Understanding translational research in schizophrenia: A novel insight into animal models.

Schizophrenia affects millions of people worldwide and is a major challenge for the scientific community. Like most psychotic diseases, it is also considered a complicated mental disorder caused by an imbalance in neurotransmitters. Due to the complexity of neuropathology, it is always a complicated disorder. The lack of proper understanding of the pathophysiology makes the disorder unmanageable in clinical settings. However, due to recent advances in animal models, we hope we can have better therapeutic approaches with more success in clinical settings. Dopamine, glutamate, GABA, and serotonin are the neurotransmitters involved in the pathophysiology of schizophrenia. Various animal models have been put forward based on these neurotransmitters, including pharmacological, neurodevelopmental, and genetic models. Polymorphism of genes such as dysbindin, DICS1, and NRG1 has also been reported in schizophrenia. Hypothesis based on dopamine, glutamate, and serotonin are considered successful models of schizophrenia on which drug therapies have been designed to date. New targets like the orexin system, muscarinic and nicotinic receptors, and cannabinoid receptors have been approached to alleviate the negative and cognitive symptoms. The non-pharmacological models like the post-weaning social isolation model (maternal deprivation), the isolation rearing model etc. have been also developed to mimic the symptoms of schizophrenia and to create and test new approaches of drug therapy which is a breakthrough at present in psychiatric disorders. Different behavioral tests have been evaluated in these specific models. This review will highlight the currently available animal models and behavioral tests in psychic disorders concerning schizophrenia.

Viscoelastic and smart swelling disposition of Carboxymethylcellulose based hydrogels substantiated by Gemini surfactant and in-vitro encapsulation and controlled release of Quercetin.

CMC-SA-12-E2-12 hydrogels were prepared from Carboxymethylcellulose (CMC), succinic acid (SA) (biocompatible cross-linker) and Ethane-1,2-diyl-bis(N, N-dimethyl-N-dodecylammoniumacetoxy) (referred as 12-E2-12) (0.0006, 0.0015, 0.003, 0.0045 mMoles) by thermal treatment with economical and easy solution polymerization strategy. The CMC-SA-12E2-12 hydrogels were characterized for mechanical and viscoelastic properties like self-healing, viscosity and modulus using rheological analysis. Further the structural, morphological and thermal properties were investigated by FTIR, SEM and TGA analysis. The investigation revealed significant modulation in mechanical, viscoelastic, self-healing and drug release behavior with the addition of 12-E2-12. The CMC-SA-12-E2-12 hydrogels were investigated for drug release studies in PBS 7.4 for 48 h using Quercetin dihydrate. The results showed sustained release behavior at optimised concentration values of surfactant. Release data fitted nicely to the Higuchi model and hence the release could be seen to be diffusion controlled phenomenon or Fickian diffusion. The biocompatibility of cross-linker and surfactant may potentially make the hydrogels suitable for drug delivery applications.

Association of SARS-CoV-2 and Polypharmacy with Gut-Lung Axis: From Pathogenesis to Treatment.

SARS-CoV-2 is a novel infectious contagion leading to COVID-19 disease. The virus has affected the lives of millions of people across the globe with a high mortality rate. It predominantly affects the lung (respiratory system), but it also affects other organs, including the cardiovascular, psychological, and gastrointestinal (GIT) systems. Moreover, elderly and comorbid patients with compromised organ functioning and pre-existing polypharmacy have worsened COVID-19-associated complications. Microbiota (MB) of the lung plays an important role in developing COVID-19. The extent of damage mainly depends on the predominance of opportunistic pathogens and, inversely, with the predominance of advantageous commensals. Changes in the gut MB are associated with a bidirectional shift in the interaction among the gut with a number of vital human organs, which leads to severe disease symptoms. This review focuses on dysbiosis in the gut-lung axis, COVID-19-induced worsening of comorbidities, and the influence of polypharmacy on MB.

In vitro cytotoxcity and interaction of new steroidal oxadiazinanones with calf thymus DNA using molecular docking, gel electrophoresis and spectroscopic techniques.

Herein we report synthesis of new steroidal oxadiazinanones from steroidal ketones. After characterization by spectral and analytical data, the interaction studies of compounds (4-6) with DNA were carried out by UV-vis, fluorescence spectroscopy and gel electrophoresis. The compounds bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb; 1.8×10(4) M(-1), 2.2×10(4) M(-1) and 2.6×10(4) M(-1), respectively, indicating the higher binding affinity of compound 6 towards DNA. Gel electrophoresis showed the concentration dependent cleavage activity of compound 6 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322 and it seems to follow the mechanistic pathway involving generation of hydroxyl radicals that are responsible for initiating DNA strand scission. Molecular simulations suggest that compounds binds through minor groove of DNA. MTT assay depicted promising anticancer activity of compound 5 and 6 particularly against HL-60 and MCF-7. The apoptotic degradation of DNA was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). The results revealed that compound 6 has better prospectus to act as cancer chemotherapeutic candidate which warrants further in vivo anticancer investigations.

Determination of the cationic amphiphilic drug-DNA binding mode and DNA-assisted fluorescence resonance energy transfer amplification.

Understanding the mechanism of drug-DNA binding is crucial for predicting the potential genotoxicity of drugs. Agarose gel electrophoresis, absorption, steady state fluorescence, and circular dichroism have been used in exploring the interaction of cationic amphiphilic drugs (CADs) such as amitriptyline hydrochloride (AMT), imipramine hydrochloride (IMP), and promethazine hydrochloride (PMT) with calf thymus or pUC19 DNA. Agarose gel electrophoresis assay, along with absorption and steady state fluorescence studies, reveal interaction between the CADs and DNA. A comparative study of the drugs with respect to the effect of urea, iodide induced quenching, and ethidium bromide (EB) exclusion assay reflects binding of CADs to the DNA primarily in an intercalative fashion. Circular dichroism data also support the intercalative mode of binding. Besides quenching, there is fluorescence exchange energy transfer (FRET) in between CADs and EB using DNA as a template.

Synthesis, characterization, DNA-binding studies and acetylcholinesterase inhibition activity of new 3-formyl chromone derivatives.

A series of new substituted 3-formyl chromone derivatives (4-6) were synthesized by one step reaction methodology by knoevenagel condensation, structurally similar to known bisintercalators. The new compounds were characterized by IR, (1)H NMR, (13)C NMR, MS and analytical data. The in vitro DNA binding profile of compounds (4-6) was carried out by absorption, fluorescence and viscosity measurements. It was found that synthesized compounds, especially compound 6 (evident from binding constant value) bind strongly with calf thymus DNA, presumably via an intercalation mode. Additionally, molecular docking studies of compounds (4-6) were carried out with B-DNA (PDBID: 1BNA) which revealed that partial intercalative mode of mechanism is operational in synthesized compounds (4-6) with CT-DNA. The binding constants evaluated from fluorescence spectroscopy of compounds with CT-DNA follows the order compound 6>compound 5>compound 4. All the compounds (4-6) were screened for acetylcholinesterase inhibition assay. It can be inferred from data, that compound (6) showed potent AChE inhibition having IC50=0.27µM, almost in vicinity to reference drug Tacrine (IC50=0.19µM).

Interaction of 6 mercaptopurine with calf thymus DNA--deciphering the binding mode and photoinduced DNA damage.

DNA is one of the major intracellular targets for a wide range of anticancer and antibiotic drugs. Elucidating the binding between small molecules and DNA provides great help in understanding drug-DNA interactions and in designing of new and promising drugs for clinical use. The ability of small molecules to bind and interfere with DNA replication and transcription provides further insight into how the drugs control the expression of genes. Interaction of an antimetabolite anticancer drug 6 mercaptopurine (6MP) with calf thymus DNA was studied using various approaches like UV-visible spectroscopy, fluorescence spectroscopy, CD, viscosity and molecular docking. UV-visible spectroscopy confirmed 6MP-DNA interaction. Steady state fluorescence experiments revealed a moderate binding constant of 7.48 × 10(3) M(-1) which was consistent with an external binding mode. Competitive displacement assays further confirmed a non-intercalative binding mode of 6MP which was further confirmed by CD and viscosity experiments. Molecular docking further revealed the minimum energy conformation (-119.67 kJ/mole) of the complex formed between DNA and 6MP. Hence, the biophysical techniques and in-silico molecular docking approaches confirmed the groove binding/electrostatic mode of interaction between 6MP and DNA. Further, photo induced generation of ROS by 6MP was studied spectrophotometrically and DNA damage was assessed by plasmid nicking and comet assay. There was a significant increase in ROS generation and consequent DNA damage in the presence of light.

Naproxen intercalates with DNA and causes photocleavage through ROS generation.

Naproxen is an important non-steroidal anti-inflammatory drug with many pharmacological and biological properties. In this study, we have attempted to ascertain the mode of action and the mechanism of binding of naproxen to DNA. We have also demonstrated that, upon irradiation with white light, naproxen generates reactive oxygen species, causing DNA cleavage. Generation of reactive oxygen species from photo-irradiated naproxen as determined spectrophotometrically was found to lead to nicking of plasmid DNA as analyzed by agarose gel electrophoresis. Without photo-irradiation, naproxen binds to DNA and forms drug-DNA complexes as revealed by spectroscopic techniques. Several experiments such as determination of the effect of urea, iodide-induced quenching and a competitive binding assay with ethidium bromide showed that naproxen binds to DNA primarily in an intercalative manner. These observations were further supported by CD analysis, viscosity measurements and molecular docking. Using DNA as a template, fluorescence resonance energy transfer between naproxen and ethidium bromide was also observed, further strengthening the evidence for intercalative binding of naproxen with DNA.

Formulation of amphiphilic drug amitriptyline hydrochloride by polyoxyethylene sorbitan esters in aqueous electrolytic solution.

In the present work, the interaction between an antidepressant drug amitriptyline hydrochloride and nonionic polyoxyethylene surfactants, with special attention to the possible contribution from the ion-dipole type of interaction, has been investigated by using multitechnique approach. Tensiometric and conductometric studies show steeper decrease on the critical micellar concentration gradient of the drug in the presence of electrolyte (NaCl) as well as nonionic surfactants. Critical assessments by applying Clint, Rubingh, Rosen, Motomura and other thermodynamic models confirm strong interactions in the mixed monolayer at the surface and in mixed micelle in the bulk of aqueous electrolytic solution. The structural difference in the drug and nonionic surfactants also plays a role in tuning the aggregational behavior of the drug-surfactant mixtures. Finally, it is shown by DLS measurements that the micellar growth of drug-surfactant aggregates is favored in terms of increase in hydrodynamic radii in the presence of electrolyte. However, the nonionic surfactants provide sufficient steric crowding causing dissociation of larger micelles into smaller ones with small radii.

Modulation of aggregation behavior of amphiphilic drug AMT under the influence of polymer molecular weight and composition.

The purpose of this study was to determine the aggregation behavior of amphiphilic drug amitriptyline hydrochloride (AMT) and to search for means which boost/suppress the aggregation behavior. Polyethylene glycols (PEGs) nonionic polymers (which are used as pharmaceutical excipients) of varying molecular weights from 400 to 35,000 were tested. To know their effect on the micellization and interfacial behavior of the drug, the critical micelle concentration (CMC) and critical aggregation concentration (CAC) were determined in presence of various polymers by tensiometric and conductivity methods. The CAC values were found to decrease while the CMC values increased with increase in the polymer concentration. The thermodynamic parameters were evaluated where ΔG°(mic) and ΔG°(agg) are found to be negative, confirming the feasibility of interaction between AMT and polymers.