Our findings highlight that treatment with DMED during, but not after, peripheral SI can prevent subsequent hippocampal neuroinflammation, overexpression of TLR-4 in microglia, and cognitive dysfunction, as mediated by the α-AR signaling pathway.
Our findings indicate that surgery-induced acute, transient, brain-wide neuroinflammation may be involved in the pathogenesis of the postoperative delirium-like cognitive deficits in rats. Furthermore, neuroinflammation may convert from acute to chronic in an age- and hippocampal-specific manner, likely resulting in the development of sustained cognitive dysfunction.
The maladaptive response of aged microglia to surgery and consequent neuroinflammation plays a key pathogenic role in postoperative cognitive dysfunction (POCD). Here, we assessed the preventive effect of resveratrol (RESV) for POCD in aged rats. The emulsified form of RESV (e-RESV) was selected to improve its oral and brain bioavailability. Animals were assigned to one of four groups: e-RESV (80 mg/kg) versus vehicle treatment by abdominal surgery versus isoflurane anesthesia alone (n = 8 in each group). The dose-dependent effects of e-RESV were also assessed in dose range of 0-60 mg/kg. Either vehicle or e-RESV was administered intragastrically 24 h before surgery. Seven days after procedure, cognitive function was evaluated using a novel object recognition test, followed by measurement of hippocampal pro-inflammatory cytokine levels. Our results showed that pre-treatment with e-RESV attenuated the surgery-induced cognitive impairment and related hippocampal neuroinflammation at 40 mg/kg or higher doses. Additionally, the ex-vivo experiments revealed that the preemptive e-RESV regimen reduced the hippocampal microglial immune reactivity to lipopolysaccharide. Furthermore, e-RESV induced neuroprotective benefits were inhibited by the concomitant administration of sirtinol, a specific SIRT1 inhibitor. Our findings imply the preventive potential of e-RESV for POCD via the SIRT1 signaling pathway.
Prior work employing functional analysis, photolabeling, and X-ray crystallography have identified three distinct binding sites for potentiating steroids in the heteromeric GABA A receptor.The sites are located in the membrane-spanning domains of the receptor at the β-α subunit interface ("Site I") and within the α ("Site II") and β subunits ("Site III"). Here, we have investigated the effects of mutations to these sites on potentiation of the rat α1β2γ2L GABA A receptor by the endogenous neurosteroid allopregnanolone (3α5αP). The mutations were introduced alone or in combination to probe the additivity of effects. We show that the effects of amino acid substitutions in Sites I and II are energetically additive, indicating independence of the actions of the two steroid binding sites. In Site III, none of the mutations tested reduced potentiation by 3α5αP nor did a mutation in Site III modify the effects of mutations in Sites I or II.We infer that the binding sites for 3α5αP act independently. The independence of steroid action at each site is supported by photolabeling data showing that mutations in either Site I or Site II selectively change steroid orientation in the mutated site without affecting labeling at the unmutated site. The findings are discussed in the context of linking energetic additivity to empirical changes in receptor function and ligand binding.Significance Statement: Prior work has identified three distinct binding sites for potentiating steroids in the heteromeric GABA A receptor. We show here that the sites act independently and additively in the presence of the steroid allopregnanolone, and provide estimates of energetic contributions made by steroid binding to each site.
BackgroundPost-herpetic itch (PHI) is a neuropathic itch syndrome following herpes zoster. It has been reported that PHI is occasionally sufficiently severe to compromise patients’ quality of life and frequently refractory to treatment. Here, we present a case of severe chronic PHI successfully treated with supraorbital nerve block using a high concentration of tetracaine dissolved in bupivacaine.Case presentationAn 82-year-old man presented with severe chronic itching in the ophthalmic branch of the left trigeminal nerve dermatome, following acute herpes zoster. The patient’s itching was unresponsive to usual medical treatments for PHI including antiepileptic drugs, topical capsaicin cream, and supraorbital nerve radiofrequency thermo-coagulation. Topical lidocaine cream could relieve the itching, but could not provide long-term relief of itching and thus failed to achieve a satisfactory result. After these conventional treatments, left supraorbital nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was conducted. Afterwards, the patient experienced long-lasting resolution of the itching with improvement of sleep disturbance. A transient, mild edema of the eyelids occurred, but there were no other complications.ConclusionsPeripheral nerve block using 4% tetracaine dissolved with 0.5% bupivacaine was beneficial in relieving PHI in the ophthalmic division of the trigeminal nerve.
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