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BackgroundAlpha 7 nicotinic acetylcholine receptor (α7nAChR) agonists have been developed to treat schizophrenia but failed in clinical trials due to rapid desensitization. GAT107, a type 2 allosteric agonist-positive allosteric modulator (ago-PAM) to the α7 nAChR was designed to activate the α7 nAChR while reducing desensitization. We hypothesized GAT107 would alter the activity of thalamocortical neural circuitry associated with cognition, emotion, and sensory perception.MethodsThe present study used pharmacological magnetic resonance imaging (phMRI) to evaluate the dose-dependent effect of GAT107 on brain activity in awake male rats. Rats were given a vehicle or one of three different doses of GAT107 (1, 3, and 10 mg/kg) during a 35 min scanning session. Changes in BOLD signal and resting state functional connectivity were evaluated and analyzed using a rat 3D MRI atlas with 173 brain areas.ResultsGAT107 presented with an inverted-U dose response curve with the 3 mg/kg dose having the greatest effect on the positive BOLD volume of activation. The primary somatosensory cortex, prefrontal cortex, thalamus, and basal ganglia, particularly areas with efferent connections from the midbrain dopaminergic system were activated as compared to vehicle. The hippocampus, hypothalamus, amygdala, brainstem, and cerebellum showed little activation. Forty-five min post treatment with GAT107, data for resting state functional connectivity were acquired and showed a global decrease in connectivity as compared to vehicle.DiscussionGAT107 activated specific brain regions involved in cognitive control, motivation, and sensory perception using a BOLD provocation imaging protocol. However, when analyzed for resting state functional connectivity there was an inexplicable, general decrease in connectivity across all brain areas.

Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5–5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current drug treatments are only partially effective and adverse side effects have spurred research into alternative treatment approaches. Recent research shows that positive allosteric modulation of the type-1 cannabinoid receptor (CB1R) reduces the frequency and duration of SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model that recapitulates the SWDs in CAE. Here, we tested additional CB1R ago-PAMs, GAT591 and GAT593, for their potential in alleviating SWD activity in GAERS. In vitro experiments confirm that GAT591 and GAT593 exhibit increased potency and selectivity in cell cultures and behave as CB1R allosteric agonists and PAMs. To assess drug effects on SWDs, bilateral electrodes were surgically implanted in the somatosensory cortices of male GAERS and EEGs recorded for 4 h following systemic administration of GAT591 or GAT593 (1.0, 3.0 and 10.0 mg/kg). Both GAT591 and GAT593 dose-dependently reduced total SWD duration during the recording period. The greatest effect on SWD activity was observed at 10.0 mg/kg doses, with GAT591 and GAT593 reducing seizure duration by 36% and 34% respectively. Taken together, these results support the continued investigation of CB1R PAMs as a potential therapeutic to alleviate SWDs in absence epilepsy.

Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo. The R-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro, and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington’s disease.

Abstract Background The α7 nicotinic acetylcholine receptor (α7 nAChR) negatively regulates the synthesis and release of pro-inflammatory cytokines by immune cells. Our previous studies showed that in encephalitogenic T cells, α7 nAChR expression is upregulated and that activation of the cholinergic system can attenuate experimental autoimmune encephalomyelitis (EAE). GAT107 is an allosteric agonist and positive allosteric modulator (ago-PAM) of α7 nAChR that can produce persistent activation of this receptor. Therefore, in the present study, we investigated the effect of GAT107 on neuroinflammation in EAE, the animal model used for the study of multiple sclerosis (MS) via α7 nAChR, and the inflammatory pathways involved. Methods EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35–55) in C57BL/6 mice. EAE mice were treated with the ago-PAM GAT107 or a placebo for 9 days, starting from the day of EAE induction. Clinical assessment and immunological evaluation of immune cells and cytokine production was performed. Results Following activation of the α7 nAChR by GAT107 during EAE, disease severity was significantly reduced by 70% and was correlated with a reduction in the extent of neuroinflammation in the CNS. The treatment reduced encephalitogenic T cell proliferation and the production of pro-inflammatory cytokines, as well as increased the production of the anti-inflammatory cytokine IL-10. Furthermore, the expression of immune cell markers was altered by GAT107 treatment, which induced a significant reduction in macrophages, dendritic cells, and B cells, as well as a reduction in anti-MOG35–55 antibodies. Additionally, GAT107 was found to directly activate α7 nAChR in murine macrophage RAW264.7 cells and in human PBMCs derived from MS patients and healthy donors. Conclusions Our results show that GAT107 can be a useful molecule for harnessing the cholinergic anti-inflammatory pathway for long-lasting and wide-ranging modulation and downregulation of neuroinflammation in EAE.

Abstract The CB2R agonist AM1710, examined in animal models of peripheral neuropathy, is effective in controlling aberrant light touch sensitivity, referred to as mechanical allodynia. However, nonspecific binding of AM1710 to CB1R, either peripherally or centrally, could be partially responsible for the analgesic effects of AM1710. Thus, we sought to determine in mice whether spinal (intrathecal; i.t.) or peripheral AM1710 administration could lead to anti‐allodynia by reducing the protein expression of spinal and dorsal root ganglia (DRG) proinflammatory cytokines and elevating the anti‐inflammatory cytokine interleukin‐10 (IL‐10) in the absence of CB1R. Macrophage cell cultures were examined to characterize AM1710‐mediated suppression of the proinflammatory cytokine tumor necrosis factor‐alpha (TNF‐α). Either i.p. or i.t. AM1710 reversed CCI‐induced mechanical allodynia to sham levels in CB1R (−/−), (+/−), (+/+) mice. CCI‐induced neuropathy decreased IL‐10 immunoreactivity (IR) in the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord, with i.t. AM1710 restoring basal IL‐10 IR. CCI‐induced elevations in proinflammatory cytokine IR were decreased within the spinal cord only after i.t. AM1710 in all mouse genotypes. Meanwhile, within DRG tissue from neuropathic mice, proinflammatory cytokines were decreased following either i.p. or i.t. AM1710. Analysis of cultured supernatants revealed AM1710 decreased TNF‐alpha protein. We conclude that CB1R is dispensable for either peripheral or central anti‐allodynic actions of AM1710 in neuropathic mice. Cannabinoid CB2R agonists produce heightened spinal IL‐10 which may be clinically relevant to successfully treat neuropathic pain.

Opioid analgesics represent a critical treatment for chronic pain in the analgesic ladder of the World Health Organization. However, their use can result in a number of unwanted side-effects including incomplete efficacy, constipation, physical dependence, and overdose liability. Cannabinoids enhance the pain-relieving effects of opioids in preclinical studies and dampen unwanted side-effects resulting from excessive opioid intake. We recently reported that a CB1 positive allosteric modulator (PAM) exhibits antinociceptive efficacy in models of pathological pain and lacks the adverse side effects of direct CB1 receptor activation. In the present study, we evaluated whether a CB1 PAM would enhance morphine’s therapeutic efficacy in an animal model of chemotherapy-induced neuropathic pain and characterized its impact on unwanted side-effects associated with chronic opioid administration. In paclitaxel-treated mice, both the CB1 PAM GAT211 and the opioid analgesic morphine reduced paclitaxel-induced behavioral hypersensitivities to mechanical and cold stimulation in a dose-dependent manner. Isobolographic analysis revealed that combinations of GAT211 and morphine resulted in anti-allodynic synergism. In paclitaxel-treated mice, a sub-threshold dose of GAT211 prevented the development of tolerance to the anti-allodynic effects of morphine over 20 days of once daily dosing. However, GAT211 did not reliably alter somatic withdrawal signs (i.e., jumps, paw tremors) in morphine-dependent neuropathic mice challenged with naloxone. In otherwise naïve mice, GAT211 also prolonged antinociceptive efficacy of morphine in the tail-flick test and reduced the overall right-ward shift in the ED50 for morphine to produce antinociception in the tail-flick test, consistent with attenuation of morphine tolerance. Pretreatment with GAT211 did not alter somatic signs of μ opioid receptor dependence in mice rendered dependent upon morphine via subcutaneous implantation of a morphine pellet. Moreover, GAT211 did not reliably alter μ-opioid receptor-mediated reward as measured by conditioned place preference to morphine. Our results suggest that a CB1 PAM may be beneficial in enhancing and prolonging the therapeutic properties of opioids while potentially sparing unwanted side-effects (e.g., tolerance) that occur with repeated opioid treatment.

In addition to its known actions as a non-selective cyclooxygenase (COX) 1 and 2 inhibitor, we hypothesized that indomethacin can act as an allosteric modulator of the type 1 cannabinoid receptor (CB1R) because of its shared structural features with the known allosteric modulators of CB1R. Indomethacin enhanced the binding of [3H]CP55940 to hCB1R and enhanced AEA-dependent [35S]GTPγS binding to hCB1R in Chinese hamster ovary (CHO) cell membranes. Indomethacin (1 μM) also enhanced CP55940-dependent βarrestin1 recruitment, cAMP inhibition, ERK1/2 and PLCβ3 phosphorylation in HEK293A cells expressing hCB1R, but not in cells expressing hCB2R. Finally, indomethacin enhanced the magnitude and duration of CP55940-induced hypolocomotion, immobility, hypothermia, and anti-nociception in C57BL/6J mice. Together, these data support the hypothesis that indomethacin acted as a positive allosteric modulator of hCB1R. The identification of structural and functional features shared amongst allosteric modulators of CB1R may lead to the development of novel compounds designed for greater CB1R or COX selectivity and compounds designed to modulate both the prostaglandin and endocannabinoid systems.

Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% O2) is a life-saving intervention for patients experiencing respiratory distress. However, prolonged exposure to hyperoxia can compromise bacterial clearance processes, due to oxidative stress-mediated impairment of macrophages, contributing to the increased susceptibility to pulmonary infections. This study reports that the activation of the α7 nicotinic acetylcholine receptor (α7nAChR) with the delete allosteric agonistic-positive allosteric modulator, GAT107, decreases the bacterial burden in mouse lungs by improving hyperoxia-induced lung redox imbalance. The incubation of RAW 264.7 cells with GAT107 (3.3 µM) rescues hyperoxia-compromised phagocytic functions in cultured macrophages, RAW 264.7 cells, and primary bone marrow-derived macrophages. Similarly, GAT107 (3.3 µM) also attenuated oxidative stress in hyperoxia-exposed macrophages, which prevents oxidation and hyper-polymerization of phagosome filamentous actin (F-actin) from oxidation. Furthermore, GAT107 (3.3 µM) increases the (1) activity of superoxide dismutase 1; (2) activation of Nrf2 and (3) the expression of heme oxygenase-1 (HO-1) in macrophages exposed to hyperoxia. Overall, these data suggest that the novel α7nAChR compound, GAT107, could be used to improve host defense functions in patients, such as those with COVID-19, who are exposed to prolonged periods of hyperoxia.

Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury. We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia. Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2−/−) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ8-tetrahydrocannabinol (Δ8-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation. Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ8-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2−/− mice. Two percent GAT228, or the combination of 0.2% Δ8-THC with 0.5% GAT229 also significantly reduced corneal inflammation. CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.

The existence of propane (C3H8) in a CO2-oil mixture has great potential for increasing CO2 solubility and decreasing minimum miscibility pressure (MMP). In this study, the enhanced solubility, reduced viscosity, and lowered MMP of CO2-saturated crude oil in the presence of various amounts of C3H8 have been systematically examined at the reservoir conditions. Experimentally, a piston-equipped pressure/volume/temperature (PVT) cell is first validated by accurately reproducing the bubble-point pressures of the pure component of C3H8 at temperatures of 30, 40, and 50 °C with both continuous and stepwise depressurization methods. The validated cell is well utilized to measure the saturation pressures of the CO2-C3H8-oil systems by identifying the turning point on a P-V diagram at a given temperature. Accordingly, the gas solubilities of a CO2, C3H8, and CO2-C3H8 mixture in crude oil at pressures up to 1600 psi and a temperature range of 25–50 °C are measured. In addition, the viscosity of gas-saturated crude oil in a single liquid phase is measured using an in-line viscometer, where the pressure is maintained to be higher than its saturation pressure. Theoretically, a modified Peng–Robinson equation of state (PR EOS) is utilized as the primary thermodynamic model in this work. The crude oil is characterized as both a single and multiple pseudo-component(s). An exponential distribution function, together with a logarithm-type lumping method, is applied to characterize the crude oil. Two linear binary interaction parameters (BIP) correlations have been developed for CO2-oil binaries and C3H8-oil binaries to accurately reproduce the measured saturation pressures. Moreover, the MMPs of the CO2-oil mixture in the presence and absence of C3H8 have been determined with the assistance of the tie-line method. It has been found that the developed mathematical model can accurately calculate the saturation pressures of C3H8 and/or CO2-oil systems with an absolute average relative deviation (AARD) of 2.39% for 12 feed experiments. Compared to CO2, it is demonstrated that C3H8 is more soluble in the crude oil at the given pressure and temperature. The viscosity of gas-saturated crude oil can decrease from 9.50 cP to 1.89 cP and the averaged MMP from 1490 psi to 1160 psi at 50 °C with the addition of an average 16.02 mol% C3H8 in the CO2-oil mixture.

This paper presents a comprehensive analysis of water injection management practices for complex and impactful onshore and offshore carbonate reservoirs. It delves into the fundamental aspects of waterflooding design, surveillance techniques, and monitoring methods tailored for the unique challenges posed by carbonate formations. Two case studies from the Permian Basin in Texas and two from Lula Field offshore Brazil and Agbami Field offshore Nigeria are examined considering scientific principles into practice to provide insights into best practices, lessons learned, and strategies to maximize the benefits derived from real noteworthy waterflood operations. The paper underscores the significance of rigorous reservoir characterization, including understanding reservoir architecture, heterogeneities, fracture networks, fluid communication pathways, and rock–fluid interactions. It emphasizes the crucial role of integrated multidisciplinary teams involving geologists, reservoir engineers, production engineers, and field operators in ensuring successful waterflood design, implementation, and optimization. Through the case studies, the paper highlights the importance of designing pattern configurations, well placements, and injection/production strategies to the specific reservoir characteristics, continually optimizing these elements based on surveillance data. It also stresses the necessity of comprehensive data acquisition, advanced analytics, numerical simulations, and frequent model updates for effective reservoir management and decision-making. The paper is impactful in terms of the lessons learned from the actual case studies, and how can these be implemented in actual field projects. Different case studies documented in the paper provide the challenges facing them and how different authors have addressed their problems in unique ways. The paper distills the information and important findings from a variety of case studies and provides succinct information that is of immense value as a reference. Important findings of these case studies are connected using creativity and are innovative as they introduce unique techniques and establish successful ideas to create new value in terms of maximizing oil recovery. Most importantly, this paper explores the application of innovative technologies, such as intelligent completions, 4D seismic monitoring, and water–alternating gas (WAG) injection, which can significantly improve waterflood performance in complex carbonate reservoirs. In summary, the paper provides a thorough understanding of the factors contributing to the success and failure of waterfloods in carbonate reservoirs through case studies based on factually and technically sound operations. It documents guidelines for optimizing waterflood performance and reducing or eliminating the potential for failures, reinforcing positive results in these challenging yet invaluable hydrocarbon resources.

The urgent need to find mitigating pathways for limiting world CO2 emissions to net zero by 2050 has led to intense research on CO2 sequestration in deep saline reservoirs. This paper reviews key advancements in lab- and simulation-scale research on petrophysical, geochemical, and mineralogical changes during CO2–brine–rock interactions performed in the last 25 years. It delves into CO2 MPD (mineralization, precipitation, and dissolution) and explores alterations in petrophysical properties during core flooding and in static batch reactors. These properties include changes in wettability, CO2 and brine interfacial tension, diffusion, dispersion, CO2 storage capacity, and CO2 leakage in caprock and sedimentary rocks under reservoir conditions. The injection of supercritical CO2 into deep saline aquifers can lead to unforeseen geochemical and mineralogical changes, possibly jeopardizing the CCS (carbon capture and storage) process. There is a general lack of understanding of the reservoir’s interaction with the CO2 phase at the pore/grain scale. This research addresses the gap in predicting the long-term changes of the CO2–brine–rock interaction using various geochemical reactive transport simulators. Péclet and Damköhler numbers can contribute to a better understanding of geochemical interactions and reactive transport processes. Additionally, the dielectric constant requires further investigation, particularly for pre- and post-CO2–brine–rock interactions. For comprehensive modeling of CO2 storage over various timescales, the geochemical modeling software called the Geochemist’s Workbench was found to outperform others. Wettability alteration is another crucial aspect affecting CO2–brine–rock interactions under varying temperature, pressure, and salinity conditions, which is essential for ensuring long-term CO2 storage security and monitoring. Moreover, dual-energy CT scanning can provide deeper insights into geochemical interactions and their complexities.

In this research, a non-fragile synchronization of bidirectional association memory (BAM) delayed neural networks is taken into consideration. The controller gain fluctuation seems in a very random manner, that obeys sure Bernoulli distributed noise sequences. Delay dependent criteria are derived to confirm the asymptotic stability of the BAM delayed neural networks. The non-fragile controller are often obtained by determination a collection of linear matrix inequalities (LMIs). A simulation example is used to demonstrate the efficiency of the developed control.

The current RF (recovery factor) of the subject reservoir is

This article, we explore the stability analysis of stochastic fractional-order competitive neural networks with leakage delay. The main objective of this paper is to establish a new set of sufficient conditions, which is for the uniform stability in mean square of such stochastic fractional-order neural networks with leakage. Specifically, the presence and uniqueness of arrangements and stability in mean square for a class of stochastic fractional-order neural systems with delays are concentrated by using Cauchy-Schwartz inequality, Burkholder-Davis-Gundy inequality, Banach fixed point principle and stochastic analysis theory, respectively. Finally, four numerical recreations are given to confirm the hypothetical discoveries.

This study investigates the problem of finite-time boundedness of a class of neural networks of Caputo fractional order with time delay and uncertain terms. New sufficient conditions are established by constructing suitable Lyapunov functionals to ensure that the addressed fractional-order uncertain neural networks are finite-time stable. Criteria for finite-time boundedness of the considered fractional-order uncertain models are also achieved. The obtained results are based on a newly developed property of Caputo fractional derivatives, properties of Mittag–Leffler functions and Laplace transforms. In addition, examples are developed to manifest the usefulness of our theoretical results.

The problem of finite-time stability of switched genetic regulatory networks (GRNs) with time-varying delays via Wirtinger’s integral inequality is addressed in this study. A novel Lyapunov–Krasovskii functional is proposed to capture the dynamical characteristic of GRNs. Using Wirtinger’s integral inequality, reciprocally convex combination technique and the average dwell time method conditions in the form of linear matrix inequalities (LMIs) are established for finite-time stability of switched GRNs. The applicability of the developed finite-time stability conditions is validated by numerical results.

In an attempt to further investigate the role of cannabinoid (CB) system in the pathogenesis of inflammatory bowel diseases, we employed two recently developed ligands, AM841 (a covalently acting CB agonist) and CB13 (a peripherally-restricted CB agonist) to establish whether central and peripheral CB sites are involved in the anti-inflammatory action in the intestine.AM841 (0.01, 0.1 and 1 mg/kg, i.p.) significantly decreased inflammation scores in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-treated mice when administered before induction of colitis or as a treatment of existing intestinal inflammation. The effect was absent in CB1, CB2 and CB(1/2)-deficient mice. A peripherally-restricted agonist CB13 did not alleviate colitis when given i.p. (0.1 mg/kg), but significantly decreased inflammation score after central administration (0.1 µg/animal).This is the first evidence that central and peripheral CB receptors are responsible for the protective and therapeutic action of cannabinoids in mouse models of colitis. Our observations provide new insight to CB pharmacology and validate the use of novel ligands AM841 and CB13 as potent tools in CB-related research.