Mohamed Naguib

Reversal of profound neuromuscular block by sugammadex administered three minutes after rocuronium: a comparison with spontaneous recovery from succinylcholine.

Background:Rocuronium in intubation doses provides similar intubation conditions as succinylcholine, but has a longer duration of action. This study compared time to sugammadex reversal of profound rocuronium-induced neuromuscular block with time to spontaneous recovery from succinylcholine. Methods:One hundred and fifteen adult American Society of Anesthesiologists Class I-II surgical patients were randomized to this multicenter, safety-assessor–blinded, parallel group, active-controlled, Phase IIIa trial. Anesthesia was induced and maintained with propofol and an opioid. Neuromuscular transmission was blocked and tracheal intubation facilitated with 1.2 mg/kg rocuronium or 1 mg/kg succinylcholine. Sugammadex (16 mg/kg) was administered 3 min after rocuronium administration. Neuromuscular function was monitored by acceleromyography. The primary efficacy endpoint was the time from the start of relaxant administration to recovery of the first train-of-four twitch (T1) to 10%. Results:One hundred and ten patients received study treatment. Mean times to recovery of T1 to 10% and T1 to 90% were significantly faster in the rocuronium-sugammadex group (4.4 and 6.2 min, respectively), as compared with the succinylcholine group (7.1 and 10.9 min, respectively; all P < 0.001). Timed from sugammadex administration, the mean time to recovery of T1 to 10%, T1 to 90%, and the train-of-four (T4/T1) ratio to 0.9 was 1.2, 2.9, and 2.2 min, respectively. Reoccurrence of the block was not observed. There were no serious adverse events related to study treatments. Conclusion:Reversal of profound high-dose rocuronium-induced neuromuscular block (1.2 mg/kg) with 16 mg/kg sugammadex was significantly faster than spontaneous recovery from 1 mg/kg succinylcholine.

Advances in neurobiology of the neuromuscular junction: implications for the anesthesiologist.

THE mammalian neuromuscular junction (NMJ) is one of the most studied and best understood synapses. Recent work has brought forth new information as to development, maturation, and function of this fundamental synapse, both in health and disease. The healthy function of the NMJ underlies one important measurement of the response to general anesthetics, immobility. “Neuromuscular blockers” acting directly at the NMJ are used as a component of many balanced anesthetic techniques, and the health of the NMJ profoundly influences anesthetic technique. For these reasons, it is imperative that anesthesiologists be aware of new developments in the field. The normal development, maturation, and function of the NMJ are discussed. Diseases of the NMJ are also reviewed with emphasis on new etiologic, pathologic, and treatment-oriented information.

Activation of the CB2 receptor system reverses amyloid-induced memory deficiency.

Cannabinoid type 2 (CB(2)) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimers disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)-a novel selective CB(2) agonist that lacks psychoactivity-on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)(1-40) fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ(1-40) fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB(2) receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimers disease.

6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction

Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC(50) = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (K(i) = 89.9 nM, EC(50) = 88.2 nM at CB2) inhibited the effect of compound 1 (MDA7), a selective CB2 agonist, in an animal model of neuropathic pain. The molecular modeling study presented here represents a first study of CB2 based on the structure of beta(2)-adrenergic receptor. A ligand-based homology model of the CB2 binding site was developed, and on the basis of our results, we propose a general binding mode for this class of inverse agonists with CB2.

Melatonin and anesthesia: a clinical perspective

Abstract:u2002 The hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a novel hypnotic‐anesthetic agent. Sublingually or orally administered melatonin is an effective premedicant in adults and children. Melatonin premedication like midazolam is associated with sedation and preoperative anxiolysis, however, unlike midazolam these effects are not associated with impaired psychomotor skills or the quality of recovery. Melatonin administration also is associated with a tendency toward faster recovery and a lower incidence of postoperative excitement than midazolam. Oral premedication with 0.2u2003mg/kg melatonin significantly reduces the propofol and thiopental doses required for loss of responses to verbal commands and eyelash stimulation. In rats, melatonin and the more potent melatonin analogs 2‐bromomelatonin and phenylmelatonin have been found to have anesthetic properties similar to those of thiopental and propofol, with the added advantage of providing potent antinociceptive effects. The exact mechanism(s) by which structurally diverse intravenous and volatile anesthetics produce general anesthesia is still largely unknown, but positive modulation of γ‐aminobutyric acid type A (GABAA) receptor function has been recognized as an important and common pathway underlying the depressant effects of many of these agents. Accumulating evidence indicates that there is interplay between the melatonergic and GABAergic systems, and it has been demonstrated that melatonin administration produces significant, dose‐dependent increases in GABA concentrations in the central nervous system. Additional in vitro data suggest that melatonin alters GABAergic transmission by modulating GABAA receptor function. Of greater importance, data from in vivo studies suggest that the central anesthetic effects of melatonin are mediated, at least in part, via GABAergic system activation, as they can be blocked or reversed by GABAA receptor antagonists. Further work is needed to better understand the general anesthetic properties of melatonin at the molecular, cellular, and systems levels.

Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency

Amyloid-induced microglial activation and neuroinflammation impair central synapses and memory function, although the mechanism remains unclear. Neuroligin 1 (NLGN1), a postsynaptic protein found in central excitatory synapses, governs excitatory synaptic efficacy and plasticity in the brain. Here we found, in rodents, that amyloid fibril–induced neuroinflammation enhanced the interaction between histone deacetylase 2 and methyl-CpG-binding protein 2, leading to suppressed histone H3 acetylation and enhanced cytosine methylation in the Nlgn1 promoter region and decreased NLGN1 expression, underlying amyloid-induced memory deficiency. Manipulation of microglia-associated neuroinflammation modulated the epigenetic modification of the Nlgn1 promoter, hippocampal glutamatergic transmission and memory function. These findings link neuroinflammation, synaptic efficacy and memory, thus providing insight into the pathogenesis of amyloid-associated diseases.

MDA7: a novel selective agonist for CB2 receptors that prevents allodynia in rat neuropathic pain models

There is growing interest in using cannabinoid type 2 (CB2) receptor agonists for the treatment of neuropathic pain. In this report, we describe the pharmacological characteristics of MDA7 (1‐[(3‐benzyl‐3‐methyl‐2,3‐dihydro‐1‐benzofuran‐6‐yl)carbonyl]piperidine), a novel CB2 receptor agonist.

Design and Synthesis of a Novel Series of N-Alkyl Isatin Acylhydrazone Derivatives that Act as Selective Cannabinoid Receptor 2 Agonists for the Treatment of Neuropathic Pain

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [(35)S]GTP-gamma-S assays. Binding affinities at human CB2 and CB1 were determined for compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.

2,3-Dihydro-1-Benzofuran Derivatives as a Series of Potent Selective Cannabinoid Receptor 2 Agonists: Design, Synthesis, and Binding Mode Prediction through Ligand-Steered Modeling

We recently discovered and reported a series of N‐alkyl‐isatin acylhydrazone derivatives that are potent cannabinoid receptoru20052 (CB2) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3‐dihydro‐1‐benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB2 agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand‐steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the Su2005enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 (compound 19) and MDA39 (compound 30) were the most potent at CB2. MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.

Suppression of central chemokine fractalkine receptor signaling alleviates amyloid-induced memory deficiency.

The abnormal accumulation of amyloid fibrils in the brain is pathognomonic of Alzheimers disease. Amyloid fibrils induce significant neuroinflammation characterized by the activation of microglia and impairment of synaptic plasticity in the brain that eventually leads to cognitive decline. Chemokine fractalkine receptor (CX3CR1) is primarily located in the microglia in the brain and its role in the amyloid fibril-induced neuroinflammation and memory deficiency remains debated. We found that bilateral microinjection of amyloid beta (Aβ)1-40 fibrils into the hippocampal CA1 area of rats resulted in significant upregulation of CX3CR1 messenger RNA (mRNA) and protein expression (via increasing histone H3 acetylation in the Cx3cr1 promoter region), synaptic dysfunction, and cognitive impairment, compared with the control group. Suppressing CX3CR1 signaling with CX3CR1 small interfering RNA in rats injected with Aβ1-40 fibrils blunted Aβ1-40-induced CX3CR1 upregulation, microglial activation, interleukin-1β expression, restored basal glutamatergic strength and electric stimuli-induced long-term potentiation, and cognitive capacities. These findings suggest that activation of CX3CR1 plays an important role in the neuroinflammatory response and Aβ-induced neuroinflammation and neurotoxicity.