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With more than 200,000 cases per year, Rheumatoid Arthritis (RA) is one of the most common autoimmune disorders in the United States. Across the globe, up to 14 million people are affected by its symptoms of joint pain, stiffness, swelling, fatigue, and even physical deformity. Rheumatoid factors (RF) are autoantibodies that correlate with RA severity and recognize epitopes in the Fc region of its antigen immunoglobulin (Ig) G, yet it is paradoxically found circulating in the blood alongside the antigen without binding to it. According to Thomsen, et. al, a 2018 study that contested the idea of IgG aggravation as the prerequisite to RF binding, the native state of IgG is present in a closed form, where the Fab fragment shields the Fc region, only exposing the Fc effector sites when a conformational change is induced. This closed form is a result of a missing galactose between the C□2 domains of the heavy chains, thus causing the IgG to self associate, forming immune complexes to fix the complement system. The subsequent heightened inflammatory response exacerbates the progression of joint damage in RA and other severe symptoms. In this study, we examined RF in relation to IgG forming immune complexes to achieve a better understanding of the immunological progression or pathogenesis of RA. The Mahtomedi MSOE Center for BioMolecular Modeling MAPS Team used 3-D modeling and printing technology to examine structure-function relationships of Fab and Fc fragments in IgG. The visual model will be a valuable tool in developing our story.
Learn More >Epoxyeicosatrienoic acids (EETs) are endogenous chemical mediators that show anti-inflammatory, antihypertensive, and analgesic effects. Soluble epoxide hydrolase (sEH) converts EETs to their corresponding dihydroxyeicosatrienoic acids, whereby the biological effects of EETs are modified. Therefore, inhibition of sEH has been suggested as a novel pharmacological approach for the treatment of inflammatory and pain-related disorders. Recently, we have discovered a new family of sEH inhibitors (sEHI) featuring a unique benzohomoadamantane scaffold. In a murine model of cerulein-induced acute pancreatitis, the administration of a selected candidate significantly reduced pancreatic damage and improved the health status of the animals. Herein we report further structure-activity relationships within this series of benzohomoadamantane-derived sEHI. Most of the novel derivatives were endowed with low nanomolar or even subnanomolar IC values at the human, murine and rat sEH. Further in vitro profiling (solubility, cytotoxicity, metabolic stability, selectivity, permeability, etc.) and pharmacokinetic studies permitted us to select a candidate for in vivo efficacy studies. This candidate reduced pain in the capsaicin-induced model of allodynia in a dose-dependent manner and outperformed other sEHI tested. In summary, these novel results and the previously reported studies using other families of sEHI, strongly suggest that sEH may be a target of clinical interest for managing pain. References: 1-Sun, C.-P.; Zhang, X.-Y.; Morisseau, C.; Hwang, S. H.; Zhang, Z.-J.; Hammock, B. D.; Ma, X.-C. J. Med. Chem. 2021, 64, 184-215. 2-Codony, S.; Calvó-Tusell, C.; Valverde, E.; Osuna, S.; Morisseau, C.; Loza, M.I.; Brea, J.; Pérez, C.; Rodríguez-Franco, M.I.; Pizarro-Delgado, J.; Corpas, R.; Griñán-Ferré, C.; Pallàs, M.; Sanfeliu, C.; Vázquez-Carrera, M.; Hammock, B. D.; Feixas, F.; Vázquez, S. J. Med. Chem., 2021, 64, 5429-5446. 3-McReynolds, C.; Morisseau, C.; Wagner, K.; Hammock, B. D. Adv. Exp. Med. Biol. 2020, 1274, 71-99.
Learn More >The astroglial glutamate transporter-1 (GLT-1) in the hippocampus and anterior cingulate cortex (ACC) is critically involved in acute and chronic nociceptive pain. We have previously shown that 3-[[(2-Methylphenyl) methyl] thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, in the hippocampus attenuates acute and chronic nociceptive pain. The cellular and molecular mechanisms of GLT-1 modulation in the hippocampus and ACC in chronic pain-induced cognitive deficits and anxiety-like behaviors are unknown. Here, we have examined the effects of LDN-212320 in complete Freund's adjuvant (CFA)-induced cognitive deficits and anxiety-like behaviors in mice. Furthermore, we have measured CFA-induced impaired spatial, working, and recognition memory using Y-maze and object-place recognition test. In addition, we have determined chronic pain-induced anxiety-like behaviors using elevated plus maze and marble burying test. We have also evaluated the effects of LDN-212320 on cAMP response element-binding protein (pCREB) expression in the hippocampus and ACC during CFA-induced cognitive deficits and anxiety-like behaviors using Western blot analysis and immunofluorescence assay. Pretreatment of LDN-212320 (20 mg/kg) significantly attenuated CFA-induced impaired spatial, working, and recognition memory. The LDN-212320 (20 mg/kg) significantly reduced CFA-induced anxiety-like behaviors. Additionally, LDN-212320 (20 mg/kg) significantly reversed CFA-induced decreased-pCREB expression in the hippocampus and ACC. Overall, these results suggest that the LDN-212320 prevents CFA-induced impaired cognitive behaviors and neuronal deficits via GLT-1 modulation in the hippocampus and ACC. Therefore, LDN-212320 may have therapeutic utility for the prevention and treatment of chronic pain-associated with cognitive impairments and anxiety-like behaviors.
Learn More >Mechanical ventilation is an uncomfortable and potentially painful intervention. Opioids, such as morphine and fentanyl, are used for analgesia and sedation but there is uncertainty whether they reduce pain in mechanically ventilated infants. Moreover, there may be short-term and long-term adverse consequences such as respiratory depression leading to prolonged mechanical ventilation and detrimental long-term neurodevelopmental effects. Despite this, opioids are widely used, possibly due to a lack of alternatives.Dexmedetomidine, a highly selective alpha-2-adrenergic agonist with analgesic and sedative effects, currently approved for adults, has come into use in newborn infants. It provides analgesia and simulates natural sleep with maintenance of spontaneous breathing and upper airway tone. Although data on pharmacokinetics-pharmacodynamics in preterm infants are scant, observational studies report that using dexmedetomidine in conjunction with opioids/benzodiazepines or on its own can reduce the cumulative exposure to opioids/benzodiazepines. As it does not cause respiratory depression, dexmedetomidine could enable quicker weaning and extubation. Dexmedetomidine has also been suggested as an adjunct to therapeutic hypothermia in hypoxic ischaemic encephalopathy and others have used it during painful procedures and surgery. Dexmedetomidine infusion can cause bradycardia and hypotension although most report clinically insignificant effects.The increasing number of publications of observational studies and clinical use demonstrates that dexmedetomidine is being used in newborn infants but data on safety and efficacy are scant and not of high quality. Importantly, there are no data on long-term neurodevelopmental impact on preterm or term-born infants. The acceptance of dexmedetomidine in routine clinical practice must be preceded by clinical evidence. We need adequately powered and well-designed randomised controlled trials investigating whether dexmedetomidine alone or with opioids/benzodiazepines in infants on mechanical ventilation reduces the need for opioids/benzodiazepine and improves neurodevelopment at 24 months and later as compared with the use of opioids/benzodiazepines alone.
Learn More >Type-2 cannabinoid receptors (CB2, encoded by the Cnr2 gene) are mainly expressed in immune cells, and CB2 agonists normally have no analgesic effect. However, nerve injury upregulates CB2 in the dorsal root ganglion (DRG), following which CB2 stimulation reduces neuropathic pain. It is unclear how nerve injury increases CB2 expression or how CB2 activity is transformed in neuropathic pain. In this study, immunoblotting showed that spinal nerve ligation (SNL) induced a delayed and sustained increase in CB2 expression in the DRG and dorsal spinal cord synaptosomes. RNAscope in situ hybridization also showed that SNL substantially increased CB2 mRNA levels, mostly in medium and large DRG neurons. Furthermore, we found that the specific CB2 agonist JWH-133 significantly inhibits the amplitude of dorsal root-evoked glutamatergic excitatory postsynaptic currents in spinal dorsal horn neurons in SNL rats, but not in sham control rats; intrathecal injection of JWH-133 reversed pain hypersensitivity in SNL rats, but had no effect in sham control rats. In addition, chromatin immunoprecipitation-qPCR analysis showed that SNL increased enrichment of two activating histone marks (H3K4me3 and H3K9ac) and diminished occupancy of two repressive histone marks (H3K9me2 and H3K27me3) at the Cnr2 promoter in the DRG. In contrast, SNL had no effect on DNA methylation levels around the Cnr2 promoter. Our findings suggest that peripheral nerve injury promotes CB2 expression in primary sensory neurons via epigenetic bivalent histone modifications and that CB2 activation reduces neuropathic pain by attenuating nociceptive transmission from primary afferent nerves to the spinal cord.
Learn More >The comorbidity of chronic pain and mental dysfunctions such as depression and anxiety disorders has long been recognized, but the underlying mechanisms remain poorly understood. Here, using a mouse model of neuropathic pain, we demonstrated neuronal plasticity in the bed nucleus of the stria terminalis (BNST), which plays a critical role in chronic pain-induced maladaptive anxiety. Electrophysiology demonstrated that chronic pain increased inhibitory inputs to lateral hypothalamus (LH)-projecting BNST neurons. Chemogenetic manipulation revealed that sustained suppression of LH-projecting BNST neurons played a crucial role in chronic pain-induced anxiety. Furthermore, using a molecular genetic approach, we demonstrated that chronic pain elevated the excitability of a specific subpopulation of BNST neurons, which express cocaine- and amphetamine-regulated transcript (CART). The elevated excitability of CART-positive neurons caused the increased inhibitory inputs to LH-projecting BNST neurons, thereby inducing anxiety-like behavior. These findings shed light on how chronic pain induces psychiatric disorders, characterized by maladaptive anxiety.
Learn More >The potential for the development of opioid-induced hyperalgesia (OIH) provokes debate about whether long-term treatment with opioids is advisable and effective. If OIH develops during acute administration, will continuation of opioids actually make the pain worse? Hence, it is not surprising that OIH is part of the rationale used to promote deprescribing opioids in patients with chronic pain. But is there evidence that OIH is a clinically relevant phenomenon? This Commentary examines the evidence for OIH in randomized clinical trials in both the acute and chronic settings. Of critical importance in such an assessment is a trial design capable of differentiating OIH, tolerance, withdrawal-mediated pain sensitivity and worsening of the disease. However, studies published to date that purport to give evidence of OIH via experimentally induced pain all lack the rigour needed to differentiate these phenomena. Patient-reported measures of pain and analgesic consumption in these trials are not consistent with the presence of clinically significant OIH. At present, there is insufficient evidence from well-designed clinical trials that OIH is a clinically relevant phenomenon. Hence, while there are other reasons to avoid long-term use of opioids, the potential for the development of hyperalgesia during chronic opioid treatment is not a sound rationale for deprescribing these drugs in patients with chronic pain.
Learn More >Isoflurane (ISO) has been widely used in clinical anesthesia, and exposure to ISO leads to cognitive dysfunction. Our paper aimed to investigate the effect of miR-128-3p on cognitive impairment, inflammation, and oxidative stress elicited by ISO anesthesia in Sprague-Dawley (SD) rats. The SD rats were treated with ISO to mimic the ISO-injured situation, and the concentration of miR-128-3p was quantified utilizing real-time PCR. The miR-128-3p's impacts in ISO-engendered rat models on the respects of inflammatory condition and oxidative activities were measured by the commercial kits. The Morris water maze test was adopted to measure the neuro-function regarding miR-128-3p. Additionally, the target was tested by the alternation of luciferase activity. The irritation of ISO suppressed miR-128-3p expression in rats, which was enhanced by the injection of miR-128-3p agomir. The adverse roles of ISO on inflammation, oxidative stress, and cognitive disorders were partially abrogated by an increment of miR-128-3p. A miR-128-3p's interconnection with specificity protein 1 (SP1) was pinpointed, and aggrandized mRNA levels of SP1 were found under ISO state. MiR-128 acted as a regulator in ISO damage in the respects of cognition, inflammation, and oxidative stress. The SP1's link of miR-128-3p was showcased.
Learn More >Changing attitudes about marijuana have led to an increase in use of medicinal marijuana, especially for painful chronic conditions. Patients ask rheumatologists for guidance on this topic. This review provides up-to-date information on the safety and efficacy of medicinal cannabis for rheumatic disease pain.
Learn More >The kappa opioid receptor has exceptional potential as an analgesic target, seemingly devoid of the many peripheral side-effects of Mu opioid receptors. Kappa-selective, small molecule pharmaceutical agents have been developed, but centrally-mediated side effects have limited their clinical translation. Here, we modify an active endogenous dynorphin peptide to improve drug-likeness and develop safer KOPr agonists for clinical use.
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