Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

Due to brain plasticity, the nervous system is capable of manifesting behavioral variations, adapted to the influences from both external and internal environment. Multiple neurotransmitters are involved in the mediation of pathological processes at the molecular, cellular, regional, and interregional levels participating in cerebral plasticity, their intervention being responsible for various structural, functional, and behavioral disturbances. The current therapeutic strategies in neuroprotection aim at blocking on different levels, the molecular cascades of the pathophysiological mechanisms responsible for neuronal dysfunctions and ultimately for neuronal death. Different agents influencing these neurotransmitters have demonstrated beneficial effects in neurogenesis and neuroprotection, proved in experimental animal models of focal and global ischemic injuries. Serotonin, dopamine, glutamate, N-methyl-D-aspartate, and nitric oxide have been shown to play a significant role in modulating nervous system injuries. The imidazoline system is one of the important systems involved in human brain functioning. Experimental investigations have revealed the cytoprotective effects of imidazoline I2 receptor ligands against neuronal injury induced by hypoxia in experimental animals. The neuroprotective effects were also highlighted for kappa and delta receptors, whose agonists demonstrated the ability to reduce architectural lesions and to recover neuronal functions of animals with experimentally induced brain ischemia

New Antidepressant Medication: Benefits Versus Adverse Effects

Depression [major depressive disorder (MDD)] is a mood disturbance of multifactorial origin, associated with high rates of morbidity and mortality, lack of work productivity, adverse health behaviors, and increased healthcare expenses. MDD is a leading cause of suicide, and it affects the prognosis of chronic conditions (heart diseases, diabetes, and cancer, among others). Current pharmacological treatment for MDD covers different classes of drugs, including tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and atypical antidepressants. The aim of this chapter is to review the literature, highlight the side effects of newer antidepressants, and especially point out the most important aspects of the latest agents approved for the treatment of MDD in adults: desvenlafaxine, levomilnacipran, vilazodone, and vortioxetine. Desvenlafaxine is a SNRI and the primary active metabolite of venlafaxine; also a SNRI, levomilnacipran is an enantiomer of the racemate milnacipran. Vilazodone and vortioxetine are multimodal antidepressants, which combine SSRI activity with additional receptor activity. Although they have proven efficacy in treating MDD and are being investigated for other possible indications, further detailed clinical trials are needed to establish their pharmaco-toxicological profile, following prolonged administration in patients who may suffer from various comorbidities

Drug delivery systems based on biocompatible imino-chitosan hydrogels for local anticancer therapy

<p>A series of drug delivery systems were prepared by chitosan hydrogelation with citral in the presence of an antineoplastic drug: 5-fluorouracil. The dynamic covalent chemistry of the imine linkage allowed the obtaining of supramolecular tridimensional architectures in which the drug has been homogenously dispersed. Fourier-transform infrared spectroscopy (FTIR), wide-angle X-ray diffraction (WXRD) and polarized light microscopy (POM) measurements were used in order to follow the hydrogelation and drug encapsulation processes. The ability of the prepared systems to release the drug has been investigated by UV–Vis spectroscopy using a calibration curve and by fitting the results with different mathematic models. To mimic the behavior of the hydrogel matrix in bio-environmental conditions in view of applications, their enzymatic degradability was monitored in the presence of lysozyme. The <i>in vivo</i> side effects of the systems, in terms of their influence on the blood elements, biochemical and immune parameters were monitored on white Swiss mice by intraperitoneal administration of the injectable obtained hydrogels. All the characteristics of the obtained systems, such as micro-porous morphology, uniform drug encapsulation, enzymatic degradability, lack of side effects, other than the one of the drug itself, along with their ability to release the drug in a sustained manner proved that these material meet the requirements for the development of drug delivery systems, making them suitable for being applied in intraperitoneal chemotherapy.</p

Evaluation of Antinociceptive Effects of Chitosan-Coated Liposomes Entrapping the Selective Kappa Opioid Receptor Agonist U50,488 in Mice

Background and Objectives: The selective kappa opioid receptor agonist U50,488 was reported to have analgesic, cough suppressant, diuretic and other beneficial properties. The aim of our study was to analyze the effects of some original chitosan-coated liposomes entrapping U50,488 in somatic and visceral nociceptive sensitivity in mice. Materials and Methods: The influence on the somatic pain was assessed using a tail flick test by counting the tail reactivity to thermal noxious stimulation. The nociceptive visceral estimation was performed using the writhing test in order to evaluate the behavioral manifestations occurring as a reaction to the chemical noxious peritoneal irritation with 0.6% acetic acid (10 mL/kbw). The animals were treated orally, at the same time, with a single dose of: distilled water 0.1 mL/10 gbw; 50 mg/kbw U50,488; 50 mg/kbw U50,488 entrapped in chitosan-coated liposomes, according to the group they were randomly assigned. Results: The use of chitosan-coated liposomesas carriers for U50,488 induced antinociceptive effects that began to manifest after 2 h, andwere prolonged but with a lower intensity than those caused by the free selective kappa opioid in both tests. Conclusion: In this experimental model, the oral administration of nanovesicles containing the selective kappa opioid agonist U50,488 determined a prolonged analgesic outcome in the tail flick test, as well as in the writhing test

Enzymatically-Crosslinked Gelatin Hydrogels with Nanostructured Architecture and Self-Healing Performance for Potential Use as Wound Dressings

Development of natural protein-based hydrogels with self-healing performance and tunable physical properties has attracted increased attention owing to their wide potential not only in the pharmaceutical field, but also in wounds management. This work reports the development of a versatile hydrogel based on enzymatically-crosslinked gelatin and nanogels loaded with amoxicillin (Amox), an antibiotic used in wound infections. The transglutaminase (TGase)-crosslinked hydrogels and encapsulating nanogels were formed rapidly through enzymatic crosslinking and self-assembly interactions in mild conditions. The nanogels formed through the self-assemble of maleoyl-chitosan (MAC5) and polyaspartic acid (PAS) may have positive influence on the self-healing capacity and drug distribution within the hydrogel network through the interactions established between gelatin and gel-like nanocarriers. The physicochemical properties of the enzymatically-crosslinked hydrogels, such as internal structure, swelling and degradation behavior, were studied. In addition, the Amox release studies indicated a rapid release when the pH of the medium decreased, which represents a favorable characteristic for use in the healing of infected wounds. It was further observed through the in vitro and in vivo biocompatibility assays that the optimized scaffolds have great potential to be used as wound dressings

Assessment of the In Vivo Release and Biocompatibility of Novel Vesicles Containing Zinc in Rats

This paper is focused on the in vivo release and biocompatibility evaluation in rats of some novel systems entrapping zinc chloride in lipid vesicles. The particles were prepared by zinc chloride immobilization inside lipid vesicles made using phosphatidylcholine, stabilized with 0.5% chitosan solution, and dialyzed for 10 h to achieve a neutral pH. The submicrometric systems were physico-chemically characterized. White Wistar rats, assigned into four groups of six animals each, were treated orally with a single dose, as follows: Group I (control): deionized water 0.3 mL/100 g body weight; Group II (Zn): 2 mg/kg body weight (kbw) zinc chloride; Group III (LV-Zn): 2 mg/kbw zinc chloride in vesicles; Group IV (LVC-Zn): 2 mg/kbw zinc chloride in vesicles stabilized with chitosan. Haematological, biochemical, and immune parameters were assessed after 24 h and 7 days, and then liver fragments were collected for histopathological examination. The use of zinc submicrometric particles—especially those stabilized with chitosan—showed a delayed zinc release in rats. No substantial changes to blood parameters, plasma biochemical tests, serum complement activity, or peripheral neutrophils phagocytic capacity were noted; moreover, the tested substances did not induce liver architectural disturbances. The obtained systems provided a delayed release of zinc, and showed good biocompatibility in rats

Synthesis, Characterization and Biocompatibility Evaluation of Novel Chitosan Lipid Micro-Systems for Modified Release of Diclofenac Sodium

The purpose of our study was the obtaining, characterization and biocompatibility estimation of novel carrier systems for diclofenac. Diclofenac is a potent nonsteroidal anti-inflammatory drug with frequent gastrointestinal side effects, impairing the quality of the patient’s life. Original diclofenac-loaded micro-vesicles coated with chitosan were prepared and physico-chemical analyzed. We investigated their in vitro hemocompatibility and in vivo biocompatibility in rats. The animals were treated orally as follows: group 1 (Control): distilled water 0.3 mL/100 g body weight; Group 2 (CHIT): 0.3 mL/100 g body weight 0.5% chitosan solution; Group 3 (DCF): 15 mg/kg body weight diclofenac; Group 4 (DCF-ves): lipid vesicles loaded with diclofenac 15 mg/kg body weight. Blood samples were collected for assessing: red blood cells, hemoglobin, hematocrit and leukocyte formula. A series of specific parameters of the liver and kidney function, some markers of immune defense, as well as the activity of some enzymes involved in oxidative processes, were also investigated. At the end of the experiment, the animals were sacrificed and fragments of liver, kidney and stomach were collected for histopathological examination. No blood hemolysis was evidenced by the in vitro test with the administration of diclofenac vesicles. The animals treated with diclofenac lipid vesicles stabilized with chitosan did not display any notable differences in their hematological and biochemical profile compared to control animals. These data correlated with the histological results, which showed the absence of architectural changes in the examined tissues. Biological in vitro and in vivo evaluation revealed that the microvesicles containing diclofenac are biocompatible, with potential to be used as delivery systems to modify the drug release, thus making them an attractive candidate for biomedical applications

Zinc Chloride Enhances the Antioxidant Status, Improving the Functional and Structural Organic Disturbances in Streptozotocin-Induced Diabetes in Rats

Background and Objectives: Diabetes mellitus (DM) is a complex disease affecting the whole metabolic balance of the body and resulting in multiple organ complications: cardiovascular, neuronal, renal, etc. Our study focuses on investigating the effect of zinc chloride (Zn) on certain blood parameters suggestive for assessing the metabolic disturbances, the liver and kidney function, the oxidative stress and the immune defense capacity in experimental-induced DM with streptozotocin (STZ) and cholesterol in rats. Materials and Methods: The animals were assigned to three groups, as follows: Group 1 (Control): buffer citrate solution 0.1 mL/100 g body; Group 2 (STZ): 20 mg/kg body STZ and fat diet (10 g cholesterol/100 g diet); Group 3 (STZ+Zn): 20 mg/kg body STZ + 5 mg/kg body Zn chloride and the same fat diet. DM was induced by administering STZ in a single take daily, for three consecutive days, Zn and citrate buffer were administered orally for a month. The protocol was approved by the Ethics Committee of the University &lsquo;Grigore T Popa&rsquo; Iasi, in agreement with the International Regulations about the handling of laboratory animals. Results: The use of STZ in rats fed with cholesterol was correlated with important weight gain, hyperglycemia, the intensification of the transaminases activity and the increase in serum alkaline phosphatase, cholesterol, triglyceride, urea, creatinine and in malondialdehyde. Conclusions: The treatment with Zn resulted in weight loss and a decrease in blood sugar in diabetic rats. Supplementation with Zn notably reduced oxidative stress, preserved the pancreatic architecture and restored the liver and kidney function and structure in STZ-induced DM in rats

Synthesis, Characterization and Biocompatibility Evaluation of Novel Chitosan Lipid Micro-Systems for Modified Release of Diclofenac Sodium

The purpose of our study was the obtaining, characterization and biocompatibility estimation of novel carrier systems for diclofenac. Diclofenac is a potent nonsteroidal anti-inflammatory drug with frequent gastrointestinal side effects, impairing the quality of the patient&rsquo;s life. Original diclofenac-loaded micro-vesicles coated with chitosan were prepared and physico-chemical analyzed. We investigated their in vitro hemocompatibility and in vivo biocompatibility in rats. The animals were treated orally as follows: group 1 (Control): distilled water 0.3 mL/100 g body weight; Group 2 (CHIT): 0.3 mL/100 g body weight 0.5% chitosan solution; Group 3 (DCF): 15 mg/kg body weight diclofenac; Group 4 (DCF-ves): lipid vesicles loaded with diclofenac 15 mg/kg body weight. Blood samples were collected for assessing: red blood cells, hemoglobin, hematocrit and leukocyte formula. A series of specific parameters of the liver and kidney function, some markers of immune defense, as well as the activity of some enzymes involved in oxidative processes, were also investigated. At the end of the experiment, the animals were sacrificed and fragments of liver, kidney and stomach were collected for histopathological examination. No blood hemolysis was evidenced by the in vitro test with the administration of diclofenac vesicles. The animals treated with diclofenac lipid vesicles stabilized with chitosan did not display any notable differences in their hematological and biochemical profile compared to control animals. These data correlated with the histological results, which showed the absence of architectural changes in the examined tissues. Biological in vitro and in vivo evaluation revealed that the microvesicles containing diclofenac are biocompatible, with potential to be used as delivery systems to modify the drug release, thus making them an attractive candidate for biomedical applications

Bioactive Collagen Hydrolysate-Chitosan/Essential Oil Electrospun Nanofibers Designed for Medical Wound Dressings

In this study, lemon balm (Melissa officinalis L.) and dill (Anethum graveolens L.) essential oils (EOs) were encapsulated into collagen hydrolysates extracted from bovine tendons and rabbit skins, both mixed with chitosan (CS) by using the coaxial electrospinning technique for potential wound dressing applications. The morphology and chemical composition of the electrospun nanofibers were investigated using scanning electron microscopy (SEM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). The antimicrobial activity of the dill EO and lemon EO, as well as the electrospun samples loaded with essential oils was determined by disk diffusion assay against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Enterococcus faecalis ATCC 29212, and Salmonella typhimurium ATCC 14028 bacterial strains; Candida albicans ATCC 10231 and Candida glabrata ATCC 90028 yeast strains; and Aspergillus brasiliensis ATCC 9642 fungal strain. In vivo biocompatibility testing of the collagen hydrolysate-chitosan/essential oil electrospun nanofibers was based on the determination of the hematological, biochemical, and immunological profile and the evaluation of the influence produced on the oxidative stress in white Swiss mice. The synergetic effect of dill and lemon balm EOs can improve the antimicrobial activity of collagen hydrolysate-chitosan nanofibers against the most important bacterial strains. The in vivo test results suggested a good biocompatibility of electrospun samples based on collagen hydrolysate extracted from bovine tendons or rabbit skin mixed with chitosan and containing dill and/or lemon balm essential oils as encapsulated bioactive compounds