Molecular Interaction Sites Research Articles

Evaluation of aspartame as a co-former in the preparation of co-amorphous formulations of dipyridamole using spray drying

Co-amorphous systems (CAMs) have shown promise in addressing the challenges associated with poorly water-soluble drugs. However, the limited selection of co-formers and the use of lab-scale techniques for their preparation present challenges in fully utilizing the advantages of CAMs. In this study, we used aspartame (a methyl ester of the aspartic acid/phenylalanine) as a model dipeptide with the BCS class II drug dipyridamole, to prepare co-amorphous systems using spray drying. The feed solutions were prepared by dissolving the drug and co-former into methanol–water mixtures. The spray drying process was evaluated and solid-state properties were compared with those of the individual amino acids, amino acid mixtures and aspartame as co-formers. Co-amorphous systems prepared with aspartame (AspPhe) exhibited better solid-state properties, including a higher glass transition temperature (Tg), compared to the individual amino acids and the mixture of amino acids. Additionally, this formulation showed improved physical stability when stored at 25 °C/60 % RH conditions. Hirshfeld Surface (HS) analysis was employed to visualize and analyse the molecular interaction sites within the crystal structures of dipyridamole and aspartame. The observed interactions were then correlated with the molecular interactions identified through FT-IR spectroscopic analysis within the CAMs. The spectroscopic analysis revealed molecular interactions between the sites found at the shortest distances in the HS analysis. The dominant hydrogen bond interactions identified in the co-amorphous DPM-AspPhe system was found to contribute significantly to its improve stability. X-ray powder diffraction in non-ambient mode reveals that both temperature and humidity play a role in the crystallization of the co-amorphous DPM-AspPhe. Crystallization rates increased notably at high temperature and humidity. To predict stability under accelerated conditions, the crystallization rates from DPM-AspPhe were fitted to a modified Arrhenius equation. However, the predictive accuracy of the resulting model was limited to a specific range of conditions.

An Alkyne-Bridged Covalent Organic Framework Featuring Interactive Pockets for Bromine Capture.

The high degree of corrosivity and reactivity of bromine, which is released from various sources, poses a serious threat to the environment. Moreover, its coexistence with iodine forming an equilibrium compound, iodine monobromide (IBr) necessitates the selective capture of bromine from halogen mixtures. The electrophilicity of halogens to π-electron rich structures enabled us to strategically design a covalent organic framework for halogen capture, featuring a defined pore environment with localized sorption sites. The higher capture capacity of bromine (4.6 g g-1) over iodine by ~41 % shows its potential in selective capture. Spectroscopic results uncovering the preferential interaction sites are supported by theoretical investigations. The alkyne bridge is a core functionality promoting the selectivity in capture by synergistic physisorption, rationalized by the higher orbital overlap of bromine due to its smaller atomic size as well as reversible chemical interactions. The slip stacking in the structure has further promoted this phenomenon by creating clusters of molecular interaction sites with bromine intercalated between the layers. The inclusion of unsaturated moieties, i.e. triple bonds and the complementary pore geometry offer a promising design strategy for the construction of porous materials for halogen capture.

Eine Alkin‐verbrückte kovalent organische Gerüstverbindung mit interaktiven Bindungstaschen für das Einfangen von Brom

AbstractDie hohe Korrosivität und Reaktivität von Brom, welches aus verschiedenen Quellen freigesetzt wird, stellt eine ernsthafte Gefahr für die Umwelt dar. Darüber hinaus erfordert seine Koexistenz mit Iod und die daraus resultierende Gleichgewichtsverbindung Iodmonobromid (IBr) die selektive Abtrennung von Brom aus Halogengemischen. Die Elektrophilie von Halogenen gegenüber π‐elektronenreichen Strukturen ermöglichte uns die strategische Entwicklung einer kovalent organischen Gerüstverbindung für die Halogenaufnahme, die eine definierte Porenumgebung mit lokalisierten Sorptionsstellen aufweist. Die um ~41 % höhere Aufnahmekapazität von Brom (4,6 g g−1) gegenüber Iod zeigt das Potenzial für die selektive Aufnahme. Die spektroskopischen Ergebnisse, welche die bevorzugten Wechselwirkungsstellen aufzeigen, werden durch theoretische Untersuchungen gestützt. Die Alkin‐Brücke ist eine Kernfunktionalität, die die Selektivität bei der Aufnahme durch synergistische Physisorption fördert, was durch die höhere Orbitalüberlappung von Brom aufgrund seiner geringeren atomaren Größe, sowie durch reversible chemische Wechselwirkungen begründet ist. Das sogenannte „slip stacking“ in der Struktur hat dieses Phänomen weiter gefördert, indem Cluster molekularer Interaktionsstellen mit zwischen den Schichten eingelagertem Brom geschaffen wurden. Die Einführung ungesättigter Einheiten, d. h. Dreifachbindungen, und die komplementäre Porengeometrie bieten eine vielversprechende Designstrategie für die Konstruktion poröser Materialien für die Halogenaufnahme.

Rutin promotes M2 phenotype microglia polarization by suppressing the JAK/STAT3 signaling to protect against retinal ischemia-reperfusion injury.

We aimed to investigate the neuroprotective effect of rutin on retinal ganglion cells (RGCs) under ischemia-reperfusion (I/R) conditions and the underlying mechanisms involving microglia polarization and JAK/STAT3 signaling. RGCs isolated from C57/Bl6 mice were co-cultured with BV2 microglial cells under normal or in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) conditions. Rutin's effects were evaluated by assessing cell viability, apoptosis rates, cytokine levels, microglial polarization markers and JAK/STAT3 phosphorylation levels. The specific target is confirmed through the inhibitory effect of rutin on the respectively activated signaling factors. Furthermore, molecular docking analyses elucidated rutin-JAK1 interactions. OGD/R conditions significantly reduced RGC viability, exacerbated by BV2 co-culture. However, both 1 μM and 5 μM rutin treatment dose-dependently enhanced RGC viability, reduced apoptosis, and suppressed pro-inflammatory cytokine levels. Western blot analysis indicated that rutin promoted the M2 microglial phenotype and suppressed JAK/STAT3 signaling. Notably, rutin selectively inhibited JAK1 phosphorylation without affecting STAT3. Molecular docking highlighted potential interaction sites between rutin and specific JAK1 pseudokinase domain. Rutin exerts neuroprotective effects against retinal I/R injury by promoting M2 microglial polarization, potentially through the selective inhibition of JAK1 phosphorylation within the JAK/STAT3 signaling pathway. These findings provide a foundation for the therapeutic potential of rutin in retinal I/R injuries.

“Windmill” shaped branched anion-conducting poly(aryl piperidine) with extra molecular interaction sites as new anion exchange membranes

“Windmill” shaped branched anion-conducting poly(aryl piperidine) with extra molecular interaction sites as new anion exchange membranes

The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition.

The Phosphatidylinositol 3-phosphate 5-kinase Type III PIKfyve is the main source for selectively generated phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a known regulator of membrane protein trafficking. PI(3,5)P2 facilitates the cardiac KCNQ1/KCNE1 channel plasma membrane abundance and therewith increases the macroscopic current amplitude. Functional-physical interaction of PI(3,5)P2 with membrane proteins and its structural impact is not sufficiently understood. This study aimed to identify molecular interaction sites and stimulatory mechanisms of the KCNQ1/KCNE1 channel via the PIKfyve-PI(3,5)P2 axis. Mutational scanning at the intracellular membrane leaflet and nuclear magnetic resonance (NMR) spectroscopy identified two PI(3,5)P2 binding sites, the known PIP2 site PS1 and the newly identified N-terminal α-helix S0 as relevant for functional PIKfyve effects. Cd2+ coordination to engineered cysteines and molecular modeling suggest that repositioning of S0 stabilizes the channel s open state, an effect strictly dependent on parallel binding of PI(3,5)P2 to both sites.

Redox Mediators in Microbial Electrochemical Systems

AbstractRedox mediators are commonly used in microbial electrochemical systems to enable or enhance the electron transfer between microorganisms and electrodes. In recent studies, new insights into the mechanism of mediated extracellular electron transfer were gained, but some questions remain unanswered. In this review, some of the most outstanding research questions regarding the use of redox mediators in microbial electrochemical systems were discussed. These included the recycling of artificial and natural redox mediators, limitations in electron transfer rates by mediator turnover, metabolic burden, membrane permeability, and the putative interaction sites between commonly used redox mediators and the proteins of the electron transport chain of diverse electroactive microorganisms. To simplify the planning of mediator‐based bioelectrochemical systems, these molecular interaction sites were defined by their redox potential and are assigned to redox mediators, known or hypothesized to be able to transfer electrons from or to the specific interaction site. Furthermore, we addressed the kinetics of mediator transfer through the membrane and the potential rate‐limiting step in mediator‐based processes.

Recent Advances in Carbon and Metal Based Supramolecular Technology for Supercapacitor Applications.

As the world moves towards renewable and sustainable energy sources, the need for systems that can quickly and safely store this energy is also rising. Supercapacitors (SCs) are among the most promising alternatives to conventional lithium-ion batteries. SCs are more stable, have higher-power densities, and can be charged much faster. However, SCs have their issues, and three of the main drawbacks of current SCs are 1) lower energy densities, 2) high cost of production, and 3) safety concerns in wearable devices. In this review, we discuss recent progress made in supramolecule-based SCs (SSCs). In supramolecular systems, molecules are held stable using non-covalent-type bonds. This allows for a flexible system in which the molecular interaction sites can easily break and reform at low energy, allowing for exposure of highly active sites and self-healing. When heterometal atoms are introduced into these supramolecular systems, this allows for further activation of the metal sites through the metal-metal interaction along with the metal-ligand interactions. This review discusses different types of SSCs (carbon-based and metal-incorporated) that have been utilized in recent years depending on their synthesis process. The working principle of SSCs and the utilization of different supramolecular elements that enhance the performance of SCs have also been discussed.

PPOs having piperidinium-based conducting head groups with extra molecular interaction sites as new anion exchange membranes

Poly(2,6-dimethyl-1,4-phenylene oxide)s [PPOs] with 4-hydroxy-piperidinium and tropinium conducting head groups are developed, and corresponding membranes are investigated as new anion exchange membranes (AEMs). Their properties are compared with piperidinium-functionalized PPO membranes. The additional OH group in the piperidinium unit further enhances the chemo-physical stability of the corresponding membrane (OH-Pip-PPO) due to physical crosslinking through hydrogen bonding. The bulky structure of tropinium provides additional free volume in the corresponding membrane (Trop-PPO). Hydrogen bonding between the polymers and water causes well-developed morphology and high dimensional stability. These membranes also contain ion-conducting highways, facilitating efficient ion transport, in agreement with molecular dynamics simulations. The 4-hydroxy-piperidinium-functionalized PPO showed the highest dimensional and alkaline stability, with slightly lower conductivity and cell performance than piperidinium-functionalized-PPO (Pip-PPO) and Trop-PPO. Trop-PPO further increases free volume and water uptake, resulting in the highest normalized conductivity among the three PPO-based membranes and fuel cell performance similar to Pip-PPO.

Molecular mechanism analysis of Erzhi Wan in treatment of aging based on network pharmacology

This present study aimed to explore the molecular mechanism of Erzhi Wan(a prescription of nourishing Yin and toni-fying liver and kidney) in treatment of aging by network pharmacology. The active constituents and target proteins of Erzhi Wan were searched from Traditional Chinese Medicine Systems Pharmacology Database(TCMSP) and PubChem databases respectively. Aging-related genes were searched from Gene and HAGR databases. Based on the Ingenuity Pathway Analysis(IPA), we analyzed the common molecular network, biological pathway and interaction sites between these two parts, and verified some of them by Western blot. Twelve active constituents of Erzhi Wan were screened by TCMSP databases, 69 protein targets were predicted through PubChem, and 148 aging-related genes were found in Gene and HAGR databases. IPA comparison showed that the molecular networks of these two were complex, with diversity of biological functions. The common pathways involved 292 pathways, mainly related to tumors. They acted on hypoxia inducible factor-1α gene(HIF1α), nuclear factor-E2 related factor(Nrf2/NFE2 L2), tumor necrosis factor(TNF) and other sites. Western blot results suggested that Erzhi Wan could down-regulate the expression of HIF1α, with statistical difference(P<0.05). It was concluded that, Erzhi Wan could intervene aging through improving pseudo-hypoxic microenvironment and inflammation. The molecular mechanism of Erzhi Wan in delaying aging was preliminarily revealed, which laid a foundation for further stu-dying the anti-aging mechanism of Erzhi Wan, and also provided a reference for the compatibility mechanism and extended application of Chinese medicine compounds.

Efficient Identification for Alcohol Homologues and Hyperthermy Based on Coordination Polymer Multiple Structural Transformations.

Recently, coordination polymer materials are of high interest due to the potential applications for chemical sensing and luminescent materials. In this work, we designed a photofluorescence coordination polymer material based on a donor-metal-acceptor structure. The donor-metal-acceptor architecture showed unusual multiple environmental responsiveness accompanied by a great change of fluorescence behaviors. Generally, organic homologue molecules are not easily distinguished by coordination polymer sensors because they have similar molecular structures and interaction sites. However, using the feature of multiple structural transformations, the accurate identification for organic homologue molecules can be realized, especially in a short time to quickly identify MeOH in other alcohol homologues (even in mixed atmospheres with only 10% MeOH). The visualization transformation of fluorescence can also be realized by single crystal to single crystal thermal-induced coordination bond ON/OFF behavior. The reversible structure conversion strategy provides new ideas for the accurate identification of organic homolog molecules or external environmental stimuli.

Fundamental Properties of Packing Materials for Liquid Chromatography

The high performance of chemically-modified silica gel packing materials is based on the utilization of pure silica gels. Earlier silica gels used to be made from inorganic silica; however, nowadays, silica gels are made from organic silanes. The surface smoothness and lack of trace metals of new silica gels permits easy surface modifications (chemical reactions) and improves the reproducibility and stability. Sharpening peak symmetry is based on developing better surface modification methods (silylation). Typical examples can be found in the chromatography of amitriptyline for silanol testing and that of quinizarin for trace metal testing. These test compounds were selected and demonstrated sensitive results in the measurement of trace amounts of either silanol or trace metals. Here, we demonstrate the three-dimensional model chemical structures of bonded-phase silica gels with surface electron density for easy understanding of the molecular interaction sites with analytes. Furthermore, a quantitative explanation of hydrophilic and hydrophobic liquid chromatographies was provided. The synthesis methods of superficially porous silica gels and their modified products were introduced.

Identification of molecular-interaction sites between lowly hydrolyzed polyvinyl alcohols and indomethacin by NMR spectroscopy

To evaluate the potency of hydrolyzed polyvinyl alcohols (PVAs) as matrices for solid dispersion (SD) formulations, we examined their inhibitory effects on precipitation of a poorly water-soluble drug, indomethacin (IND). Additionally, to clarify their mechanism, we investigated the intermolecular interaction of IND with PVAs in the supersaturated aqueous solution of IND. In the present study, we used five kinds of PVAs, i.e. JR-05 (70.0–74.0% hydrolyzed), JL-05E (80.0–84.0% hydrolyzed), JP-05 (87.0–89.0% hydrolyzed), JT-05 (93.5–94.5% hydrolyzed) and JF-05 (98.0–99.0% hydrolyzed). Of various PVAs, the lowly hydrolyzed PVAs such as JR-05 and JL-05E dramatically inhibited the precipitate formation of IND. Interestingly, the lowly hydrolyzed PVAs possessed micelle-forming ability, and inhibited the nucleation and crystal growth of IND. Moreover, strong hydrophobic interactions between vinyl acetate unit of lowly hydrolyzed PVA and hydrophobic moiety of IND were suggested based on the results of nuclear magnetic resonance (1H NMR) and nuclear overhauser effect spectroscopy (NOESY) in deuterium oxide. To the best of our knowledge, this is the first report describing the inhibitory effects of the hydrolyzed degree of PVAs on the precipitation of a drug, and demonstrating the intermolecular interaction between PVAs and a drug using NOESY in water.

Location and Character of Volatile General Anesthetics Binding Sites in the Transmembrane Domain of TRPV1.

It has been proposed that general anesthesia results from direct multisite interactions with multiple and diverse ion channels in the brain. An understanding of the mechanisms by which general anesthetics modulate ion channels is essential to clarify their underlying behavior and their role in reversible immobilization and amnesia. Despite the fact that volatile general anesthetics are drugs that primarily induce insensitivity to pain, they have been reported to sensitize and active the vanilloid-1 receptor, TRPV1, which is known to mediate the response of the nervous system to certain harmful stimuli and which plays a crucial role in the pain pathway. Currently, the mechanism of action of anesthetics is unknown and the precise molecular sites of interaction have not been identified. Here, using ∼2.5 μs of classical molecular dynamics simulations and metadynamics, we explore these enigmas. Binding sites are identified and the strength of the association is further characterized using alchemical free-energy calculations. Anesthetic binding/unbinding proceeds primarily through a membrane-embedded pathway, and subsequently, a complex scenario is established involving multiple binding sites featuring single or multiple occupancy states of two small volatile drugs. One of the five anesthetic binding sites reported was previously identified experimentally, and another one, importantly, is identical to that of capsaicin, one of the chemical stimuli that activate TRPV1. However, in contrast to capsaicin, isoflurane and chloroform binding free-energies render modest to no association compared to capsaicin, suggesting a different activation mechanism. Uncovering chloroform and isoflurane modulatory sites will further our understanding of the TRPV1 molecular machinery and open the possibility of developing site-specific drugs.

X-ray Structures of the Proprotein Convertase Furin Bound with Substrate Analogue Inhibitors Reveal Substrate Specificity Determinants beyond the S4 Pocket.

The proprotein convertase furin is a highly specific serine protease modifying and thereby activating proteins in the secretory pathway by proteolytic cleavage. Its substrates are involved in many diseases, including cancer and infections caused by bacteria and viruses. Understanding furin's substrate specificity is crucially important for the development of pharmacologically applicable inhibitors. Using protein X-ray crystallography, we investigated the extended substrate binding site of furin in complex with three peptide-derived inhibitors at up to 1.9 Å resolution. The structure of the protease bound with a hexapeptide inhibitor revealed molecular details of its S6 pocket, which remained completely unknown so far. The arginine residue at P6 induced an unexpected turnlike conformation of the inhibitor backbone, which is stabilized by intra- and intermolecular H-bonds. In addition, we confirmed the binding of arginine to the previously proposed S5 pocket (S51). An alternative S5 site (S52) could be utilized by shorter side chains as demonstrated for a 4-aminomethyl-phenylacetyl residue, which shows steric properties similar to those of a lysine side chain. Interestingly, we also observed binding of a peptide with citrulline at P4 substituting for the highly conserved arginine. The structural data might indicate an unusual protonation state of Asp264 maintaining the interaction with uncharged citrulline. The herein identified molecular interaction sites at P5 and P6 can be utilized to improve next-generation furin inhibitors. Our data will also help to predict furin substrates more precisely on the basis of the additional specificity determinants observed for P5 and P6.

Infrared Spectrum and Sites of Action of Sanguinarine by Molecular Mechanics and <i>ab initio</i> Methods

Alkaloids occupy an important position in chemistry and pharmacology. Among the various alkaloids, berberine and coralyne of the protoberberine group, sanguinarine of the benzophenanthridine group, and aristololactam-b -d-glucoside of the aristolochia group have potential to form molecular complexes with nucleic acid structures and have attracted recent attention for their prospective clinical and pharmacological utility. Sanguinarine is an alkaloid studied in the treatment of cancer cell proliferation. Found in several plants, is used in traditional medicine from several countries with Mexico and India in the natural treatment of wounds, conjunctivitis and as hallucinogen. Is a toxic quaternary ammonium salt from the group of benzylisoquinoline alkaloids. It is extracted from some plants, including bloodroot (Sanguinaria canadensis), Mexican prickly poppy (Argemone mexicana Linn) Chelidonium majus and Macleaya cordata. It is also found in the root, stem and leaves of the opium poppy but not in the capsule. Sanguinarine is a toxin that kills animal cells through its action on the Na+-K+-ATPase transmembrane protein. Due to the diverse properties of this alkaloid, via computational methods was made using quantum chemistry to try to clarify some molecular properties that characterize its main sites of action as a drug. A study was made on a molecular structure of the sanguinarine, by Molecular Mechanics, PM3, Hartree-Fock, Density Functional Theory and Moller-Plesset. For calculations a cluster of six computers was used with Prescott-256 Celeron© D processors. The first principles calculations have been performed to study the equilibrium configuration of Sanguinarine molecule. Several physical properties have been calculated, including formation enthalpies, entropies, dipole moments, and the infrared emission/absorption spectrum. The results showed that the main site of molecular interaction was determined to be the hydrogen atoms. This has a strong antioxidant potential in its structure. It probably interacts with free radicals reducing their carcinogenic effect on cells. A study of the infrared spectrum complemented the paper. Absorption peaks in the infrared spectrum at 1000 cm-1, for calculation MP2/6-31G and, 1240 and 1450 cm-1 for B3LYP/6-311G ** were obtained. The MP2 and B3LYP methods showed good results for the infrared absorption spectrum. Although the base used in the MP2 method is less accurate, compared to the B3LYP whose base xxx has more accurate and broader functionalities, they are approximately equal for frequency peaks located in the 1060.6 cm-1 and 991.1 cm-1 range.

Molecular interactions between hepatitis B virus and delta virus.

As a deficient virus due to the lack of envelope proteins, hepatitis D virus (HDV) causes chronic or fulminant "delta hepatitis" only in people with simultaneous hepatitis B virus (HBV) infection. HBV encodes three types of surface proteins known as small (S), medium (M) and large (L) envelope proteins. All three types of HBV surface antigens (HBsAgs) are present on HDV virions. The envelopment process of HDV occurs through interactions between the HDV ribonucleoprotein (RNP) complex and HBV HBsAgs. While HBsAg is the only protein required by HDV, the exact interaction sites between the S protein and pre-mature HDV are not well defined yet. In fact, these sites are distributed along the S protein with some hot spots for the envelopment process. Moreover, in most clinically studied samples, HDV infection is associated with a dramatically reduced HBV viral load, temporarily or permanently, while HBsAg resources are available for HDV packaging. Thus, beyond interacting with HBV envelope proteins, controlling mechanisms exist by which HDV inhibits HBV-DNA replication while allowing a selective transcription of HBV proteins. Here we discuss the molecular interaction sites between HBsAg and the HDV-RNP complex and address the proposed indirect mechanisms, which are employed by HBV and HDV to facilitate or inhibit each other's viral replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies for delta hepatitis.

Infrared spectral investigations of UV irradiated nucleobases adsorbed on mineral surfaces

The interaction between electromagnetic radiation and bio-molecules in heterogeneous environments is a prebiotically relevant process. Minerals may have a pivotal role in the prebiotic evolution of complex chemical systems, mediating the effects of electromagnetic radiation, influencing the photostability of bio-molecules, catalyzing important chemical reactions and/or protecting molecules against degradation. In particular, nucleobases are relevant bio-molecules to investigate both in the prebiotic context, because they are coding components of nucleic acids, and from the standpoint of the survival of biological systems in space conditions. Several studies on the photodynamics of nucleobases suggest that their structure could have been naturally selected for the ability to dissipate electronic energy through ultrafast photophysical decay. Considering the putative involvement of minerals in the prebiotic chemistry, it is necessary to study the photostability of nucleobases under space conditions in the presence of mineral matrices, to investigate both the prebiotic processes that might have had a role in the development of the first living entities on Earth and the physical and chemical processes occurring in extraterrestrial environments. We focused our study on the characterization of the nature of the interaction between nucleobases and the surface of the minerals magnesium oxide and forsterite by infrared vibrational spectroscopy. We observed that most of the characteristic bands of pure nucleobases vanished when adsorbed on magnesium oxide. On the contrary, in the case of adenine and uracil adsorbed on forsterite, very intense nucleobase absorption peaks appeared. This phenomenon pertains to the surface selection rules changes related to molecular orientation. Moreover, based on the vibrational shifts, we deduced the molecular interaction sites with the mineral surfaces. Furthermore, we investigated the photostability of nucleobases adsorbed on such minerals through in situ UV irradiation experiments. Experimental results confirm the high intrinsic photostability of such molecules, because a rather low probability of interaction between UV radiation and nucleobases was estimated, and furthermore indicate that cytosine and hypoxanthine have a greater photostability compared to adenine and uracil, both pure and adsorbed onto magnesium oxide and forsterite.

A role for synaptic plasticity in the adolescent development of executive function

Adolescent brain maturation is characterized by the emergence of executive function mediated by the prefrontal cortex, e.g., goal planning, inhibition of impulsive behavior and set shifting. Synaptic pruning of excitatory contacts is the signature morphologic event of late brain maturation during adolescence. Mounting evidence suggests that glutamate receptor-mediated synaptic plasticity, in particular long term depression (LTD), is important for elimination of synaptic contacts in brain development. This review examines the possibility (1) that LTD mechanisms are enhanced in the prefrontal cortex during adolescence due to ongoing synaptic pruning in this late developing cortex and (2) that enhanced synaptic plasticity in the prefrontal cortex represents a key molecular substrate underlying the critical period for maturation of executive function. Molecular sites of interaction between environmental factors, such as alcohol and stress, and glutamate receptor mediated plasticity are considered. The accentuated negative impact of these factors during adolescence may be due in part to interference with LTD mechanisms that refine prefrontal cortical circuitry and when disrupted derail normal maturation of executive function. Diminished prefrontal cortical control over risk-taking behavior could further exacerbate negative outcomes associated with these behaviors, as for example addiction and depression. Greater insight into the neurobiology of the adolescent brain is needed to fully understand the molecular basis for heightened vulnerability during adolescence to the injurious effects of substance abuse and stress.

Contactin 4, -5 and -6 differentially regulate neuritogenesis while they display identical PTPRG binding sites

SummaryThe neural cell-adhesion molecules contactin 4, contactin 5 and contactin 6 are involved in brain development, and disruptions in contactin genes may confer increased risk for autism spectrum disorders (ASD). We describe a co-culture of rat cortical neurons and HEK293 cells overexpressing and delivering the secreted forms of rat contactin 4–6. We quantified their effects on the length and branching of neurites. Contactin 4–6 effects were different depending on the contactin member and duration of co-culture. At 4 days in culture, contactin 4 and -6 increased the length of neurites, while contactin 5 increased the number of roots. Up to 8 days in culture, contactin 6 progressively increased the length of neurites while contactin 5 was more efficient on neurite branching. We studied the molecular sites of interaction between human contactin 4, -5 or -6 and the human Protein Tyrosine Phosphatase Receptor Gamma (PTPRG), a contactin partner, by modeling their 3D structures. As compared to contactin 4, we observed differences in the Ig2 and Ig3 domains of contactin 5 and -6 with the appearance of an omega loop that could adopt three distinct conformations. However, interactive residues between human contactin 4–6 and PTPRG were strictly conserved. We did not observe any differences in PTPRG binding on contactin 5 and -6 either. Our data suggest that the differential contactin effects on neurite outgrowth do not result from distinct interactions with PTPRG. A better understanding of the contactin cellular properties should help elucidate their roles in ASD.