Platelet-rich plasma ameliorates neurotoxicity induced by silver nanoparticles in male rats via modulation of apoptosis, inflammation, and oxidative stress.

The widespread use of silver in various forms raises concerns about its potential adverse effects. Silver nanoparticles (AgNPs) can enter the brain and subsequently induce neurotoxicity. As a source of diverse growth factors and for its cytoprotective properties, platelet-rich plasma (PRP) has received considerable attention in regenerative medicine. Our aim was to estimate the toxic effects of AgNPs on the rat brain and assess the possible protective effects of PRP against AgNPs induced neurotoxicity. A total of 40 adult male rats were divided into four groups (n = 10), namely the control, AgNPs, AgNPs+PRP, and auto-recovery groups. AgNPs were given intraperitoneally (i.p.) at a 10 mg/kg dose.bw daily for 28 days. PRP was given (a day after AgNPs treatment) i.p. at a dose of 0.5 mL/kg.bw twice weekly for 3 weeks. Rats in the auto-recovery group were left without treatment for 3 weeks after AgNP toxicity. Serum and brain tissue samples were collected for assessment of proinflammatory cytokines, oxidative stress markers, as well as the expression levels of apoptotic markers. Brain histopathological and immunohistochemistry examinations were done. AgNPs significantly increased oxidative stress markers and proinflammatory cytokines, decreased antioxidant defense markers, and induced apoptosis and histopathological brain injuries. However, PRP treatment restored brain oxidant/antioxidant balance, attenuated the inflammatory state, prevented apoptosis, and improved the brain histopathological lesions induced by AgNPs, with no significant improvements shown by auto-recovery group. Our data provided a novel protective effect for PRP against AgNPs-induced neurotoxicity due to its antioxidant, anti-inflammatory, and antiapoptotic effects.

Neuroprotective effect of lansoprazole against cisplatin-induced brain toxicity: Role of Nrf2/ARE and Akt/P53 signaling pathways.

Cisplatin is a chemotherapeutic agent usually used in treating different patterns of malignancies. One of the significant apparent complications of cisplatin chemotherapy is brain toxicity. The present study was conducted to evaluate the protective effects of lansoprazole on cisplatin-induced cortical intoxication. Thirty-two rats were allocated into four groups (8 rats/group); group I: received only a vehicle for 10 days, group II: lansoprazole was administered (50 mg/kg) via oral gavage for 10 days, group III: On 5th day of the experiment, rats were given cisplatin (10 mg/kg) i.p. once to induce cortical injury. Group IV: rats were given lansoprazole for 5 days before cisplatin and 5 days afterward. Lansoprazole administration significantly improved cisplatin-induced behavioral changes, as evidenced by decreasing the immobility time in forced swimming and open field tests. Besides, lansoprazole improved cortical histological changes, restored cortical redox balance, enhanced Nrf2/ARE expression, cisplatin-induced neuronal apoptosis, and dampened cisplatin inflammation. In addition, lansoprazole modulated cortical Akt/p53 signal. The present work was the first to show that lansoprazole co-administration reduced cortical toxicity in cisplatin-treated rats via multiple signaling pathways. The current findings provided crucial information for developing novel protective strategies to reduce cisplatin cortical toxicity.

Benzophenone-3 causes oxidative stress in the brain and impairs aversive memory in adult zebrafish.

Oxybenzone (BP-3) is an ultraviolet (UV) filter widely used in industries that is directly or indirectly released into the aquatic environment. However, little is known about its effects on brain performance. Here, we investigated whether BP-3 exposure affects the redox imbalance in zebrafish and how they respond to a task that requires memory of an aversive situation. Fish were exposed to BP-3 10 and 50 µg L-1 for 15 days and then tested using an associative learning protocol with electric shock as a stimulus. Brains were extracted for reactive oxygen species (ROS) measurement and qPCR analysis of antioxidant enzyme genes. ROS production increased for exposed animals, and catalase (cat) and superoxide dismutase 2 (sod 2) were upregulated. Furthermore, learning and memory were reduced in zebrafish exposed to BP-3. These results suggested that BP-3 may lead to a redox status imbalance, causing impaired cognition and reinforcing the need to replace the toxic UV filters with filters that minimize environmental effects.

Monitoring Hg2+ and MeHg+ poisoning in living body with an activatable near-infrared II fluorescence probe.

Noninvasively imaging mercury poisoning in living organisms is critical to understanding its toxicity and treatments. Especially, simultaneous fluorescence imaging of Hg2+ and MeHg+in vivo is helpful to disclose the mysteries of mercury poisoning. The key limitation for mercury imaging in vivo is the low imaging signal-to-background ratio (SBR) and limited imaging depth, which may result in unreliable detection results. Here, we designed and prepared a near-infrared II (NIR II) emissive probe, NIR-Rh-MS, leveraging the "spirolactam ring-open" tactic of xanthene dyes for in situ visualization of mercury toxicity in mice. The probe produces a marked fluorescence signal at 1015 nm and displays good linear responses to Hg2+ and MeHg+ with excellent sensitivity, respectively. The penetration experiments elucidate that the activated NIR-II fluorescence signal of the probe penetrates to a depth of up to 7 mm in simulated tissues. Impressively, the probe can monitor the toxicity of Hg2+ in mouse livers and the accumulation of MeHg+ in mouse brains via intravital NIR-II imaging for the first time. Thus, we believe that detecting Hg2+ and MeHg+ in different organs with a single NIR-II fluorescence probe in mice would assuredly advance the toxicologic study of mercury poisoning in vivo.

Heptafluoroisobutyronitrile (C4F7N), a gas used for insulating and arc quenching in electrical switchgear, is neurotoxic in the mouse brain.

Fluoronitrile gas (C4F7N, CAS number 42532-60-5) is one of the most promising candidates as insulating and/or breaking medium in high and medium voltage electrical equipment. Besides its promising properties, C4F7N gas is however not devoid of acute toxicity when used pure or in gas mixtures. The toxicity was not extensively analyzed and reported. The aim of the present study was to analyze in mice the consequences of a single exposure to C4F7N gas, at different concentrations and different timepoints after exposure. Male and female Swiss mice were exposed to breathable air or C4F7N gas, at 800 ppmv or 1500 ppmv, for 4 h on day 0. Behavioral tests (spontaneous alternation in the Y-maze and object recognition) were performed on days 1, 7 and 14 to assess memory alterations. The animals were then sacrificed and their brains dissected for biochemical analyses or fixed with paraformaldehyde for histology and immunohistochemistry. Results showed behavioral impairments and memory deficits, with impairments of alternation at days 1 and 7 and object recognition at day 14. Histological alterations of pyramidal neuronal layer in the hippocampus, neuroinflammatory astroglial reaction, and microglial alterations were observed, more marked in female than male mice. Moreover, the biochemical analyses done in the brain of 1500 ppmv exposed female mice showed a reductive stress with decreased lipid peroxidation and release of cytochrome c, leading to apoptosis with increases in caspase-9 cleavage and γ-H2AX/H2AX ratio. Finally, electrophysiological analyses using a multi-electrode array allowed the measure of the extracellular activity of pyramidal neurons in the CA2 area and revealed that exposure to the gas not only prevented the induction of long-term potentiation but even provoked an epileptoid-like activity in some neurons suggesting major alterations of synaptic plasticity. This study therefore showed that an acute exposure of mice to C4F7N gas provoked, particularly in female animals, memory alterations and brain toxicity characterized by a reductive stress, microglial toxicity, loss of synaptic plasticity and apoptosis. Its use in industrial installations must be done with extreme caution.

Attenuation of doxorubicin-induced oxidative damage in rat brain by regulating amino acid homeostasis with Astragali Radix.

The nervous system disorders caused by doxorubicin (DOX) are among the severe adverse effects that dramatically reduce the quality of life of cancer survivors. Astragali Radix (AR), a popular herbal drug and dietary supplement, is believed to help treat brain diseases by reducing oxidative stress and maintaining metabolic homeostasis. Here we show the protective effects of AR against DOX-induced oxidative damage in rat brain via regulating amino acid homeostasis. By constructing a clinically relevant low-dose DOX-induced toxicity rat model, we first performed an untargeted metabolomics analysis to discover specific metabolic features in the brain after DOX treatment and AR co-treatment. It was found that the amino acid (AA) metabolism pathways altered most significantly. To accurately characterize the brain AA profile, we established a sensitive, fast, and reproducible hydrophilic interaction chromatography-tandem mass spectrometry method for the simultaneous quantification of 22 AAs. The targeted analysis further confirmed the changes of AAs between different groups of rat brain. Specifically, the levels of six AAs, including glutamate, glycine, serine, alanine, citrulline, and ornithine, correlated (Pearson |r| > 0.47, p < 0.05) with the brain oxidative damage that was caused by DOX and rescued by AR. These findings present that AAs are among the regulatory targets of DOX-induced brain toxicity, and AR is a promising therapeutic agent for it.

Management of multiple brain metastases via dual-isocenter VMAT stereotactic radiosurgery.

Single-isocenter volumetric modulated arc therapy (VMAT) stereotactic radiosurgery (SRS) techniques to treat multiple brain metastases simultaneously can significantly improve treatment delivery efficiency, patient compliance, and clinic workflow. However, due to large number of brain metastases sharing the same MLC pair causing island blocking, there is higher low- and intermediate-dose spillage to the normal brain and higher dose to organs-at-risk (OAR). To minimize this problem and improve plan quality, this study proposes a dual-isocenter planning strategy that groups lesions based on hemisphere location (left vs right sided) in the brain parenchyma, providing less island blocking reducing the MLC travel distance. This technique offers simplified planning while also increasing patient comfort and compliance by allowing for large number of brain metastases to be treated in 2 groups. Seven complex patients with 5 to 16 metastases (64 total) were planned with a single-isocenter VMAT-SRS technique using a 10MV-FFF beam with a prescription of 20 Gy to each lesion. The isocenter was placed at the approximate geometric center of the targets. Each patient was replanned using the dual-isocenter approach, generating 2 plans and placing each isocenter at the approximate geometric center of the combined targets of each side with corresponding non-coplanar partial arcs. Compared to single-isocenter VMAT, dual-isocenter VMAT plans provided similar target coverage and dose conformity with less spread of intermediate dose to normal brain with reduction of dose to OAR. Reduction in total monitor units and beam on time was observed, but due to the second isocenter setup and verification, overall treatment time was increased. Dual-isocenter VMAT-SRS planning for multiple brain metastases is a simplified approach that provides superior treatment options for patient compliance who may not tolerate longer traditional treatment times as with individual isocenters to each target. This planning technique significantly reduces the amount of low- and intermediate-dose spillage, further sparing OAR and normal brain, potentially improving target accuracy though localization of left vs right-sided tumors for each isocenter set up.

A novel framework for spatial normalization of dose distributions in voxel-based analyses of brain irradiation outcomes.

PURPOSE: To devise a novel Spatial Normalization framework for Voxel-based analysis (VBA) in brain radiotherapy. VBAs rely on accurate spatial normalization of different patients' planning CTs on a common coordinate system (CCS). The cerebral anatomy, well characterized by MRI, shows instead poor contrast in CT, resulting in potential inaccuracies in VBAs based on CT alone. METHODS: We analyzed 50 meningioma patients treated with proton-therapy, undergoing planning CT and T1-weighted (T1w) MRI. The spatial normalization pipeline based on MR and CT images consisted in: intra-patient registration of CT to T1w, inter-patient registration of T1w to MNI space chosen as CCS, doses propagation to MNI. The registration quality was compared with that obtained by Statistical Parametric Mapping software (SPM), used as benchmark. To evaluate the accuracy of dose normalization, the dose organ overlap (DOO) score was computed on gray matter, white matter and cerebrospinal fluid before and after normalization. In addition, the trends in the DOOs distribution were investigated by means of cluster analysis. RESULTS: The registration quality was higher for the proposed method compared to SPM (p < 0.001). The DOO scores showed a significant improvement after normalization (p < 0.001). The cluster analysis highlighted 2 clusters, with one of them including the majority of data and exhibiting acceptable DOOs. CONCLUSIONS: Our study presents a robust tool for spatial normalization, specifically tailored for brain dose VBAs. Furthermore, the cluster analysis provides a formal criterion for patient exclusion in case of non-acceptable normalization results. The implemented framework lays the groundwork for future reliable VBAs in brain irradiation studies.

Acute acetaminophen intoxication induces direct neurotoxicity in rats manifested as astrogliosis and decreased dopaminergic markers in brain areas associated with locomotor regulation.

Acetaminophen (APAP) administration at therapeutic doses is safe, however overdosing produces hepatocellular injury via a multifactorial mechanism(s) that involves generation of reactive oxygen species (ROS), being the most common cause of acute liver failure (ALF) in the northern hemisphere. Brain alterations induced by APAP intoxication are usually considered secondary to hepatic encephalopathy development due to ALF. Although APAP is primarily metabolized in the liver, it is also distributed and metabolized homogeneously in the brain, affecting brain redox status. Nevertheless, comprehensive studies on the potential of APAP intoxication to produce brain toxicity are scarce. The aim of this study was to characterize the direct toxic effects of APAP in different regions of the brain and on behavior in rats where the magnitude of hepatotoxicity produced is not associated with ALF. The present work demonstrates that APAP intoxication producing hepatotoxicity, but not ALF in rats, is associated with marked hypolocomotion. Our studies also suggest that selective downregulation in dopamine levels in brain areas that regulate motor activity may be responsible, in part, for the decreased locomotion observed with APAP treatment. Furthermore, we observed that the brain histoarchitecture is conserved and that edema is not present. However, an increase in oxidative stress, reactive astrogliosis and a decrease in neuron processes are the main features observed in APAP-intoxicated animals. These effects might be partly due to direct toxic effects of APAP in brain, since the same reactive astrogliosis observed in rats was also observed in rat primary astrocyte cultures exposed to APAP.

Increased Aluminum Content in Certain Brain Structures is Correlated with Higher Silicon Concentration in Alcoholic Use Disorder.

INTRODUCTION: Alcohol overuse may be related to increased aluminum (Al) exposure, the brain accumulation of which contributes to dementia. However, some reports indicate that silicon (Si) may have a protective role over Al-induced toxicity. Still, no study has ever explored the brain content of Al and Si in alcoholic use disorder (AUD). MATERIALS AND METHODS: To fill this gap, the present study employed inductively coupled plasma optical emission spectrometry to investigate levels of Al and Si in 10 brain regions and in the liver of AUD patients (n = 31) and control (n = 32) post-mortem. RESULTS: Al content was detected only in AUD patients at mean ± SD total brain content of 1.59 ± 1.19 mg/kg, with the highest levels in the thalamus (4.05 ± 12.7 mg/kg, FTH), inferior longitudinal fasciculus (3.48 ± 9.67 mg/kg, ILF), insula (2.41 ± 4.10 mg/kg) and superior longitudinal fasciculus (1.08 ± 2.30 mg/kg). Si content displayed no difference between AUD and control, except for FTH. Positive inter-region correlations between the content of both elements were identified in the cingulate cortex, hippocampus, and ILF. CONCLUSIONS: The findings of this study suggest that AUD patients may potentially be prone to Al-induced neurodegeneration in their brain-although this hypothesis requires further exploration.

The Potential Liver, Brain, and Embryo Toxicity of Titanium Dioxide Nanoparticles on Mice.

Nanoscale titanium dioxide (nano-TiO2) has been widely used in industry and medicine. However, the safety of nano-TiO2 exposure remains unclear. In this study, we evaluated the liver, brain, and embryo toxicity and the underlying mechanism of nano-TiO2 using mice models. The results showed that titanium was distributed to and accumulated in the heart, brain, spleen, lung, and kidney of mice after intraperitoneal (i.p.) nano-TiO2 exposure, in a dose-dependent manner. The organ/body weight ratios of the heart, spleen, and kidney were significantly increased, and those of the brain and lung were decreased. High doses of nano-TiO2 significantly damaged the functions of liver and kidney and glucose and lipid metabolism, as showed in the blood biochemistry tests. Nano-TiO2 caused damages in mitochondria and apoptosis of hepatocytes, generation of reactive oxygen species, and expression disorders of protective genes in the liver of mice. We found ruptured and cracked nerve cells and inflammatory cell infiltration in the brain. We also found that the activities of constitutive nitric oxide synthases (cNOS), inducible NOS (iNOS), and acetylcholinesterase, and the levels of nitrous oxide and glutamic acid were changed in the brain after nano-TiO2 exposure. Ex vivo mouse embryo models exhibited developmental and genetic toxicity after high doses of nano-TiO2. The size of nano-TiO2 particles may affect toxicity, larger particles producing higher toxicity. In summary, nano-TiO2 exhibited toxicity in multiple organs in mice after exposure through i.p. injection and gavage. Our study may provide data for the assessment of the risk of nano-TiO2 exposure on human health.

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication.

Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included "standard therapy" drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-D-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC50)] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication.

A review of the neurobiology of obesity and the available pharmacotherapies.

Obesity is becoming an increasing problem worldwide. In addition to causing many physical health consequences, there is increasing evidence demonstrating that obesity is toxic to the brain and, as such, can be considered a disease of the central nervous system. Peripheral level regulators of appetite, such as leptin, insulin, ghrelin, and cholecystokinin, feed into the appetite center of the brain, which is controlled by the hypothalamus, to maintain homeostasis and energy balance. However, food consumption is not solely mediated by energy balance, but is also regulated by the mesolimbic reward system, where motivation, reward, and reinforcement factors influence obesity. The purpose of this review is to highlight the neurobiology of eating behavior and obesity and to describe various neurobiological treatment mechanisms to treat obesity.

Curcumin Protects against Monosodium Glutamate Neurotoxicity and Decreasing NMDA2B and mGluR5 Expression in Rat Hippocampus.

BACKGROUND: Monosodium glutamate (MSG) is a flavor enhancer used in food industries. MSG is well documented to induce neurotoxicity. Curcumin (CUR) reportedly possesses beneficial effects against various neurotoxic insults. Hence, this present study has been designed to evaluate the neuroprotective effect of curcumin on MSG-induced neurotoxicity in rats. METHODS: Thirty-two male Wister rats were divided into four groups (n=8): Control group, MSG group, CUR group and MSG + CUR group. CUR (Curcumin 150 mg/kg, orally) was given day after day for four weeks along with MSG (4 mg/kg, orally). After 4 weeks, rats were sacrificed and brain hippocampus was isolated immediately on ice. Inflammatory marker TNFα and acetylcholinesterase (AChE) activity (marker for cholinergic function) were estimated. Gene expressions of metabotropic glutamate receptor 5 (mGluR5) and N-methyl-D-aspartate receptor 2B (NMDA2B) along with glutamate concentration were assessed. RESULTS: Treatment with CUR significantly attenuated AChE activity and TNFα in MSG-treated animals. The anti-inflammatory properties of CUR may be responsible for this observed neuroprotective action. A possible role of CUR to attenuate both glutamate level and gene expression of NMDA2B and mGLUR5 in brain hippocampus was established when compared to MSG group. CONCLUSION: We concluded that CUR as flavor enhancer protects against MSG-induced neurotoxicity in rats.

Isotoxic radiosurgery planning for brain metastases.

PURPOSE/OBJECTIVE(S): Radionecrosis (RN) has previously been correlated with radiosurgery (RS) dose, lesion volume, and the volume of the brain receiving specific doses, i.e. V10-14Gy. A knowledge-based individualized estimation of the optimum RS dose has been derived based on lesional volume and brain toxicity parameters. METHODS AND MATERIALS: A prediction model for brain toxicity parameters and estimation of the optimum RS dose was derived using 30 historical linac-based dynamic conformal arc RS plans for single brain metastases (BM) (0.2-20.3cc) with risk-adapted dose prescription ranging from 15 to 24Gy. Derivation of the model followed a three-step process: (1) Derivation of formulas for the prediction of brain toxicity parameters V10-18Gy; (2) Establishing the relationship of the coefficients used for the prediction of V12Gy with prescription dose; (3) Derivation of the optimum prescription dose for a given maximum V12Gy as a function of a given lesion volume. Model validation was performed on 65 new patients with 138 lesions (44 with multiple BM) treated with non-coplanar volumetric modulated stereotactic arc treatment (VMAT). RESULTS: A linear dependence with the PTV size was found for all investigated brain toxicity parameters (V10-18Gy). Individualized RS prescription doses can be calculated for any given PTV size based on a linear relationship between V12Gy and PTV size, according to the formula PD=[V12Gy+0.96+(1.44×PTV)]/[0.12+(0.12×PTV)]. A very good correlation (R(2)=0.991) was found between the predicted V12Gy and the resulting V12Gy in 65 new patients with 138 lesions treated with non-coplanar VMAT technique in our clinic. CONCLUSIONS: A simple formula is proposed for estimation of the optimal individual RS dose for any given lesion volume for patients with (multiple) BM. This formula is based on calculation of the brain toxicity parameter, V12Gy, for the normal brain minus PTV.