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Abstract Neurological and psychiatric disorders contribute significantly to the global disease burden, adversely affecting the quality of life for both patients and their families. Impaired glutamatergic signaling is considered to be a major cause for most of the neurological and psychiatric disorders. Glutamate receptors are over activated in excitotoxic conditions, leading to dysregulation of Ca2+ homeostasis, triggering the production of free radicals and oxidative stress, mitochondrial dysfunction and eventually cell death. Excitotoxicity primarily results from the overactivity of NMDARs, a subtype of ionotropic glutamate receptors, due to their pronounced Ca2+ permeability and conductance characteristics. NMDAR antagonists are suggested to have therapeutic use as they can prevent excitotoxicity. Our previous studies demonstrated lobeline, an alkaloid, exerts neuroprotective action in excitotoxic conditions by blocking NMDAR. However, the atomic level interactions of lobeline with NMDAR was not characterized yet. Structural comparison of lobeline with a known NMDAR antagonist ifenprodil, followed by molecular docking and dynamics simulations revealed that lobeline could bind to the ifenprodil binding site i.e., in the heterodimer interface of GluN1-GluN2B subunits and exert ifenprodil like activities. By in silico structure guided modifications on lobeline and subsequent free energy calculations, we propose putative NMDAR antagonists derived from lobeline.

Abstract In recent years, the application of natural fiber reinforced polymer composite is rapidly increasing in different parts of the world due to its light weight, low cost, availability and feasibility of easy fabrication. This article focuses on the investigation of the physical and mechanical properties of natural fibers such as human hair, Sterculia foetida, delonix regia and caryotta obtusa fibers in terms of the analysis of the suitability of reinforcement material in composites. Untreated fibers were compared with NaOH treated fibers. Compositional analysis from Fourier Transform Infra-red Spectroscopy, tensile properties such as tensile strength, tensile modulus and percentage elongation of both untreated and treated fibers are discussed in detail. The properties of these natural fibers were compared with those of other natural fibers. The scope of addition of human hair, sterculia foetida, and delonix regia and caryotta obtusa fibers as reinforcement material in polymer composites were reported.

The objective of this work is to develop a natural fiber-reinforced epoxy composite with enhanced compatibility between resin and the fiber, achieved by amino silane treatment of Luffa fiber. Amine modification on the surface of the Luffa fiber is confirmed by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Composites with different volume fractions (2%, 4%, 6%, and 8%) of amine functionalized/un-functionalized Luffa fiber and epoxy resin are fabricated. The functionalized/un-functionalized Luffa epoxy composites are subjected to various studies such as tensile, flexural, and impact in the area of the effect of amine functionalization of fiber/epoxy composites. Dynamic mechanical analysis and fatigue analysis are carried out to enable a study on the effect of amine functionalization. Variations in thermal stability of the composites are studied using TGA analysis. A maximum tensile strength value of 18.3 MPa is reached for the 6% amine functionalized composite compared to the plain epoxy of 9.4 MPa. The amine functionalized fiber-reinforced composites show improved thermal, mechanical, and morphological properties as a result of improved interaction between the fiber and matrix.

Summary: MicroRNAs fine-tune gene regulation and can be targeted for therapeutic purposes. We investigated the physiological roles of miR-146a and miR-200b that are differentially expressed in neurological disorders such as Alzheimer's disease and schizophrenia, particularly in learning and memory mechanisms. Using bioinformatics tools and luciferase assay, we show interaction of these miRNAs with transcripts of N-methyl-D-aspartate receptor (NMDAR) subunits Grin2A and Grin2B. Overexpression of these miRNAs in primary hippocampal neurons caused downregulation of GluN2B and GluN2A proteins. Stereotactic injections of these miRNAs into rat hippocampus caused cognitive deficits in multiple behavioral tests with decreased protein levels of GluN1, GluN2A, GluN2B, AMPAR subunit GluR1, and Neuregulin 1. In pharmacologically treated rat models [MK-801 treated and methylazoxymethanol acetate (MAM) treated], we found upregulated levels of these miRNAs, implying their involvement in downregulating NMDAR subunits in these models. These results suggest the importance of miR-146a-5p and miR-200b-3p in hippocampus-dependent learning and memory.

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The complex and multifactorial nature of neuropsychiatric diseases demands multi-target drugs that can intervene with various sub-pathologies underlying disease progression. Targeting the impairments in cholinergic and glutamatergic neurotransmissions with small molecules has been suggested as one of the potential disease-modifying approaches for Alzheimer’s disease (AD). Tacrine, a potent inhibitor of acetylcholinesterase (AChE) is the first FDA approved drug for the treatment of AD. Tacrine is also a low affinity antagonist of N-methyl-D-aspartate receptor (NMDAR). However, tacrine was withdrawn from its clinical use later due to its hepatotoxicity. With an aim to develop novel high affinity multi-target directed ligands (MTDLs) against AChE and NMDAR, with reduced hepatotoxicity, we performed in silico structure-based modifications on tacrine, chemical synthesis of the derivatives and in vitro validation of their activities. Nineteen such derivatives showed inhibition with IC50 values in the range of 18.53 ± 2.09 – 184.09 ± 19.23 nM against AChE and 0.27 ± 0.05 – 38.84 ± 9.64 μM against NMDAR. Some of the selected compounds also protected rat primary cortical neurons from glutamate induced excitotoxicity. Two of the tacrine derived MTDLs, 201 and 208 exhibited in vivo efficacy in rats by protecting against behavioral impairment induced by administration of the excitotoxic agent, monosodium glutamate. Additionally, several of these synthesized compounds also exhibited promising inhibitory activitiy against butyrylcholinesterase. MTDL-201 was also devoid of hepatotoxicity in vivo. Given the therapeutic potential of MTDLs in disease-modifying therapy, our studies revealed several promising MTDLs among which 201 appears to be a potential candidate for immediate preclinical evaluations.