Komagataella pastoris KM71H modulates neuroimmune and oxidative stress parameters in animal models of depression: A proposal for a new probiotic with antidepressant-like effect.

Many studies have suggested that imbalance of the gut microbial composition leads to an increase in pro-inflammatory cytokines and promotes oxidative stress, and this are directly associated with neuropsychiatric disorders, including major depressive disorder (MDD). Clinical data indicated that the probiotics have positive impacts on the central nervous system and thus may have a key role to treatment of MDD. This study examined the benefits of administration of Komagataella pastoris KM71H (8 log UFC·g-1/animal, intragastric route) in attenuating behavioral, neurochemical, and neuroendocrine changes in animal models of depressive-like behavior induced by repeated restraint stress and lipopolysaccharide (0.83 mg/kg). We demonstrated that pretreatment of mice with this yeast prevented depression-like behavior induced by stress and an inflammatory challenge in mice. We believe that this effect is due to modulation of the permeability of the blood-brain barrier, restoration in the mRNA levels of the Nuclear factor kappa B, Interleukin 1ß, Interferon γ, and Indoleamine 2 3-dioxygenase, and prevention of oxidative stress in the prefrontal cortices, hippocampi, and intestine of mice and of the decrease the plasma corticosterone levels. Thus, we conclude that K. pastoris KM71H has properties for a new proposal of probiotic with antidepressant-like effect, arising as a promising therapeutic strategy for MDD.

Effect of supplementation of medium with Bauhinia forficata recombinant lectins on expression of oxidative stress genes during in vitro maturation of bovine oocytes.

The lectin of Bauhinia forficata (nBfL) is a protein able to bind reversibly to N-acetylgalactosamine, performing several functions and one of them is the antiproliferative activity in tumor cells, but its effects have not yet been evaluated in female gametes. The objective of the present study was to determine the additional effect of B. forficata recombinants lectins in the medium of maturation in vitro of bovine oocytes in expression of genes related to oxidative stress pathways. To get the proteins, the gene for this recombinant lectin (rBfL) and its truncated isoform (rtBfL) were cloned and expressed in Escherichia coli (E.coli). The oocytes obtained through follicular puncture were incubated in IVM medium for 24 h containing concentrations of 10 µg/mL, 50 µg/mL and 100 µg/mL of nBfL, rBfL and rtBfL, and a no treated group as a control. In the groups treated with the concentration of 100 µg / mL, the gene expression of genes involved in oxidative stress SOD2, CAT, GPX-1, GSR, NOS2 and apoptosis BAX, CASP3 were evaluated. The rtBfL increased the expression of the SOD2, GSR and NOS2 genes and all the tested lectins increased the expression of the CASP3 gene compared to the control group. These findings indicate that the tested concentrations of the B. forficata recombinants lectins probably influence the expression of oxidative stress genes and increase the expression of the apoptotic gene CASP3 during in vitro maturation of bovine oocytes.

Neuroprotective Effect of 3-[(4-Chlorophenyl)selanyl]-1-methyl-1H-indole on Hydrogen Peroxide-Induced Oxidative Stress in SH-SY5Y Cells.

Extensive data have reported the involvement of oxidative stress in the pathogenesis of neuropsychiatric disorders, prompting the pursuit of antioxidant molecules that could become adjuvant pharmacological agents for the management of oxidative stress-associated disorders. The 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) has been reported as an antioxidant and immunomodulatory compound that improves depression-like behavior and cognitive impairment in mice. However, the exact effect of CMI on specific brain cells is yet to be studied. In this context, the present study aimed to evaluate the antioxidant activity of CMI in H2O2-induced oxidative stress on human dopaminergic neuroblastoma cells (SH-SY5Y) and to shed some light into its possible mechanism of action. Our results demonstrated that the treatment of SH-SY5Y cells with 4 µM CMI protected them against H2O2 (343 µM)-induced oxidative stress. Specifically, CMI prevented the increased number of reactive oxygen species (ROS)-positive cells induced by H2O2 exposure. Furthermore, CMI treatment increased the levels of reduced glutathione in SH-SY5Y cells. Molecular docking studies demonstrated that CMI might interact with enzymes involved in glutathione metabolism (i.e., glutathione peroxidase and glutathione reductase) and H2O2 scavenging (i.e., catalase). In silico pharmacokinetics analysis predicted that CMI might be well absorbed, metabolized, and excreted, and able to cross the blood-brain barrier. Also, CMI was not considered toxic overall. Taken together, our results suggest that CMI protects dopaminergic neurons from H2O2-induced stress by lowering ROS levels and boosting the glutathione system. These results will facilitate the clinical application of CMI to treat nervous system diseases associated with oxidative stress.

Synthesis and Antioxidant Activity of New Selenium-Containing Quinolines.

BACKGROUND: Quinoline derivatives have been attracted much attention in drug discovery, and synthetic derivatives of these scaffolds present a range of pharmacological activities. Therefore, organoselenium compounds are valuable scaffolds in organic synthesis because of their pharmacological activities and their use as versatile building blocks for regio-, chemo-and stereoselective reactions. Thus, the synthesis of selenium-containing quinolines has great significance, and their applicability range from simple antioxidant agents, to selective DNA-binding and photocleaving agents. OBJECTIVE: In the present study, we describe the synthesis and antioxidant activity in vitro of new 7- chloro-N(arylselanyl)quinolin-4-amines 5 by the reaction of 4,7-dichloroquinoline 4 with (arylselanyl)- amines 3. METHODS: For the synthesis of 7-chloro-N(arylselanyl)quinolin-4-amines 5, we performed the reaction of (arylselanyl)-amines 3 with 4,7-dichloroquinoline 4 in the presence of Et3N at 120 °C in a sealed tube. The antioxidant activities of the compounds 5 were evaluated by the following in vitro assays: 2,2- diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, 2,2-azinobis-3- ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric ion reducing antioxidant power (FRAP), nitric oxide (NO) scavenging and superoxide dismutase-like activity (SOD-Like). RESULTS: 7-Chloro-N(arylselanyl)quinolin-4-amines 5a-d have been synthesized in yields ranging from 68% to 82% by the reaction of 4,7-dichloroquinoline 4 with arylselanyl-amines 3a-d using Et3N as a base, at 120 °C, in a sealed tube for 24 hours and tolerates different substituents, such as -OMe and -Cl, in the arylselanyl moiety. The obtained compounds 5a-d presented significant results concerning the antioxidant potential, which had an effect in the tests of inhibition of radical's DPPH, ABTS+ and NO, as well as in the analysis that evaluates the capacity (FRAP) and in the superoxide dismutase-like activity assay (SOD-Like). It is worth mentioning that 7-chloro- N(arylselanyl)quinolin-4-amine 5b presented excellent results, demonstrating a better antioxidant capacity when compared to the others. CONCLUSION: According to the obtained results, 7-chloro-N(arylselanyl)quinolin-4-amines 5 were synthesized in good yields by the reaction of 4,7-dichloroquinoline with arylselanyl-amines and tolerated different substituents in the arylselanyl moiety. The tested compounds presented significant antioxidant potential in the tests of inhibition of DPPH, ABTS+, and NO radicals, as well as in the FRAP and superoxide dismutase-like activity assays (SOD-Like).

Antinociceptive and anti-inflammatory effects of 4-(arylchalcogenyl)-1H-pyrazoles containing selenium or sulfur.

BACKGROUND/OBJECTIVES: 4-(Arylchalcogenyl)-1H-pyrazoles containing selenium or sulfur (0.001-50 mg/kg) were investigated regarding the intragastric route effect (ig) administration on nociception in mice. In this study, nociception and inflammation were induced by chemical agents such as formalin (0.92%), sodium L-glutamate 1-hydrate (20 µmol), croton oil (2.5%), acetic acid (1.6%) and thermic model with a hot plate test. RESULTS: Compounds 1a-c had the ability to reduce licking time in both phases (neurogenic and inflammatory) of the formalin test and glutamate. Only compounds 1a and 1b had the ability to reduce the number of abdominal writhes caused by acetic acid. The same was observed with the positive control celecoxib. To evaluate the possible anti-inflammatory activity of compounds 1a-c, the induction of paw edema by formalin and ear edema by croton oil was performed. For the inflammation induced by formalin, significant effects were observed from the dose of 0.1 mg/kg (1a-b) and 10 mg/kg (1c). In the ear edema test, it can be observed that only compound 1a had a significant effect. In the hotplate test, all the compounds had the ability to reduce the latency time. CONCLUSION: The results demonstrated that acute antinociceptive and anti-inflammatory effects of 4-(arylchalcogenyl)-1H-pyrazoles 1a is better than compared with the compound 1b and 1c in mice. This resulted in these molecules attracting the interest of researchers to perform future studies to develop new drugs to treat pain and inflammatory clinical conditions.

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole promotes recovery of neuropathic pain and depressive-like behavior induced by partial constriction of the sciatic nerve in mice.

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole (CMI) is an organoselenium compound that presents antioxidant activity, antinociceptive, anti-inflammatory and antidepressive-like effect in mice in previous studies conducted by our research group. In this study, we evaluate the anti-allodynic, anti-hyperalgesic and antidepressant-like effects of CMI on partial sciatic nerve ligation (PSNL) in male adult Swiss mice (25-35 g) as well as the involvement of oxidative stress in these effects. Mice underwent PSNL surgery and after 4 weeks they were treated with CMI (10 mg/kg, intragastric route [i.g.]) or vehicle. The treatment with CMI (10 mg/kg, i.g.) reversed the increased the percentage of response to Von-Frey Hair (VFH) stimulation, decreased the latency time to nociceptive response in the hot-plate test, increased immobility time in the forced swimming test (FST) and decreased groomings activity in the splash test, all induced by PSNL. Additionally, CMI also reversed increased the levels of reactive oxygen species (ROS) and lipid peroxidation in cortex and hippocampus and plasmatic levels of corticosterone in mice, induced by PSNL. Results demonstrate that CMI reversed behavioral and biochemical alterations in the dyad pain-depression induced by PSNL and possibly modulation of oxidative system.

3-(4-Chlorophenylselanyl)-1-methyl-1H-indole, a new selenium compound elicits an antinociceptive and anti-inflammatory effect in mice.

Several pathologies, such as pain and inflammation, are modulated by different pathways, making it necessary to develop drugs capable of modulating different pathways. Based on that, we investigated the antinociceptive and anti-inflammatory effect of 3-(4-chlorophenylselanyl)-1-methyl-1H-indole (CMI), as well as the systems involved in these actions. This study evaluated the antinociceptive and anti-inflammatory effects of CMI [0.0001-10 mg/kg administered intragastrically (i.g.)] in the formalin, glutamate, hot plate, ear edema induced by croton oil and paw edema induced by formalin tests. In addition, to investigate the mechanism of action, mice were pre-treated with antagonists of adenosinergic, monoaminergic and opioid systems before administration of CMI. The selenium-containing compound decreased the paw licking and biting time in the formalin and glutamate tests, increased the response latency in hot plate test, without ambulatory changes, evaluated in the open field test. CMI was able to reduce both paw and ear edema induced by formalin and croton oil, respectively. Additionally the antinociceptive effect of CMI (0.01 mg/kg) was blocked when mice were pretreated with the antagonists: SCH23390 [D1-receptor antagonist, 0.05 mg/kg, intraperitoneally (i.p.)], WAY100635 (5-HT1A-receptor antagonist, 0.7 mg/kg, i.p.), ondansetron (5-HT3-receptor antagonist, 0.5 mg/kg, i.p.), ketanserin (5-HT2A/2C-receptor antagonist, 0.3 mg/kg, i.p.), naloxone (non-selective antagonist 1 mg/kg, i.p.), caffeine (non-selective antagonist, 3 mg/kg, i.p.) and prazosin (α1-receptor antagonist, 0.15 mg/kg, i.p). These results demonstrate that the antinociceptive effect of CMI is mediated by monaminergic, opioidergic and adenosinergic modulations and can be a promising molecule capable of modulating different pathways for the treatment of pain and inflammation.

Contribution of dopaminergic and noradrenergic systems in the antinociceptive effect of α-(phenylalanyl) acetophenone.

BACKGROUND: This study evaluated the antinociceptive action of α-(phenylalanyl) acetophenone (PSAP) in mice. METHODS: Evaluated whether the serotonergic, adrenergic and dopaminergic systems are involved in PSAP antinociceptive activity. PSAP was administered intragastrically (ig) 30min prior to formalin or glutamate test and compared with a standard drug, meloxicam (10mg/kg, ig). RESULTS: The treatment with PSAP (10-50mg/kg) caused inhibition in the neurogenic phase and reduced the paw oedema caused by intraplantar (ipl) injection of formalin. PSAP (1-50mg/kg) decreased the nociceptive response in the inflammatory phase of the formalin test and in licking behaviour triggered by glutamate at doses of 0.1-50mg/kg. The antinociceptive effect of PSAP (1mg/kg) was abolished when the animals were pre-treated with prazosin (α1-adrenergic antagonist receptor, 0.15mg/kg, intraperitoneally, ip), yohimbine (α2-adrenergic antagonist receptor, 1mg/kg, ip) and sulpiride (D2/D3 dopamine antagonist, 5mg/kg, ip). The antinociceptive effect of PSAP (1mg/kg) was not abolished by WAY100635 (5-HT1A-selective serotoninergic antagonist, 0.7mg/kg, ip), ketanserin (selective antagonist of serotonergic 5-HT2A/2C, 0.3mg/kg, ip), ondansetron (5-HT3 selective serotoninergic antagonist, 0.5mg/kg, ip) or SCH23390 (D1 dopamine receptor antagonist, 0.05mg/kg, ip) in the glutamate test. No changes in locomotor activity were observed in the animals treated with PSAP and/or antagonists in the open field test. CONCLUSION: These results showed the antinociceptive action of PSAP in formalin and glutamate tests and the involvement of the dopaminergic and adrenergic systems in its antinociceptive activity.