piperidines and Nervous-System-Diseases

The sigma-1 (σ

Topics: Allosteric Regulation; Clinical Trials as Topic; Humans; Ligands; Nervous System Diseases; Piperidines; Receptors, sigma; Sigma-1 Receptor; Small Molecule Libraries

Topics: Humans; Nervous System Diseases; Piperidines; Receptors, Histamine H3; Sleep; Sleep Wake Disorders

Piperine is a simple and pungent alkaloid found in the seeds of black pepper (Piper nigrum). Following its isolation and full characterization, the biological properties of piperine have been extensively studied, and piperine-like derivatives have shown an interesting range of pharmacological activities. In this context, significant advances have been made in the discovery of new chemical entities based on the piperine scaffold endowed with therapeutic potential.. The aim of this review is to provide a thorough inquiry on the therapeutic potential of piperine and related derivatives. It provides an overview of recent developments in patented processes and applications thereof between 2000 and 2015.. Cumulative evidence shows that piperine is currently paving its way to become a privileged scaffold for the development of bioactive compounds with therapeutic application in multiple human diseases. In particular, piperine derivatives were shown to modulate the activity of several targets related to neurological disorders, including epilepsy, Parkinson's disease, depression and pain related disorders. Moreover, the efflux pump inhibitory ability of piperine and its analogues tackles important drug resistance mechanisms and may improve the clinical efficacy of antibiotic and anticancer drugs. Although the use of piperine as a scaffold for bioactive compounds is still in its early stages, the continuous exploration of this structure may lead to remarkable advances in drug discovery programs.

Topics: Alkaloids; Animals; Benzodioxoles; Drug Design; Drug Discovery; Drug Resistance; Humans; Nervous System Diseases; Patents as Topic; Piper nigrum; Piperidines; Polyunsaturated Alkamides; Seeds

The cannabinoid-1 receptor blockers have been proposed in the management of obesity and obesity-related liver diseases (fatty liver as NAFLD or NASH). Due to increasing number of patients to be potentially treated and the need to assess the advantage of this treatment in terms of risk/benefit, we analyze the side events reported during the treatment with rimonabant by a systematic review and meta-analysis of all randomized controlled studies.. All published randomized controlled trials using rimonabant versus placebo in adult subjects were retrieved. Relative risks (RR) with 95% confidence interval for relevant adverse events and number needed to harm was calculated.. Nine trials (n = 9635) were considered. Rimonabant 20 mg was associated with an increased risk of adverse event (RR 1.35; 95%CI 1.17-1.56), increased discontinuation rate (RR 1.79; 95%CI 1.35-2.38), psychiatric (RR 2.35; 95%CI 1.66-3.34), and nervous system adverse events (RR 2.35; 95%CI 1.49-3.70). The number needed to harm for psychiatric adverse events is 30.. Rimonabant is associated with an increased risk of adverse events. Despite of an increasing interest for its use on fatty liver, the security profile and efficacy it is needs to be carefully assessed before its recommendation. At present the use of rimonabant on fatty liver cannot be recommended.

Topics: Cannabinoid Receptor Antagonists; Fatty Liver; Humans; Mental Disorders; Nervous System Diseases; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Rimonabant; Treatment Outcome

Recently, a series of 5-HT7 receptor antagonists have been developed (24,29,36,68). Among them SB-258741, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine, (compound "13" in 36,37) was one of the most potent and specific compounds. Due to a lack of specific ligands the pharmacology of 5-HT7 receptor antagonists is still relatively unexplored. It has been suggested, however, that 5-HT7 receptor ligands could be useful in the therapy of various disorders such as sleep disorders, schizophrenia, depression, migraine, epilepsy, pain, or memory impairment. Many of these conceivable indications are not supported by pharmacological data. It is, therefore, of particular interest to review the data generated from studies of one of these most potent and specific 5-HT7 receptor antagonists, SB-258741, with a goal of testing the validity of the proposed clinical indications. In this review, the author describes pharmacology of this compound in order to define its potential clinical use. The available safety pharmacology data are discussed in an attempt to predict potential side effects of specific 5-HT7 receptor antagonists.

Topics: Animals; Brain; Mental Disorders; Models, Animal; Nervous System Diseases; Piperidines; Pyrrolidines; Receptors, Serotonin; Serotonin Antagonists; Tosyl Compounds

Glutamate is a potent candidate of the excitatory transmitter at the invertebrate NMJ and the synapse of the vertebrate CNS. But pharmacological studies have not been enough to prove that glutamate functions as an excitatory neurotransmitter. During the past 10 years, we have been studying the effects of various compounds which demonstrate the glutamate blocking action, but the glutamate responses are more effectively blocked by the drugs than the nerve-evoked synaptic response. A marked difference was revealed by TI-233, the minimum concentration of TI-233 on EJP being about a hundred times greater than the minimum threshold concentration on the glutamate-induced responses. The subsequent studies demonstrated that the action of TI-233 was able to be explained by the open channel block of the glutamate-activated ion-channel. The difference does not confute the hypothesis that glutamate is the natural transmitter substance at the crayfish NMJ, notwithstanding the fact that the action of the transmitter candidate on the postsynaptic membrane must be identical in every respect with that of the transmitter. Once something potentially useful has been found it is necessary to know not only what a substance does but how well it does it, so that comparisons can be made and better drugs discovered. Our first task therefore was to find a powerful glutamate blocker. Recently, as a result of synthesizing a series of compounds on the base of the structure-activity relationship in drug design, a series of compounds was found to reduce markedly glutamate responses at the crayfish NMJ and the mammalian central neurones at extremely low concentrations. In addition, a novel potent excitatory amino acid, acromelic acid, was found. This compound markedly excites the crayfish opener muscle and the mammalian central neurones. Agonists and antagonists have provided a very useful tool for neuroscience research, and findings of these new pharmacological tools will lead to progress in pharmacological studies to elucidate the function of glutamate in the body, in addition to other established compounds. The recent advances in our limited understanding of pharmacology of the glutamate receptor are discussed here.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Animals; Anticonvulsants; Antidepressive Agents; Azepines; Glutamates; Glutamic Acid; Membrane Potentials; Nervous System Diseases; Neurons; Oxazoles; Oxazolidinones; Piperidines; Receptors, Glutamate; Receptors, Neurotransmitter; Synapses

Topics: Amiodarone; Angina Pectoris; Benzofurans; Cerebrospinal Fluid Proteins; Electromyography; Humans; Inclusion Bodies; Lipid Metabolism; Microscopy, Electron; Movement Disorders; Muscles; Nervous System Diseases; Paresthesia; Perhexiline; Peripheral Nerves; Peripheral Nervous System Diseases; Pigments, Biological; Piperidines; Polyradiculoneuropathy; Schwann Cells; Skin; Tremor

The objective of this study was to retrospectively evaluate neurologic status pre- and posttreatment with the oral farnesyltransferase inhibitor lonafarnib in children with Hutchinson-Gilford progeria syndrome (HGPS), a rare, fatal disorder of segmental premature aging that results in early death by myocardial infarction or stroke.. The primary outcome measure for intervention with lonafarnib was to assess increase over pretherapy in estimated annual rate of weight gain. In this study, neurologic signs and symptoms were compared pre- and posttreatment with lonafarnib.. Twenty-six participants were treated for a minimum of 2 years. Frequency of clinical strokes, headaches, and seizures was reduced from pretrial rates. Three patients with a history of frequent TIAs and average clinical stroke frequency of 1.75/year during the year before treatment experienced no new events during treatment. One patient with a history of stroke died due to large-vessel hemispheric stroke after 5 months on treatment. Headache prevalence and frequency were reduced. Four patients exhibited pretherapy seizures and no patients experienced recurrent or new-onset seizures.. This study provides preliminary evidence that lonafarnib therapy may improve neurologic status of children with HGPS. To address this question, we have incorporated prospective neuroimaging and neurologic assessments as measures in subsequent studies involving children with HGPS.. This study provides Class IV evidence that lonafarnib 115-150 mg/m(2) for 24 to 29 months reduces the prevalence of stroke and TIA and the prevalence and frequency of headache over the treatment period.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Male; Nervous System Diseases; Piperidines; Progeria; Pyridines; Retrospective Studies; Treatment Outcome

In a randomised, prospective multi-centre study, we compared the intraoperative and postoperative effects of two opioids: sufentanil and remifentanil, in combination with propofol in two groups of patients undergoing neurosurgery.. After Local Ethics Committee approval and informed consent obtaining, 69 patients undergoing neurosurgery for supratentorial tumours, between 18 and 75 years of age were randomised to receive either sufentanil or remifentanil in combination with propofol. Intraoperative and postoperative haemodynamic variables, recovery times (time to eye opening and to extubation), the incidence of postoperative respiratory depression, pain, nausea and vomiting were also evaluated. The Short Orientation-Memory-Concentration Test was used to evaluate cognitive function at 15, 45 and 180 min after emergence from anesthesia.. There were no significant differences between the groups in the duration of surgery and anesthesia, mean arterial pressure, heart rate, time to eye opening or extubation. The incidence of vomiting, respiratory depression and shivering was similar in both groups. Postoperative pain requiring supplemental analgesics was significantly lower in the sufentanil group (P<0.05). Although there were no significant differences between the groups in postoperative behavioural examinations by Rancho Los Amigos Test, patients anesthetised with sufentanil had significantly better Short Orientation-Memory-Concentration Test values at 15 and 180 min postoperatively (P<0.05). CONCLUSION. We conclude that remifentanil and sufentanil are suitable adjunct to propofol for total intravenous anesthesia (TIVA). Patients receiving sufentanil have reduced analgesic requirements and better cognitive function postoperatively than those who received remifentanil.

Topics: Adult; Aged; Anesthesia, Intravenous; Anesthetics, Combined; Anesthetics, Intravenous; Female; Humans; Male; Middle Aged; Nervous System Diseases; Piperidines; Propofol; Prospective Studies; Remifentanil; Sufentanil

Two groups of patients suffering from polyneuropathy were treated by sabeluzol. The first group--a double blind placebo controlled study consisting of 30 diabetics of type II did not prove either significant differences of their subjective complaints or changes of their objective findings (the dose of sabeluzole being 2 x 10 mg/d). The second group--open study--consisting of 26 patients suffering from polyneuropathy of various origin, treated by sabeluzole 3 x 10 mg/d. The therapeutic effect was significantly higher in comparison to the above mentioned lower doses of the medicament (manifesting statistical significance of 5 and 10%); the authors make a point of sabeluzol's therapeutic efficacy, especially in cases with acute polyneuropathy onset and point out the necessity of several months lasting treatment. Positive effect upon the pseudoneurasthenic syndrome in many patients indicates its usefulness also in other disorders than are these of polyneuropathy.

Topics: Diabetic Neuropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Nervous System Diseases; Piperidines; Thiazoles

Topics: Adult; Aged; Clinical Trials as Topic; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Nervous System Diseases; Phenothiazines; Piperidines; Placebos; Tranquilizing Agents

Erdheim-Chester disease (ECD) is a rare multisystemic disease characterised by an infiltration of various organs by CD68. We report the case of a 71-year-old woman with ECD which was revealed by neurological and cutaneous manifestations. The diagnosis was confirmed by skin biopsy and the BRAFV600E mutation was identified in skin tissue, leading to the use of combined therapy targeting the RAS-RAF-ERK-MEK pathway. This therapy allowed an improvement of cutaneous manifestations but neurological manifestations lead to death, underlying their notable severity.. Our case report shows the persistent diagnostic difficulty of the ECD and the particular gravity of neurologic involvement.

Topics: Aged; Azetidines; Drug Therapy, Combination; Erdheim-Chester Disease; Female; Humans; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Nervous System Diseases; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Rare Diseases; Skin Diseases; Vemurafenib

Cardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3-4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors.. Piglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits.. Treatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets.

Topics: Animals; Asphyxia; Cell Death; Endoplasmic Reticulum Stress; Enzyme Inhibitors; Epoxide Hydrolases; Heart Arrest; Male; Motor Cortex; Nervous System Diseases; Neurons; Phenylurea Compounds; Piperidines; Putamen; Swine; Treatment Outcome

Topics: Anesthesia, Intravenous; Cataract; Child; Craniofacial Abnormalities; Humans; Male; Nervous System Diseases; Piperidines; Propofol; Rare Diseases; Remifentanil

The anesthetic management of patients requiring surgery for movement disorders needs to balance microrecording quality and patient cooperation with safety and comfort. Anesthetics can alter microrecording, although the effect on outcome is debatable. They also provide a rested and cooperative patient and minimize complications such as intracranial hemorrhage by providing better hemodynamic control. Most teams use local anesthesia with monitored anesthesia care or conscious sedation with propofol. Recently, dexmedetomidine has emerged as an alternative that, at low doses, does not affect microrecording, and that does not impair respiratory drive.. In the past 15 years, we have used in our institution local anesthesia, remifentanil, or dexmedetomidine sedation. We compared functional outcome and rate of complications in a group of 145 patients with similar characteristics.. We found 5 (3.4%) intracranial hemorrhages. Two (1.4%) were symptomatic. The remifentanil group had the highest risk of having systolic blood pressure >160 mm Hg during surgery (odds ratio [OR], 2.8; 95% confidence interval [CI], 0.9-9.9), whereas the dexmedetomidine group had the lowest (OR, 0.7; 95% CI, 0.2-1.8), compared with the local anesthesia group. Surgical time was shortest with dexmedetomidine (mean, 283 minutes) and longest with local anesthesia only (mean, 328 minutes). Functional outcome (Unified Parkinson's Disease Rating Scale, Part III motor component scale) was similar among groups. The dexmedetomidine group had a statistically significant lower risk of perioperative neurologic events compared with the local anesthesia group (OR, 0.09; 95% CI, 0.002-0.68).. Sedation can be used safely without affecting outcome, and dexmedetomidine provides better hemodynamic management. Clinical significance remains unclear and larger studies need to be undertaken.

Topics: Aged; Anesthesia, Local; Dexmedetomidine; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Movement Disorders; Nervous System Diseases; Perioperative Care; Piperidines; Remifentanil; Retrospective Studies; Statistics, Nonparametric

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Nervous System; Nervous System Diseases; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Retrospective Studies

Statins are potent cholesterol biosynthesis inhibitors that exert protective effects in humans and in experimental models of stroke. The mechanisms involved in these protective actions are not completely understood. This study evaluates whether atorvastatin (ATV) treatment affects the GluN1 and GluN2B subunits of the N-methyl-D-aspartic acid receptor in the somatosensory cerebral cortex at short and long periods following ischemia. Sham and ischemic male Wistar rats received 10 mg/kg of ATV or placebo by gavage every 24 hr for 3 consecutive days. The first dose was administered 6 hr after ischemia-reperfusion or the sham operation. ATV treatment resulted in faster recovery of neurological scores than placebo, prevented the appearance of pyknotic neurons, and restored microtubule-associated protein 2 and neuronal nuclei staining to control values in the somatosensory cerebral cortex and the hippocampus at 72 hr and 15 days postischemia. Furthermore, ATV prevented spatial learning and memory deficits caused by cerebral ischemia. Cerebral ischemia reduced the number of GluN1/PSD-95 and GluN2B/PSD-95 colocalization clusters in cortical pyramidal neurons and reduced the levels of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. These effects of the ischemic insult were prevented by ATV, which also induced GluN2B/PSD-95 colocalization in neuronal processes and an association of GluN2B with TrkB. The GluN2B pharmacological inhibitor ifenprodil prevented the increase in BDNF levels and the motor and cognitive function recovery caused by ATV in ischemic rats. These findings indicate that GluN2B is involved in the neuroprotective mechanism elicited by ATV to promote motor and cognitive recovery after focal cerebral ischemia.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Brain Ischemia; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Embryo, Mammalian; Heptanoic Acids; Male; Maze Learning; Nerve Tissue Proteins; Nervous System Diseases; Piperidines; Platelet Aggregation Inhibitors; Pyrroles; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Somatosensory Cortex; Time Factors

Effective interventions that provide obvious neuroprotection are currently fairly limited. Glucagon-like peptide-1 (GLP-1), an enhancer of insulin production with a trophic effect on β cells in the islets, has been found to be trophic for neuronal cells. Alogliptin benzoate (AGL), a selective inhibitor of dipeptidylpeptidase-4 (DPP-4) functioning as a long-acting agonist of GLP-1, is in clinical use worldwide for patients with diabetes mellitus type 2. To clarify whether administration of AGL, independent of the insulinotropic effect, protects the brain against focal ischemia, we investigated the effect of AGL on the development of cerebral infarction in non-diabetic normal mice. Male C57BL/6J mice were administered AGL (7.5, 15, or 30μg) once a day for three weeks by intragastric gavage. After the induction of temporary focal ischemia, volumes of infarcted lesions and neurological deficits were analyzed at 24h (acute phase) and seven days (chronic phase). In the acute phase, significant reductions were observed in the volumes of infarcted lesions (p=0.009), and in the severity of neurological deficits (p=0.004), in the group treated with 15μg of alogliptin benzoate, but not the 7.5 or 30μg-treated groups. This significant reduction in volumes of infarcted lesions persisted into the chronic phase. At the end of the AGL treatment; before the induction of ischemia, the levels of brain-derived neurotrophic factor (BDNF), a potent neuroprotectant in the brain, were elevated in the cortex (p=0.008), or in the whole forebrain (p=0.023). AGL could be used as a daily neuroprotectant or an enhancer of BDNF production aiming to attenuate cerebral injuries, for the growing number of people who have the risk of ischemic stroke.

Topics: Analysis of Variance; Animals; Brain Edema; Brain Infarction; Brain Ischemia; Brain-Derived Neurotrophic Factor; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred C57BL; Microcirculation; Nervous System Diseases; Piperidines; Prosencephalon; Time Factors; Uracil

Topics: Female; Humans; Male; Nervous System Diseases; Piperidines; Progeria; Pyridines

Aged people are more prone to developing neurodegenerative and infectious diseases, autoimmune disorders, and cancer due to impairment of neuroendocrine-immune functions. Neuronal degeneration and immunosuppression aided by increased generation of reactive oxygen species combined with loss of antioxidant enzyme activities promote the aging process. Bacopa monnieri (brahmi), an Ayurvedic herb, and donepezil, a reversible acetylcholinesterase inhibitor, have been used to reverse cognitive dysfunctions in several neurodegenerative diseases. The aim of this study was to investigate the effects of in vitro incubation of lymphocytes from spleens of young (3-month-old), early middle-aged (8- to 9-month-old), and old (18-month-old) F344 rats with brahmi (0.001%, 0.01%, 0.05%, 0.1%, and 1%) and donepezil (5, 10, 25, 50, and 100 μg/ml) on Concanavalin (Con A)-induced proliferation of T lymphocytes and cytokine production, and the activities of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-S-transferase (GST)]. In addition, the effects of these compounds on the expression of intracellular signaling pathway markers (ERK, p-ERK, CREB, p-CREB, Akt and p-Akt), nitric oxide (NO) production, and the extent of lipid peroxidation were measured in the splenocytes. Age-related decline in Con A-induced proliferation of T lymphocytes was not reversed by treatment with brahmi and donepezil but donepezil alone further reduced the lymphocyte proliferation in young rats. Lower doses of brahmi treatment reversed the age-related decrease in Con A-induced IL-2 and IFN-γ production by the splenocytes while their production by splenocytes was suppressed by treatment with donepezil in the young and early middle-aged rats. An age-associated decline in the activities of SOD, CAT, GPx, and GST was evident in the lymphocytes of spleen. Brahmi enhanced CAT activity of lymphocytes in all the age groups while donepezil increased SOD activity in old rats. Both brahmi and donepezil increased GPx and GST activities in a dose-dependent manner in the lymphocytes of all age groups. There was an age-related decline in NO production and increase in the extent of lipid peroxidation in the splenocytes. Brahmi and donepezil increased NO production in the lymphocytes of early middle-aged and old rats. Brahmi reversed the age-related increase in lipid peroxidation in the splenocytes of both early-middle-aged and old rats while donepezil suppres

Topics: Aging; Animals; Bacopa; Cell Proliferation; Cells, Cultured; Cytokines; Donepezil; Enzyme Activation; Gene Expression Regulation; Humans; Immunity, Cellular; In Vitro Techniques; Indans; Intracellular Signaling Peptides and Proteins; Male; Medicine, Ayurvedic; Nervous System Diseases; Oxidative Stress; Piperidines; Rats; Rats, Inbred F344; Signal Transduction; Spleen; T-Lymphocytes

Opioid agonists have been implicated in neuroprotection from hypoxic injury through regulating mitogen-activated protein kinases and cytokines. We determined the effects of remifentanil in focal brain ischemia and reperfusion (I/R) injury. Mechanisms linked to mitogen-activated protein kinases, including extracellular signaling-regulated kinase (ERK) 1/2, p38 kinases, and c-Jun N-terminal kinase (JNK), and various cytokines were also examined.. Male Sprague-Dawley rats were subjected to an I/R insult consisting of 90 minutes' middle cerebral artery occlusion (MCAO) followed by reperfusion under general anesthesia. Neurological deficit scores and infarct volume were determined after 24 hours of reperfusion. Remifentanil (5 μg/kg/min) was given alone or combined with naltrindole (δ-opioid receptor antagonist; 1 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (μ-opioid receptor antagonist; 1 mg/kg), or 5'-guanidinonaltrindole (κ-opioid receptor antagonist; 1 mg/kg). Opioid antagonists were administered 20 minutes before MCAO. Remifentanil infusion was started 10 minutes before MCAO and continued throughout. The control group was without drugs. The expression levels of ERK1/2, p38, and JNK, and also those of tumor necrosis factor-α (TNF-α) and interleukin-6, were determined after 1, 3, and 24 hours of reperfusion.. Remifentanil significantly improved the functional outcome and reduced the infarct volumes (69.0±24.3 mm(3) vs. 108.9±24.8 mm(3)), which were not affected by D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) or 5'-guanidinonaltrindole, but were abolished by naltrindole. The I/R insult enhanced the phosphorylation of ERK 1/2 and the expression of TNF-α, which were significantly reduced by remifentanil. Neither the phosphorylation of p38 and JNK nor the production of interleukin-6 was altered throughout the experiment.. Remifentanil may be neuroprotective against focal I/R injury, possibly through the activation of δ-opioid receptors and attenuation of ERK 1/2 activity and TNF-α production, in the rat brain.

Topics: Anesthetics, Intravenous; Animals; Blood Pressure; Blotting, Western; Carbon Dioxide; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Interleukin-6; Ischemic Attack, Transient; Male; Mitogen-Activated Protein Kinases; Naltrexone; Narcotic Antagonists; Nervous System Diseases; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Reperfusion Injury; Tumor Necrosis Factor-alpha

Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.

Topics: Animals; Aquaporins; Blotting, Western; Brain Edema; Brain Ischemia; Dioxanes; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Evoked Potentials, Somatosensory; Image Processing, Computer-Assisted; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Nervous System Diseases; Neuroprotective Agents; Oligopeptides; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Wistar; Stroke; Sulfonamides; Tetrazoles

Endothelin and its receptors have long been considered therapeutic targets in the treatment of ischemic stroke. Recent studies indicate that ET(B) receptors may provide both vasodilatation and neuroprotection. The purpose of this study was to determine the effect of selectively activating the ET(B) receptors following permanent middle cerebral artery occlusion in rats. IRL-1620 [Suc-[Glu9,Ala11,15]-Endothelin-1(8-12)], a highly selective ET(B) agonist, was used alone and in conjunction with BQ788, an ET(B) antagonist, to determine the role of ET(B) receptors in cerebral ischemia. Rats were assessed for neurological deficit and motor function, and their brains were evaluated to determine infarct area, oxidative stress parameters, and ET receptor protein levels. Animals treated with IRL-1620 showed significant improvement in all neurological and motor function tests when compared with both vehicle-treated and BQ788-treated middle cerebral artery occluded groups. In addition, there was a significant decrease in infarct volume 24h after occlusion in animals treated with IRL-1620 (24.47±4.37mm(3)) versus the vehicle-treated group (153.23±32.18mm(3)). Blockade of ET(B) receptors by BQ788 followed by either vehicle or IRL-1620 treatment resulted in infarct volumes similar to those of rats treated with vehicle alone (163.51±25.41 and 139.21±15.20mm(3), respectively). Lipid peroxidation, as measured by malondialdehyde, increased and antioxidants (superoxide dismutase and reduced glutathione) decreased following infarct. Treatment with IRL-1620 reversed these effects, indicating that ET(B) receptor activation reduces oxidative stress injury following ischemic stroke. Animals pretreated with BQ788 showed similar oxidative stress damage as those in the vehicle-treated group. No significant difference was observed in ET(B) receptor levels in any of the groups. The present study demonstrates that ET(B) receptor activation may be a novel neuroprotective therapy in the treatment of focal ischemic stroke.

Topics: Analysis of Variance; Animals; Brain Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin B Receptor Antagonists; Endothelins; Gene Expression Regulation; Glutathione; Infarction, Middle Cerebral Artery; Male; Malondialdehyde; Motor Activity; Muscle Strength; Nervous System Diseases; Neurologic Examination; Oligopeptides; Peptide Fragments; Piperidines; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Rotarod Performance Test; Superoxide Dismutase

Previous studies in our laboratory showed that cannabinoid CB1 receptor knockout mice (CB1-/-) presented increased anxiety-like behaviours that did not respond to the anxiolytic actions of benzodiazepines. These results suggest that the pharmacological effects of benzodiazepines may involve the participation of cannabinoid CB1 receptors. Therefore, the purpose of this study was to examine the effects of alprazolam and the cannabinoid CB1 receptor antagonist AM251 on behavioural assays (light-dark box test, neurological severity score and step-down inhibitory avoidance test) and on the functional activity of the CB1 receptor (WIN-55,212-stimulated [(35)S] guanosine triphosphate (GTP) gamma binding autoradiography).The administration of alprazolam (40 microg/kg, intraperitoneal (i.p.)) decreased anxiety-like behaviours in the light-dark box test and significantly reduced WIN-55,212-stimulated [(35)S]GTPgamma binding autoradiography in the amygdala and in the CA1 field of the hippocampus, but was without effects on CA2, CA3 and the dentate gyrus (DG) of the hippocampus. The administration of AM251 (3 mg/kg, i.p.) blocked the anxiolytic action of alprazolam (40 microg/kg, i.p.), significantly reduced the sedative (ataxia, neurological severity score in the 0.5 cm bar) and the amnesic actions (short time term memory (1 h after electric shock)) of alprazolam (0.5 mg/kg, i.p.).Taken together, these findings revealed that cannabinoid CB1 receptor plays a pivotal role in the pharmacological actions of benzodiazepines. Furthermore, these results suggest that blockade of cannabinoid CB1 receptors may be useful in the treatment of patients with problems related to the consumption of benzodiazepines. Further clinical trials are needed to test this hypothesis.

Topics: Alprazolam; Amnesia; Amygdala; Animals; Anti-Anxiety Agents; Anxiety; Avoidance Learning; Behavior, Animal; Benzodiazepines; CA1 Region, Hippocampal; GTP-Binding Protein gamma Subunits; Hypnotics and Sedatives; Male; Mice; Mice, Inbred ICR; Nervous System Diseases; Organ Specificity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Severity of Illness Index

Adenosine-induced transient flow arrest has been used to facilitate clip ligation of intracranial aneurysms. However, the starting dose that is most likely to produce an adequate duration of profound hypotension remains unclear. We reviewed our experience to determine the dose-response relationship and apparent perioperative safety profile of adenosine in intracranial aneurysm patients.. This case series describes 24 aneurysm clip ligation procedures performed under an anesthetic consisting of remifentanil, low-dose volatile anesthetic, and propofol in which adenosine was used. The report focuses on the doses administered; duration of systolic blood pressure <60 mm Hg (SBP(<60 mm Hg)); and any cardiovascular, neurologic, or pulmonary complications observed in the perioperative period.. A median dose of 0.34 mg/kg ideal body weight (range: 0.29-0.44 mg/kg) resulted in a SBP(<60 mm Hg) for a median of 57 seconds (range: 26-105 seconds). There was a linear relationship between the log-transformed dose of adenosine and the duration of a SBP(<60 mm Hg) (R(2) = 0.38). Two patients developed transient, hemodynamically stable atrial fibrillation, 2 had postoperative troponin levels >0.03 ng/mL without any evidence of cardiac dysfunction, and 3 had postoperative neurologic changes.. For intracranial aneurysms in which temporary occlusion is impractical or difficult, adenosine is capable of providing brief periods of profound systemic hypotension with low perioperative morbidity. On the basis of these data, a dose of 0.3 to 0.4 mg/kg ideal body weight may be the recommended starting dose to achieve approximately 45 seconds of profound systemic hypotension during a remifentanil/low-dose volatile anesthetic with propofol induced burst suppression.

Topics: Adenosine; Adult; Aged; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Atrial Fibrillation; Cardiovascular Diseases; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Female; Humans; Intracranial Aneurysm; Ligation; Male; Middle Aged; Nervous System Diseases; Neurosurgical Procedures; Piperidines; Postoperative Complications; Propofol; Remifentanil; Vasodilator Agents

The term neurological diseases includes a lot of disorders concerning both the central and peripheral nervous system. Low incidence on the one hand and anaesthetic relevance on the other hand requires special attention in preoperative preparing and management of general anaesthesia. The following paper presents special problems of neurodegenerative disorders, which anaesthetic relevance is of growing interest in the changed elderly population.

Topics: Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Autonomic Nervous System; Brain; Bromocriptine; Dopamine Agonists; Humans; Intubation; Levodopa; Monoamine Oxidase Inhibitors; Muscle Relaxants, Central; Nervous System Diseases; Neurodegenerative Diseases; Neurosurgery; Parkinson Disease; Piperidines; Premedication; Preoperative Care; Propofol; Remifentanil; Selegiline; Stereotaxic Techniques; Syndrome

A novel postsynaptic antagonist of N-methyl-D-aspartate (NMDA) receptors, CP-101,606-27 may attenuate the effects of focal ischemia. In current experiments, the authors investigated its neuroprotective effect alone and in combination with recombinant tissue plasminogen activator (rt-PA) in thromboembolic focal cerebral ischemia in rats.. Forty-eight male Wistar rats underwent embolization of the right middle cerebral artery to produce focal cerebral ischemia. After random division into six groups (eight rats in each group), animals received: vehicle; low-dose (LD) CP-101, 606-27, 14.4 mg/kg; high-dose (HD) CP- 101,606-27, 28.8 mg/kg; rt-PA, 10 mg/kg; low-dose combination (LDC) CP- 101,606-27, 14.4 mg/kg plus rt-PA, 10 mg/kg; or high-dose combination (HDC) CP- 101,606-27, 28.8 mg/kg plus rt-PA, 10 mg/kg) 2 hours after induction of embolic stroke. Animals were killed 48 hours after the onset of focal ischemia. Brain infarction volume, neurobehavioral outcome, poststroke seizure activity, poststroke mortality, and intracranial hemorrhage incidence were observed and evaluated. Compared with vehicle-treated animals (39.4 +/- 8.6%) 2 hours posttreatment with CP-101,606-27 or rt-PA or in combination a significant reduction in the percentage of brain infarct volume was seen (LD CP-101,606-27: 20.8 +/- 14.3%, p < 0.05; HD CP-101,606-27: 10.9 +/- 3.2%, p < 0.001; rt-PA: 21.1 +/- 7.3%, p < 0.05; LDC, 18.6 +/- 11.5%, p < 0.05; and HDC: 15.2 +/- 10.1%, p < 0.05; compared with control: 39.4 +/- 8.6%). Combination of CP-101,606-27 with rt-PA did not show a significantly enhanced neuroprotective effect. Except for the control and LDC treatment groups, neurobehavioral outcome was significantly improved 24 hours after embolic stroke in animals in all other active therapeutic groups receiving CP-101,606-27 or rt-PA or in combination. The authors also observed that treatment with HD CP-101,606-27 decreased poststroke seizure activity.. The data in this study suggested that postischemia treatment with CP-101,606-27 is neuroprotective in the current stroke model; however, the authors also note that although rt-PA may offer modest protection when used alone, combination with CP-101,606-27 did not appear to enhance its effects.

Topics: Animals; Brain Infarction; Disease Models, Animal; Drug Therapy, Combination; Male; Nervous System Diseases; Neuroprotective Agents; Piperidines; Plasminogen Activators; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Severity of Illness Index; Stroke; Thromboembolism; Tissue Plasminogen Activator

Topics: Aged; Anti-Ulcer Agents; Arrhythmias, Cardiac; Cisapride; Humans; Male; Nervous System Diseases; Parasympathomimetics; Piperidines

The risk of aspiration during tube feedings has been reduced but not abolished by percutaneous endoscopic gastrostomy (PEG). This open study was planned to evaluate whether cisapride may play some role in preventing aspiration in long-term enteral feeding via PEG. A group of 29 patients, unable to swallow because of head and neck cancer (14 cases) or neurological disorders (15 cases) entered the study; 7 neurological patients, fed via nasogastric tube before PEG placement, had suffered from aspiration pneumonia during nasogastric feeding. All patients underwent PEG, and 10 mg cisapride was routinely given via PEG before each administration of enteral feeding and 6 h after its initiation when the feeding was continued for 12 h or more. Only 1 minor complication was observed during the acute hospital setting (ileus, spontaneously resolving after 36 h). After hospital discharge, the patients were followed for a total of 4935 days of feeding (range 47-508 days, mean time per patient: 170 days) and assessed weekly for the development of complications. No episode of probable/possible aspiration pneumonia was observed during the follow-up. Two neurological patients with involuntary movements had rupture of the feeding tube, which was replaced without complications. These results support the hypothesis that cisapride might play some role in the prevention of aspiration in patients fed via PEG, and justify the planning of some controlled, double-blind trials to verify such a hypothesis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cisapride; Deglutition Disorders; Enteral Nutrition; Female; Follow-Up Studies; Gastroscopy; Gastrostomy; Head and Neck Neoplasms; Humans; Intubation, Gastrointestinal; Male; Middle Aged; Nervous System Diseases; Pilot Projects; Piperidines; Pneumonia, Aspiration; Serotonin Antagonists; Survival Rate

In the past, hemlock poisoning was only known for its neurotoxic effects; quite recently non-neurological features, consisting of rhabdomyolysis and acute renal failure, have been also described. Here we report our experience with these clinical findings, which we frequently observe in accidental hemlock poisoning. Between 1972 and 1990 we studied 18 patients: 17 of them were poisoned by conline (an alkaloid of Conium maculatim) in Apulia (Italy), and one by cicutoxin (the active principle of water hemlock) in New Mexico (USA). In the non-rapidly-fatal cases we tested myoglobinuria, serum muscle enzymes, and renal function. In the patients with acute renal failure we performed microscopical examination of kidney specimens; immunohistochemistry was carried out to identify myoglobin and actin in tubules. Coniine was detected in urine, serum, or tissues. Neurological features were present in all of our cases: coniine had a curare-like effect on the neuromuscular junction, whereas cicutoxin was convulsant on the central nervous system. In addition rhabdomyolysis was noted in the 17 subjects poisoned by coniine. Acute renal failure was observed in five patients; it was confirmed by histological evidence of tubular necrosis with intratubular deposition of myoglobin and actin released by rhabdomyolysis. Our cases seem to be the first with histopathologically proven acute tubular necrosis in coniine intoxication. In conclusion, in hemlock poisoning neurotoxic manifestations may be accompanied by rhabdomyolysis and acute tubular necrosis; increased awareness of these clinical features is recommended in order to improve the diagnostic and therapeutic procedure.

Topics: Adult; Aged; Alkaloids; Alkynes; Diynes; Fatty Alcohols; Female; Humans; Kidney Tubular Necrosis, Acute; Male; Middle Aged; Nervous System Diseases; Piperidines; Plant Poisoning; Rhabdomyolysis

Topics: Analgesics; Animals; Clinical Trials as Topic; Humans; Nervous System Diseases; Pain; Pain Measurement; Palliative Care; Paroxetine; Piperidines

The possible neurotoxic effects of the alpha-ethyl homologue of MDMA, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB), were examined following a regimen of twice daily dosing for four days. The levels of norepinephrine, serotonin and its metabolite 5-HIAA were quantitated by standard HPLC-EC techniques. In addition, the number of 5-HT uptake sites was estimated by examining the binding of [3H]-paroxetine to rat cortex homogenate. With 20 mg/kg (IP) subacute dosing of MDMA, a nearly 60% reduction in 5-HT, 5-HIAA, and 5-HT uptake sites was found, with no change in NE, two weeks posttreatment. A behaviorally equipotent dose of MBDB (25 mg/kg, IP) also produced a significant decrease in the serotonergic markers; 5-HT, 5-HIAA and [3H]-paroxetine binding sites. However, a comparison of the relative toxic effects of MDMA and MBDB indicates that MBDB may be slightly less neurotoxic. It was also found that MDMA but not MBDB caused a significant increase in dopamine levels at 3 hours following a single IP injection. The results are discussed in relation to the therapeutic index of MBDB and the relative importance of dopamine release in the neurotoxicity of MDMA.

Topics: 3,4-Methylenedioxyamphetamine; Amphetamines; Animals; Biogenic Monoamines; Brain Chemistry; Hydroxyindoleacetic Acid; Male; N-Methyl-3,4-methylenedioxyamphetamine; Nervous System Diseases; Norepinephrine; Paroxetine; Piperidines; Rats; Rats, Inbred Strains; Serotonin

3,4-Methylenedioxymethamphetamine (MDMA; 'Ecstasy') is a known neurotoxin to 5-hydroxytryptamine (5-HT) nerve terminals. Recent studies have suggested that endogenous dopamine (DA) and/or 5-HT may mediate the MDMA-induced neurotoxicity. The central monoamine stores of rats were significantly decreased with reserpine (5 mg/kg) prior to toxic injections of MDMA. Rats given MDMA (30 mg/kg) displayed significant decreases in the density of 5-HT nerve terminals labeled by [3H]paroxetine both with (51 +/- 8%) and without (43 +/- 20%) reserpine pre-treatment. These data suggest that the degeneration of 5-HT nerve terminals following MDMA is independent of the presence of endogenous stores of DA or 5-HT.

Topics: 3,4-Methylenedioxyamphetamine; Amphetamines; Animals; Cerebral Cortex; Corpus Striatum; Designer Drugs; Dopamine; Male; N-Methyl-3,4-methylenedioxyamphetamine; Nerve Endings; Nervous System Diseases; Paroxetine; Piperidines; Rats; Rats, Inbred Strains; Reserpine; Serotonin

Three children with neurological symptoms precipitated by loperamide are presented, one of them with irreversible sequelae. The use of this drug in infancy is discouraged in view of these secondary effects.

Topics: Child, Preschool; Female; Humans; Infant; Loperamide; Male; Nervous System Diseases; Piperidines

Topics: Aged; Autonomic Nervous System; Female; Humans; Male; Middle Aged; Nervous System Diseases; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Topics: Angina Pectoris; H-Reflex; Humans; Nervous System Diseases; Perhexiline; Piperidines

Perhexiline maleate (Pexid) which has been in general use in France with good results for the treatment of angina pectoris since 1973, may be associated with severe side effects including peripheral neuropathy. The present study is a comparison of the pharmacokinetics of perhexiline maleate in anginal patients with and without signs of peripheral neuropathy. Compared to the latter, those with neuropathy had higher plasma levels of perhexiline, slower hepatic metabolism and a longer plasma half-life. Thus, peripheral neuropathy associated with perhexiline maleate treatment appears to be a direct toxic effect due to accumulation of the drug. The accumulation might result either from a decreased volume of distribution secondary to a loss of body weight, possibly drug-induced, or to slow hepatic metabolism of perhexiline of genetic origin or due to hepatic disease, possibly drug-induced. The neuropathy is rarely an isolated event, as it is often associated with one or more adverse effects of perhexiline.

Topics: Aged; Angina Pectoris; Female; Humans; Kinetics; Male; Middle Aged; Nervous System Diseases; Perhexiline; Piperidines; Time Factors

Ten Caucasian patients with perhexiline maleate neurotoxicosis and weight loss are presented. Weight loss preceded symptomatic neuropathy which was detected on electromyography in one patient. Weight loss and neuropathy may be marked, but clinical improvement follows drug withdrawal.

Topics: Aged; Body Weight; Female; Humans; Male; Middle Aged; Nervous System Diseases; Perhexiline; Piperidines

Topics: Autonomic Nervous System; Diabetic Neuropathies; Humans; Male; Middle Aged; Nervous System Diseases; Perhexiline; Peripheral Nervous System Diseases; Piperidines

Topics: Aged; Humans; Male; Nervous System Diseases; Perhexiline; Piperidines

Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Nervous System Diseases; Neurotic Disorders; Nitriles; Phenothiazines; Piperidines; Psychotic Disorders; Tranquilizing Agents

Topics: Electroconvulsive Therapy; Hypnotics and Sedatives; Mental Disorders; Nervous System Diseases; Piperidines; Psychosurgery; Psychotherapy

Topics: Humans; Nervous System Diseases; Parkinson Disease; Piperidines; Trihexyphenidyl

Topics: Autonomic Agents; Hypnotics and Sedatives; Mental Disorders; Nervous System Diseases; Piperidines; Psychotherapy