DNA Damage In Brain Research Articles

Various investigations of ameliorative role of Ashwagandha seeds (Withania somnifera) against amoxicillin toxicity.

Several studies showed the adverse effects of amoxicillin on various body organs. So, this research has been designed to evaluate the modulatory role of Ashwagandha seed extract (ASE) against amoxicillin (AM) toxicity. Rats treated with AM (90mg/kg), protected by ASE doses (100, 200 and 300mg/kg), and treated by ASE at the same three doses. At the end of the experimental period, DNA comet assay, cytogenetic examinations, sperm-shape analysis, evaluation of the malondialdehyde (MDA) percentages, histopathological examinations, and biophysical tests (modulus, relaxation time, permittivity, entropy, and internal energy change of brain) were documented. The results confirmed that AM treatment induced significant elevation of DNA damage, cytogenetic aberrations, and MDA content in brain, liver, and testis tissues and sperm-shape anomalies. ASE treatment significantly minimized the genetic changes, sperm-shape anomalies, and MDA generation. These enhancements were more pronounced by protective ASE and increased by increasing the dose level. In histopathological examinations, AM treatment caused neurotoxicity in brain tissue. ASE treatment, partially, minimized these damages and the positive effects of therapeutic ASE were more noticeable. Biophysical parameters showed that therapeutic ASE was better for relaxation time, permittivity, and free energy change. Protective and therapeutic ASE were able to recover entropy and internal energy changes in variant degrees.

Brain pathology and symptoms linked to concussion history: beyond chronic traumatic encephalopathy.

Repeated head trauma acquired through sports injuries has been associated with the development of long-term disabling symptoms that negatively impact the quality of life. In this retrospective case series, 52 male former professional athletes involved in contact sports and with a history of multiple concussions were evaluated for chronic clinical symptoms and post-mortem neuropathological diagnoses. The clinical symptoms of 19 cases were examined in greater detail for symptom type, severity and duration. Information on neurological, psychiatric and physical symptoms, substance use profiles and concussion histories was obtained from the athletes' next of kin and assessed in relation to post-mortem neuropathological diagnoses. Cases were categorized into three different neuropathological groups: no major neuropathological findings, the presence of only chronic traumatic encephalopathy (CTE) and the diagnosis(es) of other neurodegenerative diseases. Age at death and the presence of DNA damage in the post-mortem brains were analysed for correlation with the clinical symptoms. In this case series, 14/52 (26.9%) cases (mean age 48.2 ± 11.4) had neuropathological evidence of low-stage/low-burden CTE. A total of 11/52 (21.2%) cases (mean age 38.7 ± 12.7) presented a similar profile and severity of behavioural symptoms to those with CTE, despite the lack of significant post-mortem neuropathological findings. A total of 27/52 (51.9%) cases (mean age 75.5 ± 8.7) presented with complex post-mortem neurodegenerative diagnoses, including Alzheimer's disease and other mixed pathologies, and clinical symptoms associated with language, memory and sensory dysfunction. The presence of DNA damage in the brain was found in all neuropathological groups, predominantly in the ependymal lining of ventricles, and phosphorylated histone H2AX staining was correlated with higher age at death (r = 0.59) and symptoms of language dysfunction (r = 0.56). Findings from our case series suggest that post-concussive symptoms are not driven by CTE. Our findings show that proteinopathies alone may not account for the complexity of the clinical manifestations and suggest the possibility of other drivers, such as DNA damage, as potentially useful markers of brain trauma. Broadening the search for biological markers that reflect the effects of brain injury, even when proteinopathy is not observed, and taking a symptom-driven approach are therefore advised.

Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability

Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances invitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA's suppression of disease-associated repeat expansions, which may extend to other DNA processes.

Breast cancer 1 (BRCA1) protection in altered gene expression and neurodevelopmental disorders due to physiological and ethanol-enhanced reactive oxygen species formation

The breast cancer 1 (Brca1) susceptibility gene regulates the repair of reactive oxygen species (ROS)-mediated DNA damage, which is implicated in neurodevelopmental disorders. Alcohol (ethanol, EtOH) exposure during pregnancy causes fetal alcohol spectrum disorders (FASD), including abnormal brain function, associated with enhanced ROS-initiated DNA damage. Herein, oxidative DNA damage in fetal brains and neurodevelopmental disorders were enhanced in saline-exposed +/- vs. +/+ Brca1 littermates. A single EtOH exposure during gestation further enhanced oxidative DNA damage, altered the expression of developmental/DNA damage response genes in fetal brains, and resulted in neurodevelopmental disorders, all of which were BRCA1-dependent. Pretreatment with the ROS inhibitor phenylbutylnitrone (PBN) blocked DNA damage and some neurodevelopmental disorders in both saline- and EtOH-exposed progeny, corroborating a ROS-dependent mechanism. Fetal BRCA1 protects against altered gene expression and neurodevelopmental disorders caused by both physiological and EtOH-enhanced levels of ROS formation. BRCA1 deficiencies may enhance the risk for FASD.

Evaluation of the biological response of propofol in zebrafish (Danio rerio): Focusing on biochemical, transcriptional, and molecular level

Propofol, one of the most widely used intravenous anesthetic in clinical practice, has been reported to impair cognitive and memory function. However, the toxicological effects of propofol on aquatic organisms are still poorly understood. This study explored the toxic effects of chronic propofol exposure (0.008, 0.04, and 0.2 mg L−1) on adult zebrafish from biochemical, transcriptional, and molecular level after 7, 14, 21 and 28 days of exposure. Results indicated that the reactive oxygen species (ROS) levels were significantly upregulated during the 28 days exposure period, and excessive ROS caused lipid peroxidation, resulting in increased malondialdehyde (MDA) contents in the zebrafish brain. In order to relieve the oxidative damage induced by the excessive ROS, the activities of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT)) were significantly activated, and detoxification enzyme (glutathione S-transferase, GST) activities showed an “activation-inhibition” trend. However, the antioxidant enzymes and detoxification enzyme system could not eliminate the excessive ROS in time and thus caused DNA damage in zebrafish brain. The olive tail moment (OTM) values displayed a “dose-response” relationship with propofol concentrations. Meanwhile, the transcription of related genes of Nrf2-Keap1 pathway was activated. Further molecular simulation experiments suggested that propofol could directly combine with SOD/CAT to change the activity of its biological enzyme. These findings indicated that zebrafish could regulate antioxidant capacity to combat oxidative stress at the early exposure stage, but the activity of antioxidant enzymes were significantly inhibited with the increase of propofol exposure time. Our results are of great importance for understanding toxicological effects of propofol on aquatic organisms.

Reversal of cisplatin triggered neurotoxicity by Acacia hydaspica ethyl acetate fraction via regulating brain acetylcholinesterase activity, DNA damage, and pro-inflammatory cytokines in the rodent model

BackgroundCisplatin (CisPT) is a chemotherapeutic that outcome in adverse effects including neurotoxicity. We examined the efficacy of hydaspica ethyl acetate extract (AHE) against CisPT-prompted neurotoxicity.MethodsGroup I: Distilled water; Group II: CisPT (12 mg/kg b.w. i.p) on the 13th day of treatment. Group III: received AHE (400 mg/kg b.w) orally for 16 days. Group IV and V received 200 and 400 mg/kg b.w AHE orally for 16 days while CisPT injection on day 13, respectively. Group VI: received Silymarin (100 mg/kg b.w) orally for 16 days and CP (12 mg/kg b.w., i.p.) on day 13. TNF-α, IL6, brain acetylcholinesterase activity (AChE), oxidative trauma markers, genotoxicity, antioxidant enzymes, and morphological alterations in cerebral hemispheres were inspected.ResultsAHE administration before CisPT considerably reduced both tissue TNF-α and IL 6 expressions compared to CisPT treated group in a dose-dependent manner. AHE treatment (400 mg/kg b.w) significantly ameliorated brain AChE activity. Brain tissue MDA, H2O2, and NO content were markedly (p < 0.001) elevated after CisPT inoculation while a noticeable (p < 0.001) diminution was observed in AHE treatment groups. AHE treatment significantly (p < 0.001) improved brain antioxidant defense in a dose-dependent manner. Furthermore, AHE efficiently recused CisPT to induce DNA damage in brain tissue as revealed by ladder assay and DNA fragmentation patterns. Histopathological findings revealed severe neurodegenerations in CisPT treated group, however, AHE treatment noticeably precluded morphological alterations and neuron damages induced by CisPT.ConclusionA. hydaspica AHE extract may be provided as a prospective adjuvant that precludes CisPT-induced neurotoxicity due to its radical scavenging and antioxidant potential.

Brain injury, genotoxic damage and oxidative stress induced by Bromuconazole in male Wistar rats and in SH-SY5Y cell line

Background Bromuconazole is a widely used triazole against various fungi disease. It’s employment provokes harmful effects on the environment and human health. In the present study, we explored bromuconazole toxic effects in both rat brain tissue and SH-SY5Y cell line. Methods Male Wistar rats were administrated orally with Bromuconazole (NOEL/4, NOEL o and NOEL ×2) daily for consecutive 28 days. In addition, neuronal SH-SY5Y cell line was used. The rat brains and SH-SY5Y cells were collected and analysed for AChE activity, oxidative stress biomarkers, genotoxicity and histopathological alterations. Results Our results showed that rat exposure to bromuconazole at doses corresponding to NOEL/4, NOEL and NOEL ×2 caused brain histopathological alteration and decrease in acetylcholine esterase (AChE) activity. In SH-SY5Y cell line, bromuconazole strongly induced cell mortality with an IC50 about 250 µM. Bromuconazole induced also DNA damage as assessed by comet assay in both rat brain tissue and SH-SY5Y cell. Moreover, bromuconazole increased ROS production, malondialdehyde (MDA) and protein carbonyl (PC) levels and enhanced the enzymatic activities of catalase (CAT), superoxide dismutase (SOD), Glutathione-S-transferase (GST) and peroxidase (GPx) in the two studied systems. Conclusion Therefore, we can deduce that bromuconazole-caused neurotoxicity may be related to oxidative statue disturbance. HIGHLIGHTS Bromuconzole causes oxidative stress in the brain tissue of male Wistar rats. Bromuconazole enhances MDA, PC levels and induces DNA damage in rat brain. Bromuconazole provokes disturbance of the neuronal antioxidant system. Bromuconazole induces histopathological alterations in rat brain. Bromuconazole exposure induced cytotoxic effects and DNA damage in SH-SY5Y cells. Bromuconazole exposure induced oxidative stress in SH-SY5Ycells.

Protective Effect of Spirulina against Aspartame Induced Oxidative Stress and Molecular Gene Brain damage

Spirulina and lipoic acid has been considered as one of the most effective in ant oxidative stress and anti-inflammatory activity.Aspartame (ASP) is one of the mostwidely used (artificial sweeteners)used in a variety of foods and feeds.This study was conducted to evaluate the possible protective effect of Spirulina and alpha-lipoic acid against aspartame induced oxidative stress and brain damage in rabbits. Forty two white male New-Zealand Rabbits were classified into seven equal groups. Group I: (Control group) received no drugs. Group II: rabbits administered with aspartame (250 mg/kg b. wt/day). Group III: rabbits received alpha- lipoic acid (100 mg/kg b. wt/day). Group IV: rabbits received spirulina platensis (1500 mg/kg. b. wt/day). Group V: rabbits received aspartame (250 mg mg/kg b. wt) and treated with alpha- lipoic acid (100 mg/kg b. wt). Group VI: rabbits received aspartame (250 mg mg/kg b.wt) and treated with spirulina platensis (1500 mg/kg b. wt). Group VII: rabbits received aspartame (250 mg mg/kg b.wt) and treated daily with alpha- lipoic acid (100 mg/kg b. wt) and spirulina platensis (1500 mg/kg b. wt) for 8 weeks. At the end of experiment brain tissue were isolated and analyzed for determination of L-malondialdehyde (L-MDA), Catalase (CAT) and reduced glutathione (GSH) in addition to Anti-inflammatory cytokines: Interlukin-10 (IL-10),Activator Protein-1(AP-1),Bax gene expression and DNA damage. The obtained results showed a significant up-regulation of Activator Protein-1(AP-1),Bax gene expression level and a significant down-regulation of Interlukin-10 (IL-10) and marked increase in L-MDA and DNA damage that was indicated by an increase in tail length and tail DNA percent in brain tissue of aspartame treated rabbits. However, brain CAT activity andGSH concentration were markedly decreased when compared with control group.Coad ministration of spirulinaand alpha lipoic acid protect aspartame induced brain damage in rabbits caused a significant improvement of all previous parameters and attenuate DNA changes. Conclusively, spirulina platensis and alpha-lipoic acid exerts a protective effect against DNA damage and oxidative stress in brain of aspartameusage through free radical scavenging and anti-inflammatory activities as well as regenerating endogenous antioxidants defense system mechanisms.

Brain DNA damage analysis in pesticide exposed wistar albino rats (Rattus norvegicus): a chemometric approach

Brain the most important organ which controls most of the regulations in the body is composed of neurons and glia. As brain has a high metabolic rate and reduced cell renewal capability, the lipids, proteins and nucleic acids become the major targets of damage. In the present study carbofuran (CF) induced brain DNA damage in male wistar albino rats at sub-lethal doses (Control-A; B-1.0, C-0.5 and D-0.3 mg/kg BW) while the groups B1,C1, D1, B2, C2, D2 and B3, C3, D3 represents the exposure duration 30, 60 and 90 days each respectively. FTIR spectroscopy based chemometric analysis of functional groups in nucleic acids are reported, changes in band area and band frequencies were examined to understand the DNA damage by constructing heat map. Significant changes were observed in the band frequency, band areas, bandwidth and intensity values (p < 0.05, 0.01, 0.001). The principal component analysis was analyzed to study the alterations at the molecular level, which revealed maximum variance of 74% in groups A, B1, C1, D1 and C2 and 13.7% variance in B2, D2, B3, C3 and D3. The present study provides significant details to analyse DNA damage using non-conventional approach and can also be used for detecting DNA damage in several neural diseases and disorders and emphasizes on using FTIR spectral data through chemometric approach to analyse the DNA damage. Communicated by Ramaswamy H. Sarma.

Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain.

Cx3cr1CreER-driven Cre recombinase (Cre) is a widely used genetic tool for enabling gene manipulation in microglia and macrophages. However, an in-depth analysis of the possible detrimental effects of Cre activity in microglia, surprisingly, remains missing. Here, we demonstrate an age-dependent sensitivity of microglia to Cx3cr1-Cre toxicity, wherein Cre induction, specifically in early postnatal microglia, is detrimental to microglial development, proliferation, and function. Tamoxifen (TAM)-induced Cre activity leads to microglial activation, type 1 interferon (IFN-1) signaling, and increased phagocytosis, causing aberrant synaptic pruning during the early postnatal period and anxious behavior at later age. The detrimental effects of Cre induction are caused by DNA-damage-induced toxicity in microglia and are limited to the early postnatal period, showing no detrimental effects in adult microglia. Thus, our study reveals an age-dependent vulnerability of microglia to Cre activity, thereby highlighting age dependency of Cre action, which could be especially applicable in the broader context of environment-responsive cell types.

Circulating exosome level of indigenous fish may be a novel biomarker for the integrated ecotoxicity effect of water environment

The deficiency of effective biomarker for the toxic effects of water pollutants greatly limits the application of biological monitoring. This study aimed to investigate the possibility of circulating exosomes of indigenous fish acting as biomarker for the ecotoxicity effect of water environment. The Helong Reservoir in Guangzhou, China, was chosen as the investigating field, of which the water quality belongs to Class V (2013) (GB 3838-2002, China). The clean drinking water source of the upper reaches of the Liuxihe Reservoir was selected as the control. Indigenous fishes including Oreochromis niloticus (Nile tilapia), Labeo rohita (Rohu), Carassius auratus (Crucian carp) were sampled during the period from July 2020 to April 2021. Circulating exosomes of fish samples were isolated by using ultracentrifugation, characterized with transmission electron microscopy (TEM) and quantified by using bicinchoninic acid (BCA) assay. Oxidative stress, DNA and chromosome damage in liver, kidney, brain, gill and blood of fish samples were measured. The results showed that there were significant differences in superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) contents, DNA and chromosome damage in fish samples between the Helong Reservoir and the control. Interestingly, there were also significant differences in circulating exosome levels of fish samples between them. Our data suggested that circulating exosome level of indigenous fish may be a novel biomarker for the ecotoxicity effects of water environment.

DNA damage in brain may lead to cognitive dysfunctions and reduced longevity in WNIN/Ob obese rats

AbstractBackgroundOne of the most common neurodegenerative diseases is Alzheimer’s disease where complex etiological alterations have been observed along with the typical pathology. Specifically, it has been proposed that epigenetic activation of specific genes due to other physiological conditions may also contribute to its pathology.MethodAgeing being one of the strongest risk factor where accumulation of DNA damage is rampant, we evaluated the extent in the brain of 15 months old WNIN/Ob obese rats. Early accumulation of DNA damage in brain can result in devastating genetic instability and wide array of physiological problems. WNIN obese rats have significantly reduced longevity (average lifespan of 15‐18 months). The extent of DNA damage in brain was studied as a hallmark of senescence in order to establish this rat as a model of aging related studies. DNA damage was assessed at the single cell level in neocortex and hippocampus of WNIN obese rats, WNIN lean littermates and normal WNIN controls at 3 and 15 months of age by Comet Assay. The samples were processed for neutral and alkaline electrophoresis, followed by fluorescent staining and analysis.ResultThe extent of DNA damage in the form of single‐strand breaks (SSBs) as well as double‐strand breaks (DSBs) in cells of neocortex and hippocampus of young WNIN obese rats was comparable with those seen in the 15 months old normal WNIN rats. Interestingly the extent of SSBs and DSBs in young WNIN lean littermates and WNIN controls were comparable.ConclusionOnset of significant DNA damage in different brain regions of obese rats at a much younger age is a plausible cause of reduced longevity observed in this novel obese rat model.

Rab7 reduces α-synuclein toxicity in rats and primary neurons

During the pathogenesis of Parkinson's disease (PD), aggregation of alpha-synuclein (αSyn) induces a vicious cycle of cellular impairments that lead to neurodegeneration. Consequently, removing toxic αSyn aggregates constitutes a plausible strategy against PD. In this work, we tested whether stimulating the autolysosomal degradation of αSyn aggregates through the Ras-related in brain 7 (Rab7) pathway can reverse αSyn-induced cellular impairment and prevent neurodegeneration in vivo. The disease-related A53T mutant of αSyn was expressed in primary neurons and in dopaminergic neurons of the rat brain simultaneously with wild type (WT) Rab7 or the T22N mutant as negative control. The cellular integrity was quantified by morphological and biochemical analyses. In primary neurons, WT Rab7 rescued the αSyn-induced loss of neurons and neurites. Furthermore, Rab7 decreased the amount of reactive oxygen species and the amount of Triton X-100 insoluble αSyn. In rat brain, WT Rab7 reduced αSyn-induced loss of dopaminergic axon terminals in the striatum and the loss of dopaminergic dendrites in the substantia nigra pars reticulata. Further, WT Rab7 lowered αSyn pathology as quantified by phosphorylated αSyn staining. Finally, WT Rab7 attenuated αSyn-induced DNA damage in primary neurons and rat brain. In brief, Rab7 reduced αSyn-induced pathology, ameliorated αSyn-induced neuronal degeneration, oxidative stress and DNA damage. These findings indicate that Rab7 is able to disrupt the vicious cycle of cellular impairment, αSyn pathology and neurodegeneration present in PD. Stimulation of Rab7 and the autolysosomal degradation pathway could therefore constitute a beneficial strategy for PD.

Lead (Pb) induced Oxidative Stress as a Mechanism to Cause Neurotoxicity in Drosophila melanogaster

The widespread use of lead (Pb) has caused global contamination, inevitable human exposure, and public health problems. Pb neurotoxicity has been linked to various human diseases, but its associated mechanism causing neurotoxicity is unknown. Drosophila melanogaster as a model organism has been used to study the mechanism involved in Pb-caused neurotoxicity and the potential role of antioxidants in ameliorating its harmful effects. The larval feeding technique was adopted to administer different concentrations of Pb (0.2-0.8 mM) to Oregon-R (ORR), superoxide dismutase (Sod), or catalase (Cat) overexpressing, and Sod or Cat knockdown flies to analyse Pb load, oxidative stress components, DNA damage, apoptosis and vacuolation in the brain. The results revealed that Pb accumulation in the Drosophila brain induces oxidative stress by generating reactive oxygen species (ROS) and lipid peroxidation (LPO), depleting antioxidant enzymes. Molecular docking studies have evidenced it. Pb directly binds to antioxidants and major grooves of DNA, leading to DNA damage. Increased DNA damage, apoptosis, vacuolation in brains of Pb-treated ORR, Sod, or Cat knockdown flies; and on the contrary, reduced oxidative DNA damage, apoptosis, and vacuolation in brains of Pb treated Sod or Cat overexpressed flies put forward that oxidative stress is the mechanism in Pb caused neurotoxicity.

NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS–STING

Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. Impaired neuronal bioenergetics and neuroinflammation are thought to play key roles in the progression of AD, but their interplay is not clear. Nicotinamide adenine dinucleotide (NAD+) is an important metabolite in all human cells in which it is pivotal for multiple processes including DNA repair and mitophagy, both of which are impaired in AD neurons. Here, we report that levels of NAD+ are reduced and markers of inflammation increased in the brains of APP/PS1 mutant transgenic mice with beta-amyloid pathology. Treatment of APP/PS1 mutant mice with the NAD+ precursor nicotinamide riboside (NR) for 5 mo increased brain NAD+ levels, reduced expression of proinflammatory cytokines, and decreased activation of microglia and astrocytes. NR treatment also reduced NLRP3 inflammasome expression, DNA damage, apoptosis, and cellular senescence in the AD mouse brains. Activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are associated with DNA damage and senescence. cGAS-STING elevation was observed in the AD mice and normalized by NR treatment. Cell culture experiments using microglia suggested that the beneficial effects of NR are, in part, through a cGAS-STING-dependent pathway. Levels of ectopic (cytoplasmic) DNA were increased in APP/PS1 mutant mice and human AD fibroblasts and down-regulated by NR. NR treatment induced mitophagy and improved cognitive and synaptic functions in APP/PS1 mutant mice. Our findings suggest a role for NAD+ depletion-mediated activation of cGAS-STING in neuroinflammation and cellular senescence in AD.

Brain DNA damage hotspots.

Unexpected high levels of recurrent DNA single-strand break repair were detected in enhancer regions of post-mitotic neurons.

N-acetylcysteine-amide improves tissue oxidative stress, DNA damage, and proteins disappearance in methamphetamine toxicity more efficiently than N-acetyl-L-cysteine

The aim of the present study is to discover a new protective agent to protect against oxidative stress, DNA damage, and proteins disappearance in brain, liver, and kidney in methamphetamine (METH) abusers. Forty male albino rats were divided into 4 equal groups: (1) Control, (2) METH, (3) N-acetyl-L-cysteine (NAC, 500 mg/kg body weight (bwt)) + METH, (4) N-acetylcysteine-amide (NACA, 250 mg/kg (bwt)) + METH. Group 1 was injected (i.p) with saline (1 ml/kg bwt) while groups 2,3 & 4 were injected (i.p) with 4 injections with METH (10 mg/kg bwt) every 2 hours over an 8-hour period. NAC and NACA were injected 30 minutes before METH injections. Reduced glutathione (GSH), glutathione peroxidase (GPx), lipid peroxidation (MDA), catalase (CAT), and protein carbonyl levels were measured in the brain, liver, and kidney tissues. The DNA and protein contents of brain, liver, and kidney tissues were also detected. The results indicated that METH induced oxidative cell stress by increasing MDA while decreasing cell GSH and the antioxidant enzymes such as CAT and GPx levels. METH induced DNA damage and proteins disappearance in brain, liver and kidney tissues. NAC or NACA injection before METH injection prevented oxidative stress, DNA damage, and proteins disappearance in brain, liver and kidney of METH-injected rats and NACA was more effective than NAC in treated animals. NACA was more effective than NAC in treated animals through preventing tissue oxidative stress, DNA damage, and proteins disappearance in METH toxicity than NAC.

Thymoquinone Improved Lead-Induced DNA Damage and Oxidative Stress in Rat Brain

Lead (Pb) is a pervasive industrial and environmental pollutant that seriously impairs the central nervous system, primarily by disrupting the redox balance. The current research was conducted to explore the possible beneficial action of thymoquinone (TQ), the main active component in Nigella sativa seed volatile oil, against brain oxidative stress and DNA damage caused by Pb. Wistar adult male rats were treated with TQ (5 mg/kg/day, per os) and/or Pb (2000 ppm of Pb acetate in drinking water) for five weeks. Results showed that Pb exposure significantly increased metal content, malondialdehyde concentration and DNA damage (assessed by comet assay), but significantly decreased the level of reduced glutathione and the activities of catalase, glutathione peroxidase, and superoxide dismutase in the brain tissue. These detrimental effects Pb-induced, except tissue metal accumulation, were significantly improved by TQ supplementation. In conclusion, our findings suggested that TQ might be a promising therapeutic alternative in Pb neurotoxicity.

MATERNAL AND FETAL TOXICITY-INDUCED BY NICKEL OXIDE NANOPARTICLES ADMINISTRATION IN ALBINO RATS DURING GESTATION

Objective: Despite the widespread of nickel oxide nanoparticles (NiO NPs) and their benefits in all fields, they have many negative effects on human life, especially expectant mothers and their fetus. The purpose of this study was to investigate the possible maternal and developmental toxicity-induced by NiO NPs administration during gestation.&#x0D; Methods: Three groups of pregnant rats were administered orally during days 5–19 of gestation, the pregnant rats were haphazardly designed into three groups (six rat/group), as follows: Control group and NiO NPs administered groups, low (4 mg/kg), and high (8 mg/kg) doses.&#x0D; Results: NiO NPs administration resulted in severe maternal and developmental toxicity which included reduction in uterine weight, mother weight gain, the average weight of placenta, the number corpora lutea, implantation sites, and the number of live fetuses. Furthermore, high pre/ postimplantation, fetal growth retardation, and morphological and skeletal anomalies, an elevation in liver and brain DNA damage in both mother and fetus, and histopathological alterations in different tissues (placenta, liver, kidney, and brain) of pregnant rats and fetuses. Lipid peroxidation showed a significant elevation in maternal, fetal liver, and brain tissues of NiO NPs ‐administered rats. Furthermore, glutathione content and catalase activity were decreased in both tissues of NiO NPs‐administered rats.&#x0D; Conclusion: Finally, the detrimental impacts of NiO NPs in dams and fetuses probably through its potential generation of reactive oxygen species.

DNA glycosylase Neil2 contributes to genomic responses in the spleen during clinical prion disease

The DNA glycosylase Neil2 is a member of the base excision repair (BER) family of enzymes, which are important for repair of oxidative DNA damage. Specifically, Neil2 participates in repair of oxidized bases in single-stranded DNA of transcriptionally active genes. Mice with genetic ablation of Neil2 (Neil2−/−) display no overt phenotypes, but an age-dependent accumulation of oxidative DNA damage and increased inflammatory responsiveness. In young mice intra-cerebrally inoculated with prions, vigorous prion propagation starts rapidly in the germinal follicles of the spleen due to inoculum spillover. Here, we compare experimental prion disease in Neil2−/− mice with that in wild-type mice at disease onset and end-stage. Specifically, we investigated disease progression, accumulation of DNA damage, and mitochondrial respiratory complex activity in brain and spleen. We used genome-wide RNA sequencing of the spleen to compare the immune responses to prion propagation between the two groups of mice, at both onset and end-stage prion disease. The Neil2−/− mice deteriorated more rapidly than wild-type mice after onset of clinical signs. Levels of DNA damage in brain increased in both mouse groups, slightly more in the Neil2−/− mice. Transcriptome data from spleen at disease onset were similar between the mouse groups with moderate genomic responses. However, at end-stage a substantial response was evident in the wild-type mice but not in Neil2−/− mice. Our data show that Neil2 counteracts toxic signaling in clinical prion disease, and this is separate from gross pathological manifestations and PrPSc accumulation.