Nano-selenium alleviates cadmium-induced neurotoxicity in cerebrum via inhibiting gap junction protein connexin 43 phosphorylation.

Cadmium (Cd) as a ubiquitous toxic heavy metal is reported to affect the nervous system. Selenium (Se) has been shown to have antagonistic effects against heavy metal toxicity. In addition, it shows potential antioxidant and anti-inflammatory properties. Thus, the purpose of this study was to determine the possible mechanism of brain injury after high Cd exposure and the mitigation of Nano-selenium (Nano-Se) against Cd-induced brain injury. In this study, the Cd-treated group showed a decrease in the number of neurons in brain tissue, swelling of the endoplasmic reticulum and mitochondria, and the formation of autophagosomes. Nano-Se intervention restored Cd-caused alterations in neuronal morphology, endoplasmic reticulum, and mitochondrial structure, thereby reducing neuronal damage. Furthermore, we found that some differentially expressed genes were involved in cell junction and molecular functions. Subsequently, we selected eleven (11) related differentially expressed genes for verification. The qRT-PCR results revealed the same trend of results as determined by RNA-Seq. Our findings also showed that Nano-Se supplementation alleviated Cx43 phosphorylation induced by Cd exposure. Based on immunofluorescence colocalization it was demonstrated that higher expression of GFAP and lower expressions of Cx43 were restored by Nano-Se supplementation. In conclusion, the data presented in this study establish a direct association between the phosphorylation of Cx43 and the occurrence of autophagy and neuroinflammation. However, it is noteworthy that the introduction of Nano-Se supplementation has been observed to mitigate these alterations. These results elucidate the relieving effect of Nano-Se on Cd exposure-induced brain injury.

Activation of the GPX4/TLR4 Signaling Pathway Participates in the Alleviation of Selenium Yeast on Deltamethrin-Provoked Cerebrum Injury in Quails.

Deltamethrin (DLM) is a member of pyrethroid pesticide widely applied for agriculture and aquaculture, and its residue in the environment seriously threatens the bio-safety. The cerebrum might be vulnerable to pesticide-triggered oxidative stress. However, there is no specific antidote for treating DLM-triggered cerebral injury. Selenium (Se) is an essential trace element functionally forming selenoprotein glutathione peroxidase (GPX) in antioxidant defense. Se yeast (SY) is a common and effective organic form of Se supplement with high selenomethionine content. Accordingly, this study focused on investigating the therapeutic potential of SY on DLM-induced cerebral injury in quails after chronically exposing to DLM and exploring the underlying mechanisms. Quails were treated with/without SY (0.4 mg kg-1 SY added in standard diet) in the presence/absence of DLM (45 mg kg-1 body weight intragastrically) for 12 weeks. The results showed SY supplementation ameliorated DLM-induced cerebral toxicity. Concretely, SY elevated the content of Se and increased GPX4 level in DLM-treated quail cerebrum. Furthermore, SY enhanced antioxidant defense system by upregulating nuclear factor-erythroid-2-related factor 2 (Nrf2) associated members. Inversely, SY diminished the changes of apoptosis- and inflammation-associated proteins and genes including toll-like receptor 4 (TLR4). Collectively, our results suggest that dietary SY protects against DLM-induced cerebral toxicity in quails via positively regulating the GPX4/TLR4 signaling pathway. GPX4 may be a potential therapeutic target for insecticide-induced biotoxicity.

Exposure to 2.45 GHz Radiation Triggers Changes in HSP-70, Glucocorticoid Receptors and GFAP Biomarkers in Rat Brain.

Brain tissue may be especially sensitive to electromagnetic phenomena provoking signs of neural stress in cerebral activity. Fifty-four adult female Sprague-Dawley rats underwent ELISA and immunohistochemistry testing of four relevant anatomical areas of the cerebrum to measure biomarkers indicating induction of heat shock protein 70 (HSP-70), glucocorticoid receptors (GCR) or glial fibrillary acidic protein (GFAP) after single or repeated exposure to 2.45 GHz radiation in the experimental set-up. Neither radiation regime caused tissue heating, so thermal effects can be ruled out. A progressive decrease in GCR and HSP-70 was observed after acute or repeated irradiation in the somatosensory cortex, hypothalamus and hippocampus. In the limbic cortex; however, values for both biomarkers were significantly higher after repeated exposure to irradiation when compared to control animals. GFAP values in brain tissue after irradiation were not significantly different or were even lower than those of nonirradiated animals in all brain regions studied. Our results suggest that repeated exposure to 2.45 GHz elicited GCR/HSP-70 dysregulation in the brain, triggering a state of stress that could decrease tissue anti-inflammatory action without favoring glial proliferation and make the nervous system more vulnerable.

Toxicology of tramadol following chronic exposure based on metabolomics of the cerebrum in mice.

Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.

Electroacupuncture ameliorates neuronal injury by Pink1/Parkin-mediated mitophagy clearance in cerebral ischemia-reperfusion.

The accumulation of dysfunctional mitochondria induced by the impairment of the autophagy-lysosome pathway (ALP), especially mitophagy is an important cause of cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture (EA) exerts remarkable effects in treating ischemic stroke; however, the detailed mechanism remains unclear. In this study, rats were treated with mitochondrial permeability transition pore (mPTP) opening inhibitor, peroxynitrite (ONOO-) scavenger, or selective inhibitor of mitophagy activation during 2-h middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion in combination with EA treatment. RNA-Seq analysis showed that EA treatment in cerebral I/R was linked to the autophagosome, the PI3K/Akt signaling pathway and metabolic pathways. We found that I/R resulted in significantly mitochondrial function impairments including decreased mitochondrial membrane potential (MMP) and ATP levels, aggregation of damaged mitochondria, excessive nitro/oxidative stress, PI3K/Akt/mTOR-mediated ALP dysfunction and deficiency of Pink1/Parkin-mediated mitophagy clearance. The treatment with EA, cyclosporine-A (CsA, a potent inhibitor of mPTP opening) or FeTMPyP (a type of ONOO- scavenger) could significantly increase MMP and/or ATP levels, improve mitochondrial function and decrease neuronal injury. At the same time, EA also improved ALP dysfunction and the deficiency of mitophagy clearance; however, mitochondrial division inhibitor-1 (Mdivi-1, a selective inhibitor of mitophagy activation) blocked mitophagy clearance and aggravated neuronal injury. Taken together, EA ameliorates nitro/oxidative stress-induced mitochondrial functional damage and decreases the accumulation of damaged mitochondria via Pink1/Parkin-mediated mitophagy clearance to protect cells against neuronal injury in cerebral I/R.

Effects of nimodipine on postoperative delirium in elderly under general anesthesia: A prospective, randomized, controlled clinical trial.

Nimodipine is a clinical commonly used calcium antagonistscan lowering the apoptosis rate of hippocampal neuron to reduce the incidence of postoperative cognitive dysfunction (POCD). This study was designed to evaluate the effects of nimodipine on postoperative delirium in elderly under general anesthesia.Sixty patients shceduced spine surgery under general anesthesia were randomly assigned into 2 groups using a random number table: control group (Group C) and nimodipine group (Group N). In Group N, nimodipine 7.5 µg/(kg × h) was injected continually 30 minutes before anesthesia induction, while the equal volume of normal saline was given in Group C. At 0 minute before injection, 0 minute after tracheal intubation, 1 hour after skin incision and surgery completed (T1-4), blood samples were taken from the radial artery and jugular bulb for blood gas analysis. Cerebral oxygen metabolism-related indicators were calculated at the same time. Concentration of S100ß and glial fibrillary acidic protein (GFAP) were tested by ELISA. The incidence of postoperative delirium within 7 days after surgery was recorded.Cerebral oxygen metabolism-related indicators fluctuationed in the normal range in 2 groups at different time points and the difference were not statistically significant. Compared with Group C, S100ß and GFAP decreased and incidence of postoperative delirium reduced at T3-4 in Group N, the difference was statistically significant (P<.05).The present study suggests that nimodipine can reduce the development of postoperative delirium in elderly patients under general anesthesia, the reduction of brain injury and improvement of cerebral oxygen metabolism may be involved in the mechanism.

Protective effects of puerarin on acute lung and cerebrum injury induced by hypobaric hypoxia via the regulation of aquaporin (AQP) via NF-κB signaling pathway.

OBJECTIVE: Hypobaric hypoxia, frequently encountered at high altitude, may lead to lung and cerebrum injury. Our study aimed to investigate whether puerarin could exert ameliorative effects on rats exposed to hypobaric hypoxia via regulation of aquaporin (AQP) and NF-κB signaling pathway in lung and cerebrum. MATERIALS AND METHODS: 40 Sprague Dawley rats were divided into four groups (normal control group, hypobaric hypoxia group, puerarin group and dexamethasone group). Wet/dry ratio, blood gas, pathological changes of lung and cerebrum and spatial memory were observed in each group. Inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were determined with ELISA and expression of AQP1, AQP4, NF-κB signaling pathway in lung and cerebrum with western blot RESULTS: Puerarin showed significant preventative effects on tissue injury and behavioral changes, as evidenced by histopathological findings and Morris water maze. In addition, levels of inflammatory cytokines in BALF decreased in the two preventative groups compared with those of hypobaric hypoxia group. AQP in lung and cerebrum increased under the condition of hypobaric hypoxia while was down regulated in both two preventative groups. NF-κB and IκB was also inhibited by puerarin. CONCLUSION: Our study suggested that lung and cerebrum injury, increased inflammatory cytokines in BALF and increased AQP1, AQP4 and NF-κB signaling pathway occurred under the condition of hypobaric hypoxia. Moreover, puerarin could prevent lung and cerebrum injury of rats exposed to hypobaric hypoxia via down-regulation of inflammatory cytokines, AQP1 and AQP4 expression and NF-κB signaling pathway.

Gallic Acid Ameliorates Cyclophosphamide-Induced Neurotoxicity in Wistar Rats Through Free Radical Scavenging Activity and Improvement in Antioxidant Defense System.

Cyclophosphamide (CPA) is a widely used anticancer chemotherapeutic agent and its toxicity has been associated with its toxic metabolites phosphormide mustard. Therefore, the ameliorative effect of Gallic acid against neurotoxicity was examined in this study. Sixty rats were grouped into 10 rats per group. Group 1 received saline orally. Group 2 received CPA at 100 mg/kg single dose intraperitoneally on day 1. Groups 3 and 4 were treated with Gallic acid (GA) at 60 and 120 mg/kg body weight only for 10 days and also received a single dose of CPA (100 mg/kg) intraperitoneally on day 1, respectively. Rats in groups 5 and 6 received GA at 60 and 120 mg/kg body weight only for 10 days. Groups 3, 4, 5, and 6 received GA orally. The cerebellar and cerebral malondialdehyde (MDA) contents and hydrogen peroxide generation were significantly (p < .05) elevated. The cerebellar and cerebral catalase (CAT), superoxide dismutase and glutathione-S-transferase (GST) activities were significantly (p < .05) reduced in CPA treated group. The activity of glutathione peroxidase (GPx) was significantly increased in rats that were treatment with CPA. Also, nitrite content was significantly elevated in the brain of rats that received the toxic dose of CPA. All these findings suggest that treatment with GA (60 and 120 mg/kg) ameliorated the neurotoxicity induced by CPA via reduction of oxidative stress and increase in antioxidant defense system. Combining all, chemotherapeutic agents with structure/function similar to GA could be of potential benefit to the pharmaceutical industries as an adjuvant in chemotherapy with little or no side effects.

Intracerebral Distribution of a-Pinene and the Anxiolytic-like Effect in Mice Following Inhaled Administration of Essential Oil from Chamaecyparis obtuse.

The anxiolytic-like and stress reduction effects following inhaled administration of essential oil from Chamaecyparis obtusa (EOCO) have been reported. Volatile components are thought to produce these effects of EOCO by neurological transfer and pharmacological transfer. The regions of the brain in which inhaled compounds are found due to pharmacological transfer of EOCO are not known. This research was undertaken to clarify the relationship between the intracerebral distribution of α-pinene, which is the main component of EOCO, and emotional behavior. α-Pinene was detected as the main component of volatile EOCO. The amount of α-pinene in each region of the brain was measured following inhaled administration of EOCO. The amount of α-pinene was different in each region of the brain. With inhaled administration of 32 µL/L air EOCO, a high concentration of α-pinene was observed. However, no significant differences in the concentration of α-pinene among brain regions were found. A therapeutic concentration of α-pinene (8 µL/L air EOCO) in each region of the brain may induce an anxiolytic-like effect, and a high concentration of α-pinene (32 µL/L air EOCO) in each region of the brain may induce an excitatory-like effect. The increases in the concentration of α-pinene from 8 to 32 µL/L air EOCO in the striatum and the hippocampus were significantly lower compared with the increases in other brain regions. These results indicate that regions besides the striatum and the hippocampus participated in the increase in locomotor activity due to the high concentration of α-pinene in the brain.

(1)H NMR-Based Metabolomics and Neurotoxicity Study of Cerebrum and Cerebellum in Rats Treated with Cinnabar, a Traditional Chinese Medicine.

Cinnabar, an important traditional Chinese mineral medicine, has been widely used as a Chinese patent medicine ingredient for sedative therapy. Nevertheless, the neurotoxic effects of cinnabar have also been noted. In this study, (1)H NMR-based metabolomics, combined with multivariate pattern recognition, were applied to investigate the neurotoxic effects of cinnabar after intragastrical administration (dosed at 2 and 5 g/kg body weight) on male Wistar rats. The metabolite variations induced by cinnabar were characterized by increased levels of glutamate, glutamine, myo-inositol, and choline, as well as decreased levels of GABA, taurine, NAA, and NAAG in tissue extracts of the cerebellum and cerebrum. These findings suggested that cinnabar induced glutamate excitotoxicity, neuronal cell loss, osmotic state changes, membrane fluidity disruption, and oxidative injury in the brain. We also show here that there is a dose- and time-dependent neurotoxicity of cinnabar, and that cerebellum was more sensitive to cinnabar induction than cerebrum. This work illustrates the utility and reliability of (1)H NMR-based metabolomics approach for examining the potential neurotoxic effects of cinnabar and other traditional Chinese medicines.

Zinc down regulates Apaf-1-dependent Bax/Bcl-2 mediated caspases activation during aluminium induced neurotoxicity.

Aluminium (Al), a ubiquitous element in nature is associated with the onset of Alzheimer's disease. On the other hand, zinc (Zn) is an essential trace element that regulates large number of physiological processes in the human body. The present study was conducted to explore the role of zinc, if any, in regulating apoptotic machinery during Al induced neurodegeneration in rat. Male sprague dawley rats weighing 140-160 g were divided into four different groups viz: Normal control, Al treated (100 mg/kg b.wt./day), Zn treated (227 mg/l) and combined Al and Zn treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment resulted in a significant increase in the protein expressions of cytochrome c, Bax, Apaf-1, caspase 9, caspase 3 (p17), caspase 8, caspase 6, caspase 7 but decreased the Bcl-2 in both the cerebrum and cerebellum. However, Zn supplementation to Al treated rats resulted in a reduction in the protein expressions of cytochrome c, Bax, Apaf-1, caspase 9, caspase 3 (p17), caspase 8, caspase 6 and caspase 7 whereas it elevated the Bcl-2 in both the regions. Further, gene expressions of caspase 3 and caspase 9 were also found to be elevated after Al treatment, which however were reduced following Zn co-treatment. The electron-microscopic analysis of brain revealed that Al intoxication resulted in a number of degenerative signs at ultrastructural level, which were appreciably improved upon Zn supplementation. The present study suggests that Zn provides protection against Al induced neurotoxicity by triggering anti-apoptotic machinery.

Electroacupuncture improves cerebral blood flow and attenuates moderate ischemic injury via Angiotensin II its receptors-mediated mechanism in rats.

BACKGROUND: To investigate the effects and potential mechanism of electroacupuncture intervention on expressions of Angiotensin II and its receptors-mediated signaling pathway in experimentally induced cerebral ischemia. METHODS: Totally 126 male Wistar rats were randomly divided into control group, model group and EA group. The latter two were further divided into ten subgroups (n = 6) following Middle Cerebral Artery Occlusion (MCAO). Changes in regional cerebral blood flow (rCBF) and expressions of Angiotensin II and its receptors (AT1R, AT2R), as well as effector proteins in phosphatidyl inositol signal pathway were monitored before and at different times after MCAO. RESULTS: MCAO-induced decline of ipsilateral rCBF was partially suppressed by electroacupuncture, and contralateral blood flow was also superior to that of model group. Angiotensin II level was remarkably elevated immediately after MCAO, while electroacupuncture group exhibited significantly lower levels at 1 to 3 h and the value was significantly increased thereafter. The enhanced expression of AT1R was partially inhibited by electroacupuncture, while increased AT2R level was further induced. Electroacupuncture stimulation attenuated and postponed the upregulated-expressions of Gq and CaM these upregulations. ELISA results showed sharply increased expressions of DAG and IP3, which were remarkably neutralized by electroacupuncture. CONCLUSIONS: MCAO induced significant increases in expression of Angiotensin II and its receptor-mediated signal pathway. These enhanced expressions were significantly attenuated by electroacupuncture intervention, followed by reduced vasoconstriction and improved blood supply in ischemic region, and ultimately conferred beneficial effects on cerebral ischemia.

Influence of zinc on calcium-dependent signal transduction pathways during aluminium-induced neurodegeneration.

Metals perform important functions in the normal physiological system, and alterations in their levels may lead to a number of diseases. Aluminium (Al) has been implicated as a major risk factor, which is linked to several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. On the other hand, zinc (Zn) is considered as a neuromodulator and an essential dietary element that regulates a number of biological activities in our body. The aim of the present study was to investigate the effects of Zn supplementation, if any, in ameliorating the changes induced by Al on calcium signalling pathway. Male Sprague Dawley rats weighing 140-160 g were divided into four different groups viz.: normal control, aluminium treated (100 mg/kg b.wt./day via oral gavage), zinc treated (227 mg/l in drinking water) and combined aluminium and zinc treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment decreased the Ca(2+) ATPase activity whereas increased the levels of 3', 5'-cyclic adenosine monophosphate, intracellular calcium and total calcium content in both the cerebrum and cerebellum, which, however, were modulated upon Zn supplementation. Al treatment exhibited a significant elevation in the protein expressions of phospholipase C, inositol triphosphate and protein kinase A but decreased the expression of protein kinase C, which, however, was reversed upon Zn co-treatment. Al treatment also revealed alterations in neurohistoarchitecture in the form of calcium deposits, which were improved upon zinc co-administration. The present study, therefore, suggests that zinc regulates the intracellular calcium signalling pathway during aluminium-induced neurodegeneration.

Resveratrol increases cerebral glycogen synthase kinase phosphorylation as well as protein levels of drebrin and transthyretin in mice: an exploratory study.

Alzheimer's disease (AD) is characterized by intraneuronal ß-amyloid plaques and hyperphosphorylated tau, leading to neuronal cell death and progressive memory losses. This exploratory work investigates if dietary resveratrol, previously shown to have broad anti-aging effects and improve AD pathology in vivo, leads to neuroprotective changes in specific protein targets in the mouse brain. Both wild-type and APP/PS1 mice, a transgenic AD mouse model, received control AIN-93G diet or AIN-93G supplemented with resveratrol. Pathology parameters and AD risk were assessed via measurements on plaque burden, levels of phosphorylated glycogen synthase kinase 3-ß (GSK3-ß), tau, transthyretin and drebrin. Dietary resveratrol treatment did not decrease plaque burden in APP/PS1 mice. However, resveratrol-fed mice demonstrated increases in GSK3-ß phosphorylation, a 3.8-fold increase in protein levels of transthyretin, and a 2.2-fold increase in drebrin. This study broadens our understanding of specific mechanisms and targets whereby resveratrol provides neuroprotection.

Influence of zinc on the biokinetics of (65)Zn in brain and whole body and its bio-distribution in aluminium-intoxicated rats.

The present study was designed to understand the influence of zinc (Zn) if any, on the biokinetics of (65)Zn in brain as well as whole body and its bio-distribution following aluminium (Al) treatment to rats. Male Sprague-Dawley rats weighing 140-160 g were divided into four different groups viz: normal control, aluminium treated (100 mg/kg b.wt./day via oral gavage), zinc treated (227 mg/L in drinking water) and combined aluminium and zinc treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment showed a significant increase in fast component (Tb1) but revealed a significant decrease in slow component (Tb2) of biological half-life in brain as well as in whole body. However, Zn supplementation to Al-treated rats reversed the trend in both brain and whole body, which indicates a significant decrease in Tb1 component while the Tb2 component was significantly increased. Further, Al treatment showed an increased percent uptake value of (65)Zn in cerebrum, cerebellum, heart, liver and lungs whereas a decrease in uptake was found only in blood. On the other hand, there was a significant decline in (65)Zn activity in nuclear and mitochondrial fractions of brain of Al-treated rats. However, Zn treatment reversed the altered (65)Zn uptake values in different organs as well as in various subcellular fractions. The study demonstrates that Zn shall prove to be effective in regulating the biokinetics of (65)Zn in brain and whole body and its distribution at the tissue and subcellular levels in Al-treated rats.

The protective activity of imperatorin in cultured neural cells exposed to hypoxia re-oxygenation injury via anti-apoptosis.

Apoptosis is believed to play important roles in neuronal cell death associated with cerebral ischemia. We now provided evidence that imperatorin (IMp), the main composition of the dried root or rhizome of R Radix Angelicae Dahuricae, took advantage on oxygen glucose deprivated/reperfusion (OGD-R) SH-SY5Y cell line through neuronal apoptosis inhibition. Our data had shown that imperatorin reduced the number of apoptosis cells after OGD-R, this effect was associated with the inhibition of the apoptosis factors Bax and caspase-3, and the upregulation of anti-apoptosis factor Bcl-2. In the meantime, the protective factor BDNF was upregulated significantly by imperatorin treatment. In our experiment in vivo, imperatorin decreased the infract volume significantly in dose of 5 mg/kg and 10 mg/kg, and the behavior ability was increased in the 10mg/kg of imperatorin. Our observations show that imperatorin exerted protective effect on cerebral ischemia both in vitro and in vivo, this effect is associated with its anti-apoptosis function.

Penehyclidine hydrochloride attenuates the cerebral injury in a rat model of cardiopulmonary bypass.

This study investigated the effect of penehyclidine hydrochloride (PHC) on regulatory mediators during the neuroinflammatory response and cerebral cell apoptosis following cardiopulmonary bypass (CPB). Forty-eight rats were randomly divided among 4 groups as follows: sham-operation, vehicle, low-dose PHC (0.6 mg·(kg body mass)(-1)), and high-dose PHC (2.0 mg·(kg body mass)(-1)). CPB was performed in the latter 3 groups. The plasma levels of neuron specific enolase (NSE) and S-100B were tested with ELISA. Real-time PCR and Western blotting were used to evaluate the expression levels of matrix metalloproteinase-9 (MMP-9), IL-10, caspase-3, Bcl-2, and p38 in brain tissue. The ultrastructure of hippocampus tissue was examined under an electron microscope. PHC attenuated the increase of plasma NSE and S-100B following CPB. MMP-9, cleaved caspase-3, and phosphorylated p38 expression were substantially increased in the vehicle group compared with the sham-operation group and gradually diminished with increasing doses of PHC. IL-10 and Bcl-2 expression were markedly lower in the vehicle group than in the sham-operation group and gradually recovered with increasing doses of PHC. PHC attenuated the histopathological changes of cerebral injury following CPB. PHC favorably regulates the inflammatory response and reduces markers of neuronal injury following CPB, potentially by reducing p38 and caspase-3 activation.

Zinc, a neuroprotective agent against aluminum-induced oxidative DNA injury.

Aluminum (Al) has been considered as one of the most abundant elements and comprises nearly 8 % of the Earth's crust. Despite of its immense presence, studies regarding the molecular basis of its interaction with the physiological system are rather sparse. On the other hand, zinc (Zn), an essential micronutrient, has been regarded as the second most important metal for brain functioning. The objective of the present study was to investigate the protective potential of Zn, if any, during Al-induced detrimental effects on DNA, tritiated thymidine uptake as well as expression of stress marker genes and proteins in rat brain. Male Sprague-Dawley rats weighing 140-160 g were divided into four different groups viz.: normal control, Al treated (100 mg/kg b wt/day via oral gavage), Zn treated (227 mg/l in drinking water), and combined Al and Zn treated. All the treatments were carried out for a total duration of 8 weeks. Agarose gel electrophoresis revealed DNA laddering pattern and comets in the rat brain following Al treatment, which however, were attenuated upon Zn treatment. Further, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, number of apoptotic brain cells, and uptake of tritiated thymidine were increased after Al treatment but were decreased upon Zn supplementation. Western blot and mRNA expressions of p53 and nuclear factor κB (NF-κB) were also found to be significantly elevated after Al treatment, which however, were reversed following Zn treatment. Hence, Zn shall prove to be an effective agent in mitigating the detrimental effects caused by Al in the rat brain.

Furanodien-6-one from Commiphora erythraea inhibits the NF-κB signalling and attenuates LPS-induced neuroinflammation.

We investigated the in vitro anti-inflammatory activity of 1(10),4-furanodien-6-one, one the most active compounds of the hexane extract of Commiphora erythraea (Ehrenb.) Engl., by exposing microglial BV-2 cells to lipopolysaccharide. We showed that furanodien-6-one pre-treatment restored cell viability and ROS to control levels while halving NO generation. Production of pro-inflammatory IL-6, IL-23, IL-17, TGF-ß, and INF-γ, significantly induced by LPS, was also markedly reduced by furanodien-6-one treatment. We further showed that furanodien-6-one protects primary neuronal cultures against the inflammatory/toxic insults of LPS-treated BV-2 conditioned media, indicating that furanodien-6-one exerts anti-inflammatory/cytoprotective effects in neuronal cells. We then investigated whether furanodien-6-one exerts anti-inflammatory properties in an in vivo model of microglial activation. In adult mice ip-injected with LPS we found that furanodien-6-one had strong cerebral anti-inflammatory properties by inhibiting liver and brain TNFα as well as IL-1ß expression. Results were not unexpected since FTIR-metabolomic analyses showed that furanodien-6-one-treated mice had a reduced dissimilarity to control animals and that the response to LPS treatment was markedly modified by furanodien-6-one. In conclusion our data provide strong evidence of the anti-inflammatory properties of furanodien-6-one that could be exploited to counteract degenerative pathologies based on neuroinflammation.

The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway.

Spontaneous intracranial hemorrhage is a debilitating form of stroke, often leading to death or permanent cognitive impairment. Many of the causative genes and the underlying mechanisms implicated in developmental cerebral-vascular malformations are unknown. Recent in vitro and in vivo studies in mice have shown inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway to be effective in stabilizing cranial vessels. Using a combination of pharmacological and genetic approaches to specifically inhibit the HMGCR pathway in zebrafish (Danio rerio), we demonstrate a requirement for this metabolic pathway in developmental vascular stability. Here we report that inhibition of HMGCR function perturbs cerebral-vascular stability, resulting in progressive dilation of blood vessels, followed by vessel rupture, mimicking cerebral cavernous malformation (CCM)-like lesions in humans and murine models. The hemorrhages in the brain are rescued by prior exogenous supplementation with geranylgeranyl pyrophosphate (GGPP), a 20-carbon metabolite of the HMGCR pathway, required for the membrane localization and activation of Rho GTPases. Consistent with this observation, morpholino-induced depletion of the ß-subunit of geranylgeranyltransferase I (GGTase I), an enzyme that facilitates the post-translational transfer of the GGPP moiety to the C-terminus of Rho family of GTPases, mimics the cerebral hemorrhaging induced by the pharmacological and genetic ablation of HMGCR. In embryos with cerebral hemorrhage, the endothelial-specific expression of cdc42, a Rho GTPase involved in the regulation of vascular permeability, was significantly reduced. Taken together, our data reveal a metabolic contribution to the stabilization of nascent cranial vessels, requiring protein geranylgeranylation acting downstream of the HMGCR pathway.