IN SILICO TARGET IDENTIFICATION OF NOOTROPIC BIOACTIVE COMPOUNDS FROM AYURVEDIC HERBS

Numerous plants are listed in the Ayurvedic pharmacopoeia, and several different plant parts are being used in Ayurvedic formulations. The bioactive ingredients of many of these medicinal have been identified. A key step in Ayurvedic drug development is the identification and validation of biological targets of these bioactive ingredients. Most of the experimental techniques involving genomic, proteomic and metabolomic approaches for target identification are laborious and expensive. Computational approaches allow an efficient alternative approach for in silico target prediction of bioactive compounds. Here, we have used computational methods to predict the target proteins of major bioactive compounds present in seven medicinal plants (Bacopa monnieri, Centella asiatica, Clitoria ternatea, Acorus calamus Glycyrrhiza glabra Celastrus paniculatus  Nardostachys jatamansi) known for their nootropic properties. These plants/plant parts are being used in various traditional Ayurveda formulations intended for cognitive enhancement and memory boosting. Even though these plants are widely used in the treatment of cognitive deficits, their scientific evaluation is lacking. Till date, very few studies have attempted to elucidate the targets or to explain the mode of action of bioactive ingredients in nootropic medicinal plants. We have chosen three databases for target prediction- ChEMBL, Swiss Target Prediction, and Binding DB. Based on available literature, we also examined if any of the predicted target proteins have brain-related functions. Pertinent to the nootropic properties of the medicinal plants, our study revealed several potential target proteins such as CYP19A1, MAPT, PTGS1, ACHE, SLC6A2, SLC6A3, MAOA and MAOB implicated in neurodevelopment, neuroprotection, learning and memory.

Decreased expression of axon-guidance receptors in the anterior cingulate cortex in autism

<p>Abstract</p> <p>Background</p> <p>Axon-guidance proteins play a crucial role in brain development. As the dysfunction of axon-guidance signaling is thought to underlie the microstructural abnormalities of the brain in people with autism, we examined the postmortem brains of people with autism to identify any changes in the expression of axon-guidance proteins.</p> <p>Results</p> <p>The mRNA and protein expression of axon-guidance proteins, including ephrin (EFN)A4, eEFNB3, plexin (PLXN)A4, roundabout 2 (ROBO)2 and ROBO3, were examined in the anterior cingulate cortex and primary motor cortex of autistic brains (n = 8 and n = 7, respectively) and control brains (n = 13 and n = 8, respectively) using real-time reverse-transcriptase PCR (RT-PCR) and western blotting. Real-time RT-PCR revealed that the relative expression levels of EFNB3, PLXNA4A and ROBO2 were significantly lower in the autistic group than in the control group. The protein levels of these three genes were further analyzed by western blotting, which showed that the immunoreactive values for PLXNA4 and ROBO2, but not for EFNB3, were significantly reduced in the ACC of the autistic brains compared with control brains.</p> <p>Conclusions</p> <p>In this study, we found decreased expression of axon-guidance proteins such as PLXNA4 and ROBO2 in the brains of people with autism, and suggest that dysfunctional axon-guidance protein expression may play an important role in the pathophysiology of autism.</p

Association of Transcription Factor Gene LMX1B with Autism

Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report

Two genetic variants of CD38 in subjects with autism spectrum disorder and controls

金沢大学医薬保健研究域医学系The neurobiological basis of autism spectrum disorder (ASD) remains poorly understood. Given the role of CD38 in social recognition through oxytocin (OT) release, we hypothesized that CD38 may play a role in the etiology of ASD. Here, we first examined the immunohistochemical expression of CD38 in the hypothalamus of post-mortem brains of non-ASD subjects and found that CD38 was colocalized with OT in secretory neurons. In studies of the association between CD38 and autism, we analyzed 10 single nucleotide polymorphisms (SNPs) and mutations of CD38 by re-sequencing DNAs mainly from a case-control study in Japan, and Caucasian cases mainly recruited to the Autism Genetic Resource Exchange (AGRE). The SNPs of CD38, rs6449197 (p 70; designated as high-functioning autism (HFA)) in the U.S. 104 AGRE family trios, but not with Japanese 188 HFA subjects. A mutation that caused tryptophan to replace arginine at amino acid residue 140 (R140W; (rs1800561, 4693C>T)) was found in 0.6-4.6% of the Japanese population and was associated with ASD in the smaller case-control study. The SNP was clustered in pedigrees in which the fathers and brothers of T-allele-carrier probands had ASD or ASD traits. In this cohort OT plasma levels were lower in subjects with the T allele than in those without. One proband with the T allele who was taking nasal OT spray showed relief of symptoms. The two variant CD38 poloymorphysms tested may be of interest with regard of the pathophysiology of ASD. © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society

Hypomethylation of Wnt signaling regulator genes in developmental language disorder

Supplementary figure 1Supplementary table 1 Supplementary table 2</p

Fluoxetine Increases the Expression of miR-572 and miR-663a in Human Neuroblastoma Cell Lines

<div><p>Evidence suggests neuroprotective effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on the developed neurons in the adult brain. In contrast, the drug may be deleterious to immature or undifferentiated neural cells, although the mechanism is unclear. Recent investigations have suggested that microRNAs (miRNA) may be critical for effectiveness of psychotropic drugs including SSRI. We investigated whether fluoxetine could modulate expressions of neurologically relevant miRNAs in two neuroblastoma SK-N-SH and SH-SY5Y cell lines. Initial screening results revealed that three (miR-489, miR-572 and miR-663a) and four (miR-320a, miR-489, miR-572 and miR-663a) miRNAs were up-regulated in SK-N-SH cells and SH-SY5Y cells, respectively, after 24 hours treatment of fluoxetine (1–25 μM). Cell viability was reduced according to the dose of fluoxetine. The upregulation of miR-572 and miR-663a was consistent in both the SH-SY5Y and SK-N-SH cells, confirmed by a larger scale culture condition. Our data is the first <i>in vitro</i> evidence that fluoxetine could increase the expression of miRNAs in undifferentiated neural cells, and that putative target genes of those miRNAs have been shown to be involved in fundamental neurodevelopmental processes.</p></div

Up-regulated expression of miR-572 and miR-663a in 10 μM fluoxetine-treated (a) SK-N-SH cells and (b) SH-SY5Y cells compared to DMSO-treated control cells.

<p>Error bars represent standard error. *<i>p</i> < 0.05.</p

Western blot showing expression of SLC6A4 protein in SK-N-SH and SH-SY5Y cells at ~83 kDa (SAB4200039).

<p>Abbreviations: M, molecular weight marker; Sk, SK-N-SH cells; Sh, SH-SY5Y cells. Concentration of sample per lane is 1.9 ug/μl.</p