Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aß amyloidosis.

SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-ß (Aß) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.

Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations.

Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aß, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aß, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aß clearance. Reductions in Aß and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy.

The effect of Abi3 locus deletion on the progression of Alzheimer's disease-related pathologies.

Human genetics studies of Alzheimer's disease (AD) have identified the ABI3 gene as a candidate risk gene for AD. Because ABI3 is highly expressed in microglia, the brain's immune cells, it was suggested that ABI3 might impact AD pathogenesis by regulating the immune response. Recent studies suggest that microglia have multifaceted roles in AD. Their immune response and phagocytosis functions can have beneficial effects in the early stages of AD by clearing up amyloid-beta (Aß) plaques. However, they can be harmful at later stages due to their continuous inflammatory response. Therefore, it is important to understand the role of genes in microglia functions and their impact on AD pathologies along the progression of the disease. To determine the role of ABI3 at the early stage of amyloid pathology, we crossed Abi3 knock-out mice with the 5XFAD Aß-amyloidosis mouse model and aged them until 4.5-month-old. Here, we demonstrate that deletion of the Abi3 locus increased Aß plaque deposition, while there was no significant change in microgliosis and astrogliosis. Transcriptomic analysis indicates alterations in the expression of immune genes, such as Tyrobp, Fcer1g, and C1qa. In addition to the transcriptomic changes, we found elevated cytokine protein levels in Abi3 knock-out mouse brains, strengthening the role of ABI3 in neuroinflammation. These findings suggest that loss of ABI3 function may exacerbate AD progression by increasing Aß accumulation and inflammation starting from earlier stages of the pathology.

Impaired spatial memory in adult vitamin D deficient BALB/c mice is associated with reductions in spine density, nitric oxide, and neural nitric oxide synthase in the hippocampus.

Vitamin D deficiency is prevalent in adults and is associated with cognitive impairment. However, the mechanism by which adult vitamin D (AVD) deficiency affects cognitive function remains unclear. We examined spatial memory impairment in AVD-deficient BALB/c mice and its underlying mechanism by measuring spine density, long term potentiation (LTP), nitric oxide (NO), neuronal nitric oxide synthase (nNOS), and endothelial NOS (eNOS) in the hippocampus. Adult male BALB/c mice were fed a control or vitamin D deficient diet for 20 weeks. Spatial memory performance was measured using an active place avoidance (APA) task, where AVD-deficient mice had reduced latency entering the shock zone compared to controls. We characterised hippocampal spine morphology in the CA1 and dentate gyrus (DG) and made electrophysiological recordings in the hippocampus of behaviourally naïve mice to measure LTP. We next measured NO, as well as glutathione, lipid peroxidation and oxidation of protein products and quantified hippocampal immunoreactivity for nNOS and eNOS. Spine morphology analysis revealed a significant reduction in the number of mushroom spines in the CA1 dendrites but not in the DG. There was no effect of diet on LTP. However, hippocampal NO levels were depleted whereas other oxidation markers were unaltered by AVD deficiency. We also showed a reduced nNOS, but not eNOS, immunoreactivity. Finally, vitamin D supplementation for 10 weeks to AVD-deficient mice restored nNOS immunoreactivity to that seen in in control mice. Our results suggest that lower levels of NO and reduced nNOS immunostaining contribute to hippocampal-dependent spatial learning deficits in AVD-deficient mice.

Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer's disease in a mouse model of Aß amyloidosis.

Recently, large-scale human genetics studies identified a rare coding variant in the ABI3 gene that is associated with an increased risk of Alzheimer's disease (AD). However, pathways by which ABI3 contributes to the pathogenesis of AD are unknown. To address this question, we determined whether loss of ABI3 function affects pathological features of AD in the 5XFAD mouse model. We demonstrate that the deletion of Abi3 locus significantly increases amyloid ß (Aß) accumulation and decreases microglia clustering around the plaques. Furthermore, long-term potentiation is impaired in 5XFAD;Abi3 knockout ("Abi3−/−") mice. Moreover, we identified marked changes in the proportion of microglia subpopulations in Abi3−/− mice using a single-cell RNA sequencing approach. Mechanistic studies demonstrate that Abi3 knockdown in microglia impairs migration and phagocytosis. Together, our study provides the first in vivo functional evidence that loss of ABI3 function may increase the risk of developing AD by affecting Aß accumulation and neuroinflammation.

Levocarnitine Improves AlCl3-Induced Spatial Working Memory Impairment in Swiss albino Mice.

Background: Aluminum, a neurotoxic substance, causes oxidative stress induced-neurodegenerative diseases. Several lines of evidence suggest that levocarnitine has an antioxidant effect and also plays an important role in beta-oxidation of fatty acids. However, the role of levocarnitine in aluminum-induced neurotoxicity has not been well documented. Here we aimed to investigate the effect of levocarnitine on aluminum chloride (AlCl3)-induced oxidative stress and memory dysfunction. Methods: Male Swiss albino mice (n = 30) were treated with either control (saline) or AlCl3 or AlCl3 plus levocarnitine or levocarnitine or astaxanthin plus AlCl3 or astaxanthin alone. The spatial working memory was determined by radial arm maze (RAM). In addition, we measured the lipid peroxidation (MDA), glutathione (GSH), advanced oxidation of protein products (AOPP), nitric oxide (NO) and activity of superoxide dismutase (SOD) in the various brain regions including prefrontal cortex (PFC), striatum (ST), parietal cortex (PC), hippocampus (HIP) hypothalamus (HT) and cerebellum (CB). We used astaxanthin as a standard antioxidant to compare the antioxidant activity of levocarnitine. Results: The RAM data showed that AlCl3 treatment (50 mg/kg) for 2 weeks resulted in a significant deficit in spatial learning in mice. Moreover, aluminum exposure significantly (p < 0.05) increased the level of oxidative stress markers such as MDA, GSH, AOPP and NO in the various brain regions compared to the controls. In addition, combined administration of levocarnitine and AlCl3 significantly (p < 0.05) lowered the MDA, AOPP, GSH and NO levels in mice. Conclusion: Our results demonstrate that levocarnitine could serve as a potential therapeutic agent in the treatment of oxidative stress associated diseases as well as in memory impairment.

Adult vitamin D deficiency disrupts hippocampal-dependent learning and structural brain connectivity in BALB/c mice.

Converging evidence from human and animal studies support an association between vitamin D deficiency and cognitive impairment. Previous studies have shown that hippocampal volume is reduced in adults with vitamin D deficiency as well as in a range of disorders, such as schizophrenia. The aim of the current study was to examine the effect of adult vitamin D (AVD) deficiency on hippocampal-dependent spatial learning, and hippocampal volume and connectivity in healthy adult mice. Ten-week-old male BALB/c mice were fed a control (vitamin D 1500 IU/kg) or vitamin D-depleted (vitamin D 0 IU/kg) diet for a minimum of 10 weeks. The mice were then tested for hippocampal-dependent spatial learning using active place avoidance (APA) and on tests of muscle and motor coordination (rotarod and grip strength). The mice were perfused and brains collected to acquire ex vivo structural and diffusion-weighted images using a 16.4 T MRI scanner. We also performed immunohistochemistry to quantify perineuronal nets (PNNs) and parvalbumin (PV) interneurons in various brain regions. AVD-deficient mice had a lower latency to enter the shock zone on APA, compared to control mice, suggesting impaired hippocampal-dependent spatial learning. There were no differences in rotarod or grip strength, indicating that AVD deficiency did not have an impact on muscle or motor coordination. AVD deficiency did not have an impact on hippocampal volume. However, AVD-deficient mice displayed a disrupted network centred on the right hippocampus with abnormal connectomes among 29 nodes. We found a reduction in PNN positive cells, but no change in PV, centred on the hippocampus. Our results provide compelling evidence to show that AVD deficiency in otherwise healthy adult mice may play a key role in hippocampal-dependent learning and memory formation. We suggest that the spatial learning deficits could be due to the disruption of right hippocampal structural connectivity.

Astaxanthin ameliorates scopolamine-induced spatial memory deficit via reduced cortical-striato-hippocampal oxidative stress.

Alzheimer's disease is characterized by progressive disruption of cholinergic neurotransmission and impaired cognitive functions. In rodents, scopolamine has been used to induce cholinergic dysfunction resulting in cognitive impairments and an increment of oxidative stress in the brain. Here we tested whether oxidative stress can be attenuated via an antioxidant (astaxanthin) to rescue scopolamine-induced spatial memory. For this purpose, we administered either 0.9% saline (control), or scopolamine (SCP), or scopolamine plus astaxanthin (SCP + AST) to Swiss albino mice (ten weeks old; n = 20) for 28 consecutive days and subsequently examined animals' locomotor activity, spatial learning, and memory performance. The mice were then euthanized and prefrontal cortex (PFC), striatum (ST), hippocampus (HP), and liver tissues were assayed for antioxidant enzymes, glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and nitric oxide (NO). The SCP group exhibited impaired spatial learning and significantly altered levels of antioxidant enzymes and NO in the PFC, ST, and HP. In contrast, SCP + AST treatment did not cause spatial learning deficits. Furthermore, this condition also showed unaltered levels of SOD and NO in the ST and HP. Taken together, our results show that scopolamine may interrupt the striatal-hippocampal cholinergic activity resulting in impaired spatial memory. At the same time, these impairments are extinguished with astaxanthin by preventing oxidative damage in the striatal-hippocampal cholinergic neurons. Therefore, we suggest astaxanthin as a potential treatment to slow the onset or progression of cognitive dysfunctions that are elicited by abnormal cholinergic neurotransmission in Alzheimer's disease.

Pretreatment With Risperidone Ameliorates Systemic LPS-Induced Oxidative Stress in the Cortex and Hippocampus.

Risperidone (RIS), an atypical antipsychotic has been found to show anti-inflammatory effect against lipopolysaccharide (LPS)-induced inflammation. In vitro study has revealed that RIS inhibits the LPS-induced reactive oxygen species (ROS) formation. We investigated the antioxidant effects of RIS on LPS-induced oxidative stress markers in Swiss albino mice. Ten weeks old male Swiss albino mice (30 ± 2 g) were pretreated with either distilled water (control) or RIS (3 mg/kg) for 7 days. On day 8, animals were challenged with a single dose of LPS (0.8 mg/kg) while control animals received distilled water only. The animals were sacrificed after 24 h of LPS administration and tissue samples were collected. RIS administration significantly (p < 0.05) reduced the LPS-induced elevated levels of lipid peroxidation product malondialdehyde (MDA), advanced protein oxidation products, and nitric oxide (NO) in the cortex. Catalase (CAT) and superoxide dismutase (SOD) levels were also diminished while the level of glutathione (GSH) was enhanced. Hippocampus data showed that RIS significantly (p < 0.05) reduced the LPS-induced increased levels of MDA and NO, and SOD activity. Our results suggest that LPS-induced neuronal oxidative damage can be alleviated by the pretreatment with RIS and the effect is shown presumably by scavenging of the ROS by risperidone as an antioxidant.

Picture Novelty Influences Response Selection and Inhibition: The Role of the In-Group Bias and Task-Difficulty.

The human visual system prioritizes processing of novel information, leading to faster detection of novel stimuli. Novelty facilitates conflict resolution through the enhanced early perceptual processing. However, the role of novel information processing during the conflict-related response selection and inhibition remains unclear. Here, we used a face-gender classification version of the Simon task and manipulated task-difficulty and novelty of task-relevant information. The novel quality of stimuli was made task-irrelevant, and an in-group bias was tightly controlled by manipulation of a gender of picture stimuli. We found that the in-group bias modulated the role of novelty in executive control. Novel opposite-sex stimuli facilitated response inhibition only when the task was not demanding. By contrast, novelty enhanced response selection irrespective of the in-group factor when task-difficulty was increased. These findings support the in-group bias mechanism of visual processing, in cases when attentional resources are not limited by a demanding task. The results are further discussed along the lines of the attentional load theory and neural mechanisms of response-inhibition and locomotor activity. In conclusion, our data showed that processing of novel information may enhance executive control through facilitated response selection and inhibition.

Astaxanthin ameliorates aluminum chloride-induced spatial memory impairment and neuronal oxidative stress in mice.

Aluminum chloride induces neurodegenerative disease in animal model. Evidence suggests that aluminum intake results in the activation of glial cells and generation of reactive oxygen species. By contrast, astaxanthin is an antioxidant having potential neuroprotective activity. In this study, we investigate the effect of astaxanthin on aluminum chloride-exposed behavioral brain function and neuronal oxidative stress (OS). Male Swiss albino mice (4 months old) were divided into 4 groups: (i) control (distilled water), (ii) aluminum chloride, (iii) astaxanthin+aluminum chloride, and (iv) astaxanthin. Two behavioral tests; radial arm maze and open field test were conducted, and OS markers were assayed from the brain and liver tissues following 42 days of treatment. Aluminum exposed group showed a significant reduction in spatial memory performance and anxiety-like behavior. Moreover, aluminum group exhibited a marked deterioration of oxidative markers; lipid peroxidation (MDA), nitric oxide (NO), glutathione (GSH) and advanced oxidation of protein products (AOPP) in the brain. To the contrary, co-administration of astaxanthin and aluminum has shown improved spatial memory, locomotor activity, and OS. These results indicate that astaxanthin improves aluminum-induced impaired memory performances presumably by the reduction of OS in the distinct brain regions. We suggest a future study to determine the underlying mechanism of astaxanthin in improving aluminum-exposed behavioral deficits.

Astaxanthin ameliorates prenatal LPS-exposed behavioral deficits and oxidative stress in adult offspring.

BACKGROUND: Prenatal maternal lipopolysaccharide (LPS) exposure leads to behavioral deficits such as depression, anxiety, and schizophrenia in the adult lives. LPS-exposure resulted in the production of cytokines and oxidative damage. On the contrary, astaxanthin is a carotenoid compound, showed neuroprotective properties via its antioxidant capacity. This study examines the effect of astaxanthin on the prenatal maternal LPS-induced postnatal behavioral deficit in mice. RESULTS: We found that prenatal LPS-exposed mice showed extensive immobile phase in the tail suspension test, higher frequent head dipping in the hole-board test and greater hypolocomotion in the open field test. All these values were statistically significant (p < 0.05). In addition, a marked elevation of the level of lipid peroxidation, advanced protein oxidation product, nitric oxide, while a pronounced depletion of antioxidant enzymes (superoxide dismutase, catalase and glutathione) were observed in the adult offspring mice that were prenatally exposed to LPS. To the contrary, 6-weeks long treatment with astaxanthin significantly improved all behavioral deficits (p < 0.05) and diminished prenatal LPS-induced oxidative stress markers in the brain and liver. CONCLUSIONS: Taken together, these results suggest that prenatal maternal LPS-exposure leads to behavioral deficits in the adults, while astaxanthin ameliorates the behavioral deficits presumably via its antioxidant property.

The antioxidant effect of astaxanthin is higher in young mice than aged: a region specific study on brain.

Astaxanthin is a potential antioxidant which shows neuroprotective property. We aimed to investigate the age-dependent and region-specific antioxidant effects of astaxanthin in mice brain. Animals were divided into 4 groups; treatment young (3 months, n = 6) (AY), treatment old (16 months, n = 6) (AO), placebo young (3 months, n = 6) (PY) and placebo old (16 months, n = 6) (PO) groups. Treatment group was given astaxanthin (2 mg/kg/day, body weight), and placebo group was given 100 µl of 0.9% normal saline orally to the healthy Swiss albino mice for 4 weeks. The level of non-enzymatic oxidative markers namely malondialdehyde (MDA); nitric oxide (NO); advanced protein oxidation product (APOP); glutathione (GSH) and the activity of enzymatic antioxidants i.e.; catalase (CAT) and superoxide dismutase (SOD) were determined from the isolated brain regions. Treatment with astaxanthin significantly (p < 0.05) reduces the level of MDA, APOP, NO in the cortex, striatum, hypothalamus, hippocampus and cerebellum in both age groups. Astaxanthin markedly (p < 0.05) enhances the activity of CAT and SOD enzymes while improves the level of GSH in the brain. Overall, improvement of oxidative markers was significantly greater in the young group than the aged animal. In conclusion, we report that the activity of astaxanthin is age-dependent, higher in young in compared to the aged brain.

Antioxidant and cytotoxic activity of stems of Smilax zeylanica in vitro.

BACKGROUND: Plant-derived phytochemicals consisting of phenols and flavonoids possess antioxidant properties, eventually rendering a lucrative tool to scavenge reactive oxygen species. This study was carried out to evaluate in vitro antioxidant and cytotoxic potential of methanolic extract and petroleum ether extracts of Smilax zeylanica L. stems. METHODS: Phytochemical screening was done following standard procedures. Antioxidant activity was tested using several in vitro assays, viz., 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, NO assay, H2O2 assay, CUPRAC assay, FRAP assay and total antioxidant capacity assay. Total phenol and flavonoid contents were determined by colorimetric method. Brine shrimp lethality and MTT cell viability assays were used for cytotoxic potential. RESULTS: Preliminary phytochemical study revealed the presence of flavonoids and glycosides in both extracts. Methanolic extract was found to possess stronger antioxidant potential than petroleum ether extracts in all assays. The IC50 value of methanolic extract was 29.14±0.39 µg/mL, 120.30±3.32 µg/mL and 78.41±5.53 µg/mL in DPPH assay, NO assay and H2O2 assay, respectively. Likewise, total phenol [56.78 mg/g gallic acid (GAE)] and flovonoid [125.69 mg/g quercetin equivalents (QE)] were higher in methanolic extract. In cytotoxicity assays, petroleum ether extract showed stronger activity in both brine shrimp lethality (LC50 2.85±0.13 µg/mL) and MTT cell viability assay (IC50 15.49±1.18 µg/mL). CONCLUSIONS: These findings demonstrate that methanolic extracts could be considered as potential sources of natural antioxidant, whereas petroleum ether extracts could be explored for promising anticancer molecules.

Astaxanthin improves behavioral disorder and oxidative stress in prenatal valproic acid-induced mice model of autism.

Prenatal exposure to valproic acid on gestational day 12.5 may lead to the impaired behavior in the offspring, which is similar to the human autistic symptoms. To the contrary, astaxanthin shows neuroprotective effect by its antioxidant mechanism. We aimed to (i) develop mice model of autism and (ii) investigate the effect of astaxanthin on such model animals. Valproic acid (600 mg/kg) was administered intraperitoneally to the pregnant mice on gestational day 12.5. Prenatal valproic acid-exposed mice were divided into 2 groups on postnatal day 25 and astaxanthin (2mg/kg) was given to the experimental group (VPA_AST, n=10) while saline was given to the control group (VPA, n=10) for 4 weeks. Behavioral test including social interaction, open field and hot-plate were conducted on postnatal day 25 and oxidative stress markers such as lipid peroxidation, advanced protein oxidation product, nitric oxide, glutathione, and activity of superoxide dismutase and catalase were estimated on postnatal day 26 to confirm mice model of autism and on postnatal day 56 to assess the effect of astaxanthin. On postnatal day 25, prenatal valproic acid-exposed mice exhibited (i) delayed eye opening (ii) longer latency to respond painful stimuli, (iii) poor sociability and social novelty and (iv) high level of anxiety. In addition, an increased level of oxidative stress was found by determining different oxidative stress markers. Treatment with astaxanthin significantly (p<0.05) improved the behavioral disorder and reduced the oxidative stress in brain and liver. In conclusion, prenatal exposure to valproic day in pregnant mice leads to the development of autism-like features. Astaxanthin improves the impaired behavior in animal model of autism presumably by its antioxidant activity.

Analgesic, anti-inflammatory, and anti-oxidant activities of Phlogacanthus thyrsiflorus leaves.

BACKGROUND: Our present study was carried out to explore the potential role of the methanol extract from the leavesof Phlogocanthus thyrsiflorus (PT) Nees. in central and peripheral analgesic activities using hot plate and acetic acid-induced writhing methods. We also tested the antiinflammatory effects and anti-oxidant activity using carrageenan-induced paw edema and the DPPH method, respectively. METHODS: Methanol extracts of PT leaves were prepared using 500 g powder in 1.8 L methanol by percolation method, followed by evaporation in a rotary evaporator under controlled temperature and pressure. The crude methanol extract was dried by freeze drier and preserved at 4 °C. RESULTS: Oral administration of PT significantly (p < 0.05)increased the reaction time at 55.73% (250 mg/kg) and 72.81% (500 mg/kg) inhibition (p < 0.05) in the hot plate test at 3 h. PT significantly (p < 0.05) inhibited 42.17% (250 mg/kg) and 56.63% (500 mg/kg) acetic acid-induced writhing. PT leaves (250 and 500 mg/kg) also significantly (p < 0.05) inhibited paw edema 6 h after carrageenan injection. Furthermore, this plant showed significant (p < 0.05) free radical-scavenging activity at a dose range of 25­800 µg/mL. CONCLUSIONS: Based on the findings, we can conclude that PT leaf possesses analgesic, anti-inflammatory, and antioxidant activities. Preliminary phytochemical study of PT leaves revealed the presence of flavonoids, tannins and triterpens in methanol extract which could be correlated with its observed biological activities.

Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice.

Tadalafil, a type-5 phosphodiesterase enzyme inhibitor with long half-life used to treat erectile dysfunction. Recently it has been reported that tadalafil improves cognitive function. Here, we aimed to investigate the age dependent effects of tadalafil on memory, locomotor, behavior, and oxidative stress in the hippocampus. Tadalafil was orally administered everyday (5 mg/kg) to young (2 months) and old (16 months) healthy mice for 4 weeks. Control mice from each group received equal volume of 0.9% normal saline for the same duration. Memory and locomotor activity were tested using radial arm maze and open field test respectively. The level of malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was analyzed and catalase activity was determined from the isolated hippocampus. Treatment with tadalafil in aged mice improves working memory than the corresponding tadalafil treated young mice in radial arm maze test. Tadalafil treated mice traveled less distance in the center and the mean speed of tadalafil treated aged mice was significantly lower than the tadalafil treated young mice in open field test. Tadalafil treatment elicited a decrease of MDA level in the hippocampus of aged mice than that of young mice. APOP level was decreased only in aged mice treated with tadalafil. Treatment with tadalafil decreased NO and increased catalase activity in both young and aged mice. On the basis of previous and our findings, we conclude that tadalafil treatment reduces oxidative stress while increased cGMP level in the hippocampus might be responsible for memory enhancement.

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception.

BACKGROUND: Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. METHODS: Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. RESULTS: Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12-24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. CONCLUSIONS: The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given, the more effective it seems to be.

Neuroinflammation: Contemporary anti-inflammatory treatment approaches.

We investigated the idea of possible anti-inflammatory treatment approaches for inflammatory disorders in the CNS. The articles used for this review were searched through PubMed, PsycINFO, and Google scholar and published between January 2000 and July 2013. The CNS has its own type of defensive mechanism. The crosstalk between neurons and the immune system take place via small molecules called cytokines that are secreted from glial cells. Previous study suggested that the imbalance of cytokines facilitates the development of CNS disorders. For instance, the interleukin-6 level is raised in the astrocyte cell during depressive episodes, while axons are damaged by the activated lymphocytes and microglia in multiple sclerosis. Several studies demonstrated that cytokines and inflammatory compounds are closely linked to neuropsychiatric and neurodegenerative disorders. Here, we have accumulated and summarized evidence from those papers that support the anti-inflammatory treatment options for inflammatory CNS disorders.