investigations for natural sources of antimicrobial agents and published reports demonstrating that plant extracts are widely applied in modern medicine, reporting potential activity that may be due to polyphenol compounds. Interestingly, the effects of polyphenols on the sensitivity of bacteria to antibiotics have not been well-studied. Hence, the current review encompasses the prospective application of plant-based phenolic extracts from plants of Indian origin. The emergence of resistance to antimicrobial agents has increased the inefficacy of many antimicrobial drugs. Several strategies have been developed in recent times to overcome this issue. A combination of antimicrobial agents is employed for the failing antibiotics, which restores the desirable effect but may have toxicity-related issues. Phytochemicals such as some polyphenols have demonstrated their potent activity as antimicrobial agents of natural origin to work against resistance issues. These agents alone or in combination with certain antibiotics have been shown to enhance the antimicrobial activity against a spectrum of microbes. However, the information regarding the mechanisms and structure-activity relationships remains elusive. The present review also focuses on the possible mechanisms of natural compounds based on their structure- activity relationships for incorporating polyphenolic compounds in the drug-development processes. Besides this work, polyphenols could reduce drug dosage and may diminish the unhidden or hidden side effects of antibiotics. Pre-clinical findings have provided strong evidence that polyphenolic compounds, individually and in combination with already approved antibiotics, work well against the development of resistance. However, more studies must focus on in vivo results, and clinical research needs to specify the importance of polyphenol-based antibacterials in clinical trials.

Exploring role of natural compounds in molecular alterations associated with brain ageing: A perspective towards nutrition for ageing brain.

Aging refers to complete deterioration of physiological integrity and function. By midcentury, adults over 60 years of age and children under 15 years will begin to outnumber people in working age. This shift will bring multiple global challenges for economy, health, and society. Eventually, aging is a natural process playing a vital function in growth and development during pediatric stage, maturation during adult stage, and functional depletion. Tissues experience negative consequences with enhanced genomic instability, deregulated nutrient sensing, mitochondrial dysfunction, and decline in performance on cognitive tasks. As brain ages, its volume decreases, neurons & glia get inflamed, vasculature becomes less developed, blood pressure increases with a risk of stroke, ischemia, and cognitive deficits. Diminished cellular functions leads to progressive reduction in functional and emotional capacity with higher possibility of disease and finally death. This review overviews cellular as well as molecular aspects of aging, biological pathway related to accelerated brain aging, and strategies minimizing cognitive aging. Age-related changes include altered bioenergetics, decreased neuroplasticity and flexibility, aberrant neural activity, deregulated Ca2+ homeostasis in neurons, buildup of reactive oxygen species, and neuro-inflammation. Unprecedented progress has been achieved in recent studies, particularly in terms of how herbal or natural substances affect genetic pathways and biological functions that have been preserved through evolution. Herein, the present work provides an overview of ageing and age-related disorders and explore the molecular mechanisms that underlie therapeutic effects of herbal and natural chemicals on neuropathological signs of brain aging.

Older PLHIV are at Higher Cardiovascular Risk with Poor Quality of Life.

BACKGROUND: People with HIV (PLHIV) face increased cardiovascular disease (CVD) risk due to inflammation and immune activation. Aging further amplifies this risk. Limited data exist on CVD risk in older PLHIV in India despite 2.14 million PLHIV with higher CVD risk factors. METHODS: In a cross-sectional study in Bihar, India, 73 PLHIV and 30 control participants were enrolled. Demographics, social factors, clinical information, and CVD risk factors were collected. HbA1c levels and lipid profiles were analyzed, and 10-year CVD risk scores were calculated using the Framingham risk score (FRS) and Qrisk3. Quality of life (QoL) was assessed using WHOQOL- HIV-BREF. RESULTS: Results showed higher LDL levels in non-HIV older participants and higher HDL levels in younger PLHIV participants. BMI differed significantly, with higher BMI in non-HIV older individuals and lower BMI in younger PLHIV individuals. Older PLHIV participants had significantly higher mean FRS and Q-Risk scores compared to older non-PLHIV and younger PLHIV groups. Among older PLHIV participants, six had higher CVD risk per FRS, while none in the other groups were classified as high CVD risk. Psychological, social relations and spirituality domains were highly deteriorated in older PLHIV, scoring 44.48, 42.72, and 41.2, respectively. The physical domain scored 57.6, and the environment scored 52.72 in the WHOQOL-HIV bref. CONCLUSION: In conclusion, older PLHIV in Bihar, India, face higher CVD risk compared to younger PLHIV and non-HIV individuals. FRS and Q-Risk scores effectively assessed CVD risk, identifying higher risk in older PLHIV. Age and BMI were significant predictors of high CVD risk. These findings emphasize CVD risk assessment and tailored management for older PLHIV. The QoL assessment findings indicate moderate deterioration in psychological, social relations, and spirituality domains among older PLHIV individuals. These results suggest greater challenges in psychological well-being, social interactions, and spirituality compared to the overall sample. Further research with larger samples and longitudinal designs is needed to confirm and extend these findings.

Targeted delivery of panitumumab-scaffold bosutinib-encapsulated polycaprolactone nanoparticles for EGFR-overexpressed colorectal cancer.

Aims: Panitumumab (anti-Erb)-conjugated polycaprolactone (PCL) nanoparticles loaded with bosutinib (BTNB) were used to develop a targeted drug-delivery system for colon cancer cells. Materials & methods: Using carbodiimide coupling, anti-Erb was conjugated to BTNB-loaded PCL nanoparticles. Dynamic light scattering, scanning electron microscopy, transmission electron microscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, x-ray diffraction and thermogravimetric analysis were used to analyze nanoparticles. Results: According to in vitro studies, anti-Erb-BTNB-PCL nanoparticles inhibited HCT116 cells more than BTNB alone. Cell arrest at different phases was examined for apoptotic potential. An in vivo efficacy study showed that anti-Erb-BTNB-PCL nanoparticles could target tumors selectively. Conclusion: Anti-Erb-conjugated BTNB nanoparticles could specifically target colon cancer.

Monoamine Oxidase: A Potential Link in Papez circuit to Generalized Anxiety Disorders.

Anxiety is a common mental illness that affects a large number of people around the world, and its treatment is often based on the use of pharmacological substances such as benzodiazepines, serotonin, and 5-hydroxytyrosine (MAO) neurotransmitters. MAO neurotransmitters levels are deciding factors in the biological effects. This review summarizes the current understanding of the MAO system and its role in the modulation of anxiety-related brain circuits and behavior. The MAO-A polymorphisms have been implicated in the susceptibility to generalized anxiety disorder (GAD) in several investigations. The 5-HT system is involved in a wide range of physiological and behavioral processes, involving anxiety, aggressiveness, stress reactions, and other elements of emotional intensity. Among these, 5-HT, NA, and DA are the traditional 5-HT neurons that govern a range of biological activities, including sleep, alertness, eating, thermoregulation, pains, emotion, and memory, as anticipated considering their broad projection distribution in distinct brain locations. The DNMTs (DNA methyltransferase) protein family, which increasingly leads a prominent role in epigenetics, is connected with lower transcriptional activity and activates DNA methylation. In this paper, we provide an overview of the current state of the art in the elucidation of the brain's complex functions in the regulation of anxiety.

Unveiling the therapeutic potential of cabozantinib-loaded poly D,L-lactic-co-glycolic acid and polysarcosine nanoparticles in inducing apoptosis and cytotoxicity in human HepG2 hepatocellular carcinoma cell lines and in vivo anti-tumor activity in SCID female mice.

Introduction: The study aimed to develop a nano-based drug delivery system for the treatment of hepatocellular carcinoma (HCC), a type of liver cancer that accounts for 90% of all liver malignancies. The study focused on the use of cabozantinib (CNB), a potent multikinase inhibitor that targets the VEGF receptor 2, as the chemotherapeutic drug. We developed CNB-loaded nanoparticles made from Poly D, L-lactic-co-glycolic acid, and Polysarcosine (CNB-PLGA-PSar-NPs) for use in human HepG2 cell lines. Methods: By O/W solvent evaporation method, the polymeric nanoparticles were prepared. The various techniques, such as photon correlation spectroscopy, scanning electron microscopy, and transmission electron microscopy were used, to determine the formulation's particle size, zeta potential, and morphology. SYBR Green/ROX qPCR Master Mix and RT-PCR equipment used to measure liver cancer cell line and tissue mRNA expression and MTT assay to test HepG2 cell cytotoxicity. Cell cycle arrest analysis, annexin V assay, and ZE5 Cell Analyzer apoptosis assay were also performed. Results: The results of the study showed that the particle diameters were 192.0 ± 3.67 nm with 0.128 PDI and -24.18 ± 3.34 mV zeta potential. The antiproliferative and proapoptotic effects of CNB-PLGA-PSar-NPs were evaluated using MTT and flow cytometry (FCM). The IC50 value of CNB-PLGA-PSar-NPs was 45.67 µg/mL, 34.73 µg/mL, and 21.56 µg/mL for 24, 48, and 72 h, respectively. The study also found that 11.20% and 36.77% of CNB-PLGA-PSar-NPs-treated cells were apoptotic at 60 µg/mL and 80 µg/mL, respectively, suggesting that the nanoparticles were effective in inducing apoptosis in the cancer cells. It can also conclude that, CNB-PLGA-PSar-NPs inhibit human HepG2 hepatocellular carcinoma cells and kill them by upregulating the tumour suppressor genes MT1F, MT1X, and downregulating MTTP, APOA4. Further in vivo antitumor activity was well reported in SCID female mice. Discussion: Overall, this study suggests that the CNB-PLGA-PSar-NPs are a promising drug delivery system for the treatment of HCC, and further research is needed to investigate their potential in clinical treatment.

CD4 + Count: a Variable to Be Considered to Prioritize COVID-19 Vaccination in PLHIV.

The outbreak of the COVID-19 propagates, pressurizing the healthcare system by emphasizing and worsening the inequities. While many vaccines have shown excellent efficacy in protecting the general public from the COVID-19 infection, the efficacy of these vaccines for people living with HIV (PLHIV), especially those having a different range of CD4 + T-cell, has yet to be thoroughly investigated. Few studies have uncovered the escalated infection and death rates due to the COVID-19 infection in individuals with low CD4 + T-cells. Additionally, PLHIV has a low CD4 + count; furthermore, specific CD4 + T cells for coronavirus have a vigorous Th1 role and are related to the protective antibody responses. Follicular helper T cells (TFH) are vulnerable to HIV and virus-specific CD4 & CD8 T-cells which are essential for viral infection clearance and defective immune responses which further contributes to the development of illness. The specific CD8 & CD4 + T-cell reaction to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) was identified in almost all COVID-19 recovered individuals, which is related to the size of antibodies of immunoglobulin G. It has previously been demonstrated that PLHIV has decreased responses to certain vaccines and that these responses are reliant on CD4 + T-cell levels. COVID-19 vaccines will likely have a lower response or limited effect, in PLHIV having low CD4 + T-cells.

Mitochondria-lysosome crosstalk in GBA1-associated Parkinson's disease.

Organelle crosstalk is significant in regulating their respective functions and subsequent cell fate. Mitochondria and lysosomes are amongst the essential organelles in maintaining cellular homeostasis. Mitochondria-lysosome connections, which may develop dynamically in the human neurons, have been identified as sites of bidirectional communication. Aberrancies are often associated with neurodegenerative disorders like Parkinson's disease (PD), suggesting the physical and functional link between these two organelles. PD is often linked with genetic mutations of several mutations discovered in the familial forms of the disease; some are considered risk factors. Many of these genes are either associated with mitochondrial function or belong to endo-lysosomal pathways. The recent investigations have indicated that neurons with mutant glucosylceramidase beta (GBA1) exhibit extended mitochondria-lysosome connections in individuals with PD. This may be due to impaired control of the untethering protein, which aids in the hydrolysis of Rab7 GTP required for contact untethering. A GCase modulator may be used to augment the reduced GBA1 lysosomal enzyme activity in the neurons of PD patients. This review focuses on how GBA1 mutation in PD is interlinked with mitochondria-lysosome (ML) crosstalk, exploring the pathways governing these interactions and mechanistically comprehending the mitochondrial and lysosomal miscommunication in the pathophysiology of PD. This review is based on the limited literature available on the topic and hence may be subject to bias in its views. Our estimates may be conservative and limited due to the lack of studies under the said discipline due to its inherent complex nature. The current association of GBA1 to PD pathogenesis is based on the limited scope of study and further research is necessary to explore the risk factors further and identify the relationship with more detail.

Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases.

Nuclear factor κB (NFκB) is a unique protein complex that plays a major role in lung inflammation and respiratory dysfunction. The NFκB signaling pathway, therefore becomes an avenue for the development of potential pharmacological interventions, especially in situations where chronic inflammation is often constitutively active and plays a key role in the pathogenesis and progression of the disease. NFκB decoy oligodeoxynucleotides (ODNs) are double-stranded and carry NFκB binding sequences. They prevent the formation of NFκB-mediated inflammatory cytokines and thus have been employed in the treatment of a variety of chronic inflammatory diseases. However, the systemic administration of naked decoy ODNs restricts their therapeutic effectiveness because of their poor pharmacokinetic profile, instability, degradation by cellular enzymes and their low cellular uptake. Both structural modification and nanotechnology have shown promising results in enhancing the pharmacokinetic profiles of potent therapeutic substances and have also shown great potential in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. In this review, we examine the contribution of NFκB activation in respiratory diseases and recent advancements in the therapeutic use of decoy ODNs. In addition, we also highlight the limitations and challenges in use of decoy ODNs as therapeutic molecules, cellular uptake of decoy ODNs, and the current need for novel delivery systems to provide efficient delivery of decoy ODNs. Furthermore, this review provides a common platform for discussion on the existence of decoy ODNs, as well as outlining perspectives on the latest generation of delivery systems that encapsulate decoy ODNs and target NFκB in respiratory diseases.

The Cannabinoid Receptor 1 Reverse Agonist AM251 Ameliorates Radiation-Induced Cognitive Decrements.

Despite advancements in the radiotherapeutic management of brain malignancies, resultant sequelae include persistent cognitive dysfunction in the majority of survivors. Defining the precise causes of normal tissue toxicity has proven challenging, but the use of preclinical rodent models has suggested that reductions in neurogenesis and microvascular integrity, impaired synaptic plasticity, increased inflammation, and alterations in neuronal structure are contributory if not causal. As such, strategies to reverse these persistent radiotherapy-induced neurological disorders represent an unmet medical need. AM251, a cannabinoid receptor 1 reverse agonist known to facilitate adult neurogenesis and synaptic plasticity, may help to ameliorate radiation-induced CNS impairments. To test this hypothesis, three treatment paradigms were used to evaluate the efficacy of AM251 to ameliorate radiation-induced learning and memory deficits along with disruptions in mood at 4 and 12 weeks postirradiation. Results demonstrated that acute (four weekly injections) and chronic (16 weekly injections) AM251 treatments (1 mg/kg) effectively alleviated cognitive and mood dysfunction in cranially irradiated mice. The beneficial effects of AM251 were exemplified by improved hippocampal- and cortical-dependent memory function on the novel object recognition and object in place tasks, while similar benefits on mood were shown by reductions in depressive- and anxiety-like behaviors on the forced swim test and elevated plus maze. The foregoing neurocognitive benefits were associated with significant increases in newly born (doublecortin+) neurons (1.7-fold), hippocampal neurogenesis (BrdU+/NeuN+mature neurons, 2.5-fold), and reduced expression of the inflammatory mediator HMGB (1.2-fold) in the hippocampus of irradiated mice. Collectively, these findings indicate that AM251 ameliorates the effects of clinically relevant cranial irradiation where overall neurological benefits in memory and mood coincided with increased hippocampal cell proliferation, neurogenesis, and reduced expression of proinflammatory markers.

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

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.

Sex-Specific Cognitive Deficits Following Space Radiation Exposure.

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 (4He) show significantly higher levels of neuroinflammation and more extensive cognitive deficits than females. Twelve weeks following 4He 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 4He 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.

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

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.

Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy.

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.

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

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.

Alterations in synaptic density and myelination in response to exposure to high-energy charged particles.

High-energy charged particles are considered particularly hazardous components of the space radiation environment. Such particles include fully ionized energetic nuclei of helium, silicon, and oxygen, among others. Exposure to charged particles causes reactive oxygen species production, which has been shown to result in neuronal dysfunction and myelin degeneration. Here we demonstrate that mice exposed to high-energy charged particles exhibited alterations in dendritic spine density in the hippocampus, with a significant decrease of thin spines in mice exposed to helium, oxygen, and silicon, compared to sham-irradiated controls. Electron microscopy confirmed these findings and revealed a significant decrease in overall synapse density and in nonperforated synapse density, with helium and silicon exhibiting more detrimental effects than oxygen. Degeneration of myelin was also evident in exposed mice with significant changes in the percentage of myelinated axons and g-ratios. Our data demonstrate that exposure to all types of high-energy charged particles have a detrimental effect, with helium and silicon having more synaptotoxic effects than oxygen. These results have important implications for the integrity of the central nervous system and the cognitive health of astronauts after prolonged periods of space exploration.

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

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.

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

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.

Epigenetic determinants of space radiation-induced cognitive dysfunction.

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.