Background
GPR18 is a recently deorphanized receptor which was reported to act with several endogenous cannabinoid ligands. Here, we aimed to describe the role of GPR18 in intestinal inflammation and ...inflammatory pain.
Methods
The anti‐inflammatory activity of selective GPR18 agonist, PSB‐KK‐1415, and antagonist, PSB‐CB5, was characterized in semi‐chronic and chronic mouse models of colitis induced by 2,4,6‐trinitrobenzenesulfonic acid (TNBS). The extent of inflammation was evaluated based on the macroscopic and microscopic scores, quantification of myeloperoxidase (MPO) activity, and Western blot analyses of tumor necrosis factor‐α (TNF‐α) and interleukin‐6 in colonic tissue. The expression of GPR18 in colonic samples from patients with Crohn's disease (CD) was quantified using real‐time PCR. The anti‐nociceptive potential of the agonist in intestinal inflammation was evaluated in the mouse model of inflammatory pain.
Key Results
In semi‐chronic colitis, PSB‐KK‐1415 reduced macroscopic score (1.79 ± 0.22 vs. 2.61 ± 0.48), expression of TNF‐α (1.89 ± 0.36 vs. 2.83 ± 0.64), and microscopic score (5.00 ± 0.33 vs. 6.45 ± 0.40), all compared to mice with colitis. In chronic colitis, PSB‐KK‐1415 decreased macroscopic score (3.33 ± 1.26 vs. 4.00 ± 1.32) and MPO activity (32.23 ± 8.51 vs. 41.33 ± 11.64) compared to inflamed mice. In the mouse model of inflammatory pain, PSB‐KK‐1415 decreased the number of pain‐induced behaviors in both, controls (32.60 ± 2.54 vs. 58.00 ± 6.24) and inflamed mice (60.83 ± 2.85 vs. 85.00 ± 5.77) compared to animals without treatment with PSB‐KK‐1415 (P < 0.005 for both). Lastly, we showed an increased expression of GPR18 in CD patients compared to healthy controls (3.77 ± 1.46 vs. 2.38 ± 0.66, p = 0.87).
Conclusions & Inferences
We showed that GPR18 is worth considering as a potential treatment target in intestinal inflammation and inflammatory pain.
A recently deorphanized receptor, GPR18 showed to act with several endogenous cannaboinoid ligands. Among several potent functionalities the receptor activation also leads to the induction of anti‐infammatory and antinociceptive action. By using highly selective agonist of GPR18, PSB‐KK‐1415 we achieved an inflammation alleviation in two mouse models of colitis and a reduction in pain‐induced behaviors in mouse model of inflammatory pain.
Full text
Available for:
DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The histaminergic system is a promising target for the development of new analgesics, as histamine H
and H
receptors are expressed in regions concerned with nociceptive transmission. Here we have ...determined the analgesic effects of new H
and H
receptor antagonists in naive and neuropathic mice.
We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effects of a new H
receptor antagonist, E-162(1-(5-(naphthalen-1-yloxy)pentyl)piperidine) and H
receptor antagonist, TR-7(4-(4-chlorophenyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine) were assessed on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli in mice with and without CCI (7 days after injury). Effects of these antagonists on morphine analgesia were also evaluated, along with the possible participation of H
receptors in their effects. We analysed the compounds in binding and functional cAMP assays at the H
and H
receptors and determined metabolic stability.
E-162 and TR-7 attenuated nociceptive responses and profound morphine analgesia in males with CCI. These antagonists showed analgesia in naive mice (tail flick test) and produced prolonged analgesia in neuropathic females. E-162-induced analgesia was reversed by pyrilamine, an H
receptor antagonist. E-162 bound potently to H
receptors (K
= 55 nM) and inhibited cAMP accumulation (IC
= 165 nM). TR-7 showed lower affinity for H
receptors (K
= 203 nM) and IC
of 512 nM.
We describe a therapeutic use for new H
(E-162) and H
receptor (TR-7) antagonists in neuropathy. Targeting H
and H
receptors enhanced morphine analgesia, consistent with multimodal pain therapy.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The resolution of inflammation is the primary domain of specialised pro-resolving mediators (SPMs), which include resolvins, protectins, and their forms synthesised under the influence of aspirin and ...the maresins. The role of these SPMs has been discussed by many authors in the literature, with particular reference to neuroinflammation and significant neurological disorders. This review discusses the role of G protein-coupled receptor 18 (GPR18), resolvin D2 (RvD2) activity, and the GPR18-RvD2 signalling axis, as well as the role of small molecule ligands of GPR18 in inflammation in various health disorders (brain injuries, neuropathic pain, neurodegenerative/cardiometabolic/cardiovascular/gastrointestinal diseases, peritonitis, periodontitis, asthma and lung inflammation, Duchenne muscular dystrophy, SARS-CoV-2-induced inflammation, and placenta disorders. The idea of biological intervention through modulating GPR18 signalling is attracting growing attention because of its great therapeutic potential. With this paper, we aimed to present a comprehensive review of the most recent literature, perform a constructive view of data, and point out research gaps.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
GPR18 receptor protein was detected in the heart and vasculature and appears to play a functional role in the cardiovascular system. We investigated the effects of the new GPR18 agonists PSB-MZ-1415 ...and PSB-MZ-1440 and the new GPR18 antagonist PSB-CB-27 on isolated human pulmonary arteries (hPAs) and compared their effects with the previously proposed, but unconfirmed, GPR18 ligands NAGly, Abn-CBD (agonists) and O-1918 (antagonist). GPR18 expression in hPAs was shown at the mRNA level. PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD fully relaxed endothelium-intact hPAs precontracted with the thromboxane A
analog U46619. PSB-CB-27 shifted the concentration-response curves (CRCs) of PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD to the right; O-1918 caused rightward shifts of the CRCs of PSB-MZ-1415 and NAGly. Endothelium removal diminished the potency and the maximum effect of PSB-MZ-1415. The potency of PSB-MZ-1415 or NAGly was reduced in male patients, smokers and patients with hypercholesterolemia. In conclusion, the novel GPR18 agonists, PSB-MZ-1415 and PSB-MZ-1440, relax hPAs and the effect is inhibited by the new GPR18 antagonist PSB-CB-27. GPR18, which appears to exhibit lower activity in hPAs from male, smoking or hypercholesterolemic patients, may become a new target for the treatment of pulmonary arterial hypertension.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Antimicrobial resistance (AMR) represents a hot topic in drug discovery. Besides the identification of new antibiotics, the use of nonantibiotic molecules to block resistance mechanisms is a powerful ...alternative. Bacterial efflux pumps exert an early step in AMR development by allowing bacteria to grow at subinhibitorial drug concentrations. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR. Given our experience in developing Staphylococcus aureus NorA EPIs, in this work, starting from the 2-phenylquinoline hit 1, we planned the introduction of methoxy groups on the basis of their presence in known NorA EPIs. Among the 35 different synthesized derivatives, compounds 3b and 7d exhibited the best NorA inhibition activity by restoring at very low concentrations ciprofloxacin MICs against resistant S. aureus strains. Interestingly, both compounds displayed EPI activities at nontoxic concentrations for human cells as well as highlighted promising results by preliminary pharmacokinetic studies.
The human orphan G protein-coupled receptor GPR18, activated by Δ9-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However, studies on GPR18 are hampered by ...the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in β-arrestin recruitment assays. Structure–activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Compound 51 (PSB-KK1415, EC50 19.1 nM) was the most potent GPR18 agonist showing at least 25-fold selectivity versus CB receptors. The most selective GPR18 agonist 50 (PSB-KK1445, EC50 45.4 nM) displayed >200-fold selectivity versus both CB receptor subtypes, GPR55, and GPR183. The new GPR18 agonists showed minimal species differences, while THC acted as a weak partial agonist at the mouse receptor. The newly discovered compounds represent the most potent and selective GPR18 agonists reported to date.
Background and Purpose
The histaminergic system is a promising target for the development of new analgesics, as histamine H3 and H4 receptors are expressed in regions concerned with nociceptive ...transmission. Here we have determined the analgesic effects of new H3 and H4 receptor antagonists in naive and neuropathic mice.
Experimental Approach
We used chronic constriction injury (CCI) to the sciatic nerve in mice to model neuropathy. Effects of a new H3 receptor antagonist, E‐162(1‐(5‐(naphthalen‐1‐yloxy)pentyl)piperidine) and H4 receptor antagonist, TR‐7(4‐(4‐chlorophenyl)‐6‐(4‐methylpiperazin‐1‐yl)‐1,3,5‐triazin‐2‐amine) were assessed on mechanical (von Frey) and thermal (cold plate, tail flick) stimuli in mice with and without CCI (7 days after injury). Effects of these antagonists on morphine analgesia were also evaluated, along with the possible participation of H1 receptors in their effects. We analysed the compounds in binding and functional cAMP assays at the H3 and H4 receptors and determined metabolic stability.
Key Results
E‐162 and TR‐7 attenuated nociceptive responses and profound morphine analgesia in males with CCI. These antagonists showed analgesia in naive mice (tail flick test) and produced prolonged analgesia in neuropathic females. E‐162‐induced analgesia was reversed by pyrilamine, an H1 receptor antagonist. E‐162 bound potently to H3 receptors (Ki = 55 nM) and inhibited cAMP accumulation (IC50 = 165 nM). TR‐7 showed lower affinity for H4 receptors (Ki = 203 nM) and IC50 of 512 nM.
Conclusions and Implications
We describe a therapeutic use for new H3 (E‐162) and H4 receptor (TR‐7) antagonists in neuropathy. Targeting H3 and H4 receptors enhanced morphine analgesia, consistent with multimodal pain therapy.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted/repetitive behavior patterns or interests. Antagonists targeting ...histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15 mg/kg, i.p.) on sociability, social novelty, anxiety, and aggressive/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15 mg/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15 mg/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15 mg/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1 mg/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15 mg/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1β, IL-6 and TNF-α exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study demonstrated the anticancer efficacy of chalcones with indole moiety (MIPP, MOMIPP) in fibrosarcoma cells for the first time. The results showed that MIPP and MOMIPP reduced the viability ...of HT-1080 cells in a concentration-dependent manner. MOMIPP was more active than MIPP in HT-1080 cells, showing lower IC50 values (3.67 vs. 29.90 μM). Both compounds at a concentration of 1 μM induced apoptosis in HT-1080 cells, causing death strictly related to caspase activation, as cell viability was restored when the caspase inhibitor Z-VAD was added. Reactive oxygen species production was approximately 3-fold higher than in control cells, and cotreatment with the inhibitor of mitochondrial ATPase oligomycin diminished this effect. Such effects were also reflected in mitochondrial dysfunction, including decreased membrane potential. Interestingly, the compounds that were studied caused massive vacuolization in HT-1080 cells. Immunocytochemical staining and TEM analysis showed that HT-1080 cells exhibited increased expression of the LC3-II protein and the presence of autophagosomes with a double membrane, respectively. Both compounds induced apoptosis, highlighting a promising link between autophagy and apoptosis. This connection could be a new target for therapeutic strategies to overcome chemoresistance, which is a significant cause of treatment failure and tumour recurrence in fibrosarcoma following traditional chemotherapy.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
► Global bacterial regulators control the expression of transport mechanisms including influx (porins) and efflux (pumps) ► They conjointly contribute to the membrane barrier, the first line of ...bacterial defense against antibacterial agents. ► Increasing the antibiotic influx and blocking the efflux improve the intracellular concentration of antibiotics. ► Various strategies bypassing the membrane barrier can restore the activity of antibiotics against resistant bacteria.
In Gram-negative bacteria, the envelope is a sophisticated barrier protecting the cell against external toxic compounds. Membrane transporters, e.g., porins or efflux pumps, are main filters regulating the internal accumulation of various hydrophilic molecules.
Regarding bacterial susceptibility towards antibacterial agents, membrane permeability is part of the early bacterial defense. The bacterium manages the translocation process, influx and efflux, to control the intracellular concentration of various molecules. Antibiotics and biocides are substrates of these mechanisms and the continuing emergence of multidrug resistant isolates is a growing worldwide health concern. Different strategies could be proposed to bypass the bacterial membrane barrier, comprising influx and efflux mechanisms, in order to restore the activity of antibiotics against resistant bacteria.
Full text
Available for:
BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
