European journal of pharmacology
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Randomized Controlled Trial
Effect of intravenous infusion of dobutamine hydrochloride on the development of early postoperative cognitive dysfunction in elderly patients via inhibiting the release of tumor necrosis factor-α.
To investigate the effects of dobutamine hydrochloride on early postoperative cognitive dysfunction (POCD) and plasma tumor necrosis factor (TNF)-α concentration in patients undergoing hip arthroplasty, 124 patients undergoing unilateral total hip arthroplasty, aged 70-92 years old, were randomly assigned to four groups (n=31) as follows: a control group of patients receiving only saline (intravenous infusion, i.v.); and groups receiving 2, 4, or 6μgkg(-1)min(-1) (i.v.) of dobutamine hydrochloride. Cognitive functions were assessed on the day before surgery (T1), and the 1st day (T2), 3rd day (T3), and 7th day (T4) postsurgery using the Mini Mental State Examination (MMSE). The plasma TNF-α protein level was determined 10min before anesthesia (Ta), and 10min (Tb), 30min (Tc), and 60min (Td) after anesthesia by an enzyme-linked immunosorbent assay. ⋯ Administration of 2 or 4μgkg(-1)min(-1) dobutamine hydrochloride was able to reverse the early POCD. Simultaneously, an increase of plasma TNF-α levels 30min after anesthesia was observed (41.34±9.61 vs. 27.75±5.45), which was significantly suppressed by the administration of low-dose dobutamine hydrochloride (29.23±7.32 vs. 41.34±9.61) but not by high-dose dobutamine hydrochloride (45.9±12.11 vs. 41.34±9.61). Together, our data indicated that the plasma concentration of TNFα was engaged in the effect of dobutamine hydrochloride on POCD.
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Targeting functionally independent receptors may provide synergistic analgesic effects in neuropathic pain. To examine the interdependency between different opioid receptors (µ-opioid peptide [MOP], δ-opioid peptide [DOP] and κ-opioid peptide [KOP]) and the nociceptin/orphanin FQ peptide (NOP) receptor in streptozotocin (STZ)-induced diabetic polyneuropathy, nocifensive activity was measured using a hot plate test in wild-type and NOP, MOP, DOP and KOP receptor knockout mice in response to the selective receptor agonists Ro65-6570, morphine, SNC-80 and U50488H, or vehicle. Nocifensive activity was similar in non-diabetic wild-type and knockout mice at baseline, before agonist or vehicle administration. ⋯ Partial or near-complete reductions in efficacy were observed with Ro65-6570 in DOP and KOP receptor knockouts, with SNC-80 in NOP, MOP and KOP receptor knockouts, and with U50488H in NOP and DOP receptor knockouts. There was no evidence of NOP and MOP receptor interdependency in response to selective agonists for these receptors. These findings suggest that concurrent activation of NOP and MOP receptors, which showed functional independence, may yield an effective and favorable therapeutic analgesic profile.
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Mitochondrial dysfunction plays a critical role in brain injury after cardiac arrest and cardiopulmonary resuscitation (CPR). Recent studies demonstrated that hydrogen sulfide (H2S) donor compounds preserve mitochondrial morphology and function during ischemia-reperfusion injury. In this study, we sought to explore the effects of sodium hydrosulfide (NaHS) on brain mitochondria 24h after cardiac arrest and resuscitation. ⋯ We also observed that NaHS therapy reduced intracellular reactive oxygen species generation and calcium overload, inhibited mitochondrial permeability transition pores, preserved mitochondrial membrane potential, elevated ATP level and ameliorated the cytochrome c abnormal distribution. Further studies indicated that NaHS administration increased mitochondrial biogenesis in cortex at the same time. Our findings suggested that administration of NaHS 1min prior CPR and followed by a continuous infusion ameliorated neurological dysfunction 24h after resuscitation, possibly through mitochondria preservation as well as by promoting mitochondrial biogenesis.
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Previously it was reported that combining antibiotics with L-97-1, an adenosine A1 receptor antagonist, significantly improves survival and blocks acute lung injury induced by Yersinia pestis CO 99 in a rat model of pneumonic plague. In the current studies using a conscious rat model of cecal ligation and puncture (CLP) sepsis, L-97-1 was administered in daily intravenous infusions in combination with antibiotics to simulate the use of L-97-1 as an anti-sepsis therapeutic in the clinical setting. ⋯ Moreover, in these studies, in combination with antibiotics L-97-1 dose-dependently protects the kidney, significantly improving renal function at 24 h post CLP at 10 mg/kg/h (P<0.001), 12.5 mg/kg/h (P<0.0001), and 15 mg/kg/h (P<0.0001) vs. antibiotics alone (ANOVA followed by Tukey׳s post-hoc test for pair-wise comparisons). The results of these studies support efficacy for L-97-1 as an anti-sepsis therapeutic.
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Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01 mg/kg) and decreased response rate (ED50=0.064 mg/kg). ⋯ Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.