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At least 649 records · Page 36Linked to original sources
PubMed2003

Prodrugs to enhance central nervous system effects of the TRH-like peptide pGlu-Glu-Pro-NH2.

Potential prodrugs for the TRH-like tripeptide pGlu-Glu-Pro-NH(2) were synthesized either by esterifying the Glu side-chain of the parent peptide in solution with alcohols in the presence of resin-bound dicyclohexylcarbodiimide or by solid-phase peptide chemistry. Affinities of these ester prodrugs to lipid membranes as predictors of the transport across the blood-brain barrier were compared by immobilized artificial membrane chromatography, and prodrug activation was tested in the brain tissue of experimental animals. Esters of pGlu-Glu-Pro-NH(2) with long-chain primary alcohols emerged as potentially useful prodrugs to improve the central nervous system activity of pGlu-Glu-Pro-NH(2) upon systemic administration, as revealed by the enhancement of analeptic activity in mice.

Animals↗
PubMed2004

Centrally acting and metabolically stable thyrotropin-releasing hormone analogues by replacement of histidine with substituted pyridinium.

Metabolically stable and centrally acting thyrotropin-releasing hormone (TRH) analogues were designed by replacing the central histidine with substituted pyridinium moieties. Their analeptic and acetylcholine-releasing actions were evaluated to assess their potency as central nervous system (CNS) agents. A strong experimental connection between these two CNS-mediated actions of the TRH analogues was obtained in subject animals. The analogue 3-(aminocarbonyl)-1-(3-[2-(aminocarbonyl)pyrrolidin-1-yl]-3-oxo-2-[[(5-oxopyrrolidin-2-yl)carbonyl]amino]propyl)pyridinium (1a) showed the highest (TRH-equivalent) potency and longest, dose-dependent duration of action from a series of homologous compounds in antagonizing pentobarbital-induced narcosis when administered intravenously in its CNS-permeable prodrug form (2a) obtained via reduction of the pyridinium moiety to the nonionic dihydropyridine. The maximum change in hippocampal acetylcholine concentration upon perfusion of the pyridinium-containing tripeptides into the hippocampus of rats was also achieved with 1a. No binding to the endocrine TRH receptor was measured for the TRH analogues reported here; therefore, our design afforded a novel lead for centrally acting TRH analogues. We have also demonstrated the benefits of the prodrug approach on the pharmacokinetics and brain uptake/retention of pyridinium-containing TRH analogues (measured by in vivo microdialysis sampling) upon systemic administration.

Acetylcholine↗
PubMed1992

High-dose methotrexate does not affect the pharmacodynamics of phenobarbital hypnotic action but decreases the central nervous system (CNS) sensitivity to pentylenetetrazol-induced maximal seizures in rats.

Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. We determined whether the altered neuronal function after HD-MTX [such as the reduced regional cerebral metabolic glucose rate (rCMRGlc) and slow electroencephalographic pattern] affects the sensitivity of the CNS to centrally acting drugs: the depressant phenobarbital, which reduces rCMRGlc, and the analeptic agent pentylenetetrazol (PTZ), which elevates rCMRGlc. Adult male Sabra rats received an i.v. infusion of MTX, 0.51 mg/min, to induce neurotoxicity or saline solution for 24 hr. Subsequently, MTX-treated and control groups were infused in one experiment with phenobarbital until loss of the righting reflex and in the second experiment with PTZ until the onset of maximal seizures. HD-MTX did not affect the infused hypnotic dose or serum, brain, and cerebrospinal fluid concentrations of phenobarbital at the onset of anesthesia. The convulsive dose and PTZ concentrations in the serum and brain at the onset of maximal seizures were significantly higher in the HD-MTX-treated animals. These outcomes indicate that HD-MTX and the reduced rCMRGlc that follows this treatment do not contribute to the hypnotic action of phenobarbital. On the other hand, treatment with HD-MTX exhibited anticonvulsant properties as evidenced by the reduced CNS sensitivity to PTZ-induced seizures.

Animals↗
PubMed2004

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport.

1 Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. 2 The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (P<0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (P<0.001). 3 Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. 4 There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. 5 Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis.

Animals↗
PubMed2003

Antisense knockdown of the Shaker-like Kv1.1 gene abolishes the central stimulatory effects of amphetamines in mice and rats.

Amphetamine (AMPH) is an indirect sympathomimetic compound classified as a substrate-type releaser that distinguishes it from other stimulants that act as uptake 1 blockers, such as cocaine (COC). In mammals, AMPH elicits central stimulation, hypermotility, anorexia, analgesia and analeptic activity, mainly through the increase of extracellular brain dopamine (DA). The inversion of vesicular transporters and/or intravesicular alkalinization is assumed to have a role in AMPH-induced exocytosis. However, the action mechanism of this compound has not yet been completely clarified. Recent evidence on the action of AMPHs indicates potassium channel-blocking properties in peripheral tissues. We investigated the possible involvement of a Shaker-like Kv1.1 channel subtype in the central effects of AMPH, using an antisense oligodeoxyribonucleotide (aODN) that specifically and reversibly inhibits the expression of these channels in the brain. The effect of aODN pretreatments was studied by evaluating the modification of behavioral effects induced in mice through the intracerebroventricular administration of AMPH, COC, or other compounds. The aODN in mice almost completely blocked the stimulatory effects of AMPH and other releasers but was ineffective in reducing the central activity of COC. In aODN-pretreated rats a strong reduction of the AMPH, but not of the COC-stimulated DA efflux from nucleus accumbens was observed. Our results suggest that the stimulant effects of AMPH and chemically related compounds, but not COC, require the presence of functionally active Kv1.1 channels in the brain.

Amphetamine↗
PubMed1999

Central effects of 5-HT on respiratory rhythm in newborn rats in vivo.

The role of 5-HT in inducing apnoeas (a major element in sudden infant death syndrome) is controversial because while 5-HT is a respiratory depressant in vivo, it evokes respiratory analeptic effects when applied to the isolated brainstem of the newborn rat. In decerebrate newborn rats, the electrical activity of the diaphragm and that of a hypoglossally innervated tongue muscle, as well as the cardiac frequency (Fc), were recorded before and after the application of 5-HT and related agents to the floor of the IVth ventricle. To assess the spontaneous variability in inspiratory frequency (Fi) and Fc, a sham group was studied. A decrease in Fi was observed in response to 5-HT. This respiratory depressant effect was associated with an activation of the tongue muscle, but there was no change in Fc. Application of agonists elicited a small increase in Fi linked to activation of 5-HT1A receptors, and decreases in both Fi and the activity of the tongue muscle resulting predominantly from activation of 5-HT2 receptors. The decrease in Fi was much smaller in newborn rats than that reported in newborn kittens. Indeed, in newborn rats, we did not observe long-lasting apnoeas. Our results differ from those obtained from the newborn rat in vitro, inasmuch as in vivo 5-HT essentially depressed the respiratory rhythm generator. The role of the afferent system appears to be crucial in modulating the action of 5-HT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Maximal ventilation assessment in healthy calves.

In order to define a reliable method for estimating maximal ventilation in cattle, 12 healthy calves underwent a rebreathing trial and injections of increasing doses of lobeline, a respiratory analeptic. The effects of these tests on the main ventilatory parameters (tidal volume, VT; respiratory frequency, fRand minute volume,.VE) recorded during the 15 s of maximal response were studied and compared. The sharp rise in.VE(4.8 times higher than the resting value) observed during the rebreathing trial was mainly due to an increase in VT. This rise in ventilation was the highest ever reported in calves. Lobeline dose-dependently enhanced ventilation up to a threshold dose of 0.25 mg/kg, which always produced a maximal response. This maximal response (3.7 times higher than the resting value), reflecting both an increase in fR and VT, was reproducible at an interval of 12 h and was highly correlated with that observed during the rebreathing trial (R = 0.98, P< 0.001). These results suggest that: (1) rebreathing trial is a reliable method to induce and measure maximal ventilation in calves; and (2) lobeline administration (0.25 mg/kg) is a reliable means of accurately estimating this variable. Lobeline administration, unlike the rebreathing trial, is safe and easy to standardize, and the test therefore seems to be the preferred way of studying maximal ventilation in calves.

Animals↗
PubMed1995

Effects of corticotropin-releasing hormone on respiratory parameters during sleep in normal men.

Corticotropin-releasing hormone (CRH) is well-known to be a centrally acting respiratory stimulant after systemic application both in healthy subjects and in patients suffering from respiratory failure. In order to study the effects of CRH on sleep EEG and respiratory parameters during sleep, 14 healthy male volunteers were investigated in a single-blind placebo controlled design. After an adaptation night, polysomnography was performed during two successive nights between 23.00 hrs. and 7.00 hrs. During one night placebo was applied, on the other 50 micrograms ovine CRH was administered intravenously as a bolus every hour from 0.00 hrs. to 6.00 hrs. For the assessment of respiration, blood oxygen saturation and thoracic wall movements were measured, as well as nasal and oral airflow using the thermistor method. Sleep efficiency parameters and subjective perception of sleep quality were not affected following CRH. The following alterations were found regarding sleep architecture: REM sleep as well as slow wave sleep showed a tendency to decrease under CRH, whereas light sleep tended to increase. After an injection of CRH a stimulation of respiration could be observed, with an increase of tidal volume over a time interval of a few minutes. Blood oxygen saturation was only slightly increased. Cortisol and ACTH concentrations were found to be constantly elevated. These results indicate that respiration during sleep is clearly affected by CRH with only slight alterations of global sleep parameters. No association was found between stimulation of ventilation and the occurrence of arousals; the respiratory analeptic effect of CRH thus appears to be specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed2004

Antitumor and antimetastatic activities of 4-hydroxyderricin isolated from Angelica keiskei roots.

The roots of Angelica keiskei Koizumi (Umbelliferae) have traditionally been used as a health food considered to have diuretic, laxative, analeptic and lactagogue effects. Recently, it has been thought that the roots and herbs of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. It has been reported that chalcone derivatives, such as xanthoangelol and 4-hydroxyderricin, are isolated as main components from this root. Recently, we reported that the 50 % ethanol extract, the ethyl acetate-soluble fraction and the isolated xanthoangelol, inhibited tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. In the present study, we examined the effects of 4-hydroxyderricin on tumor growth and metastasis to the lung or liver in subcutaneous or intrasplenic LLC-implanted C57BL/6J female mice. 4-Hydroxyderricin at a dose of 50 mg/kg x 2/day orally inhibited the tumor growth in subcutaneous LLC-implanted mice and inhibited the lung metastasis and prolonged the survival time in mice after the removal of subcutaneous tumors by surgical operation. Doxorubicin (5 mg/kg x 2/week, i. p.) inhibited the tumor growth and metastasis to the lung, but it shortened the survival time and reduced the survival rate compared to those in 4-hydroxyderricin-treated mice. 4-Hydroxyderricin inhibited DNA synthesis in LLC cells at a concentration of 100 microM, but it had no effect on the DNA synthesis in human umbilical vein endothelial cells (HUVECs) or on the adherence of LLC cells to HUVECs. 4-Hydroxyderricin inhibited Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 10 to 100 microM. The weights of the spleen and thymus in mice with subcutaneously implanted LLC were maintained close to those of normal mice by orally administered 4-hydroxyderricin. In addition, 4-hydroxyderricin (50 mg/kg x 2/day) inhibited the reduction of the numbers of lymphocytes, CD4+, CD8+ and natural killer (NK)-T cells in the spleen of tumor-removed mice. Doxorubicin reduced the numbers of lymphocytes, CD4+, CD8+ and NK cells compared to those in LLC-removed mice. These results suggest that the antitumor and antimetastatic activities of 4-hydroxyderricin may be modulated by the immune system and the inhibition of angiogenesis.

Angelica↗
PubMed2006

Bupropion augmentation in the treatment of chronic fatigue syndrome with coexistent major depression episode.

While psychoeducational strategies and general support are always indicated for the treatment of chronic fatigue syndrome (CFS), pharmacological strategies are yet not well established. Antidepressants such as selective serotonin re-uptake inhibitors have been shown to influence positively symptoms and immunological parameters. However, a considerable part of CFS patients do not satisfactorily respond to them. Bupropion, a centrally acting catecholamine-transporter blocker without classic psycho-analeptic properties, shows theoretical potential to improve fatigue symptoms. In the reported case paroxetine was augmented with bupropion at high dosage, a strategy which consecutively led to a rapid relief of CFS-symptoms.

Adult↗
PubMed1999

Progesterone and neurology.

Neurological diseases are frequently observed in perimenopausal women and can be characterized by their gender-specific occurrence. These observations raise the question whether sex steroids are also involved in neurological diseases. Epidemiological data have shown that in Austria in 1993, the prescription rate of psychotropics, hypnotics, and analeptics for women aged 50-55 years increased over 300% compared to other age groups. In males of the same age, an increase of the prescription rate was not observed. Molecular pharmacology research over the last ten years has shown that sex steroids may interact with the central nervous system via GABA receptors as well as with the peripheral nervous system. These observations confirm the epidemiological finding that neurological and psychological functions may also be directly influenced by sex steroids and their metabolites.

Adult↗
PubMed1980

Postoperative effects of methylphenidate.

A double-blind study is described in which the analgesic and analeptic properties of methylphenidate were investigated in 63 patients following surgery. No effect of methylphenidate on postoperative pain was observed. However, methylphenidate reduced sedation up to 30 min after operation, and improved respiratory function up to 180 min in patients receiving halothane. No conclusive evidence of improvement in mood was obtained, and occasional undesirable behavioural effects of methylphenidate were seen.

Adolescent↗
PubMed1980

Ventilatory depression of the newborn of women receiving pethidine or pentazocine. A double-blind comparative trial.

Forty-two women at term received pethidine 100 mg and 43 received pentazocine 45 mg, both given in a double-blind randomized manner. There was no difference in analgesic effect between the groups, but twelve patients were judged to need more than one injection of pentazocine, compared with seven in the pethidine group. The Apgar scores at 1 and 5 min were significantly less in the pethidine group. Four neonates in the pethidine group and two in the pentazocine group were severely depressed and received naloxone between 5 and 15 min after birth. The remainder of the infants received naloxone 200 microgram i.m. 15 min after birth. From 5 min after birth, end-expiratory carbon dioxide concentrations and from 15 min transcutaneous PO2 were recorded. A significantly smaller end-tidal carbon dioxide concentration was measured when more than one injection of pentazocine had been given. Repeated doses of pethidine, on the other hand, resulted in a greater end-tidal carbon dioxide concentration. Vigorous ventilation was even more pronounced when naloxone was given indicating an analeptic effect when two drugs with antagonistic activity are combined. At no time was transcutaneous PO2 less than 6.1 kPa. We conclude that both pethidine and pentazocine produce adequate pain relief during labour, but more than one injection of pethidine is associated with greater neonatal depression.

Anesthesia, Obstetrical↗
PubMed1982

Effect of physostigmine on morphine-induced postoperative pain and somnolence.

The effects of physostigmine 1 mg i.v. were studied on the analgesia, sedation and reduction in respiratory rate induced by morphine 10 mg/60 kg i.v. in 10 patients recovering from surgery. Within 5-10 min, physostigmine abolished the somnolent effect of morphine and restored the respiratory rate to pre-drug values. Analgesia, assessed by an independent observer and by the patient was, if anything, increased by physostigmine. The analeptic effect of physostigmine lasted 40-60 min.

Adult↗
PubMed1978

Naloxone does not antagonize general anesthesia in the rat.

The administration of naloxone 2, 10, 50, or 250 mg/kg intravenously did not alter halothane requirement (MAC) in Sprague-Dawley rats (12 per group). Two rats convulsed when given 50 mg/kg while anesthetized with halothane. In a separate group of awake rats, seven of nine animals convulsed when given naloxone, 100 mg/kg. It is concluded that any effect of naloxone on anesthetic requirement must be small (not significant in our study), and that if an effect exists it is the result of a nonspecific analeptic action of naloxone rather than a specific action at opiate receptors.

Anesthesia, Inhalation↗
PubMed1986

Mechanism of antagonism by physostigmine of acute flunitrazepam intoxication.

The effect of physostigmine on the loss of consciousness and respiratory depression induced in rabbits by flunitrazepam, 1 mg/kg, was studied to demonstrate whether the restoration of consciousness and respiration rate results from an increase in central cholinergic activity or from an interference by physostigmine with specific binding of flunitrazepam to its receptors. Physostigmine, 0.1-0.4 mg/kg iv, caused a dose-related reversal of consciousness and respiration rate within 15 min of its injection, which lasted 15-30 min depending on the dose. This was associated with peak inhibition of acetylcholinesterase (AChE) in the frontal cortex and medulla, at 15 min, ranging from 35-51%. The analeptic effect of physostigmine in flunitrazepam-treated rabbits was prevented by pretreatment with scopolamine, 1 mg/kg. The effective dose range for physostigmine, 3-12 mumol/kg, is close to concentrations of this agent that inhibit activity in solubilized preparations of AChE from rabbit cortex, 1-3 X 10(-8) M. However, physostigmine, 10(-9) -10(-4) M, failed to displace 3H flunitrazepam from specific binding sites on membranes prepared from rabbit cerebral cortex. It is concluded that physostigmine antagonizes the somnolence and respiratory depression induced by benzodiazepines by restoring cholinergic transmission to normal levels. The effective dose range of physostigmine is small, and serious side effects from overdose can occur as a result of excess cholinergic activity at neuromuscular synapses.

Acetylcholinesterase↗
PubMed2003

Novel diketopiperazine enhances motor and cognitive recovery after traumatic brain injury in rats and shows neuroprotection in vitro and in vivo.

The authors developed a novel diketopiperazine that shows neuroprotective activity in a variety of in vitro models, as well as in a clinically relevant experimental model of traumatic brain injury (TBI) in rats. Treatment with 1-ARA-35b (35b), a cyclized dipeptide derived from a modified thyrotropin-releasing hormone (TRH) analog, significantly reduced cell death associated with necrosis (maitotoxin), apoptosis (staurosporine), or mechanical injury in neuronal-glial cocultures. Rats subjected to lateral fluid percussion-induced TBI and then treated with 1 mg/kg intravenous 35b thirty minutes after trauma showed significantly improved motor recovery and spatial learning compared with vehicle-treated controls. Treatment also significantly reduced lesion volumes as shown by magnetic resonance imaging, and decreased the number of TUNEL-positive neurons observed in ipsilateral hippocampus. Unlike TRH or traditional TRH analogs, 35b treatment did not change mean arterial pressure, body temperature, or thyroid-stimulating hormone release, and did not have analeptic activity. Moreover, in contrast to TRH or typical TRH analogs, 35b administration after TBI did not alter free-magnesium concentration or cellular bioenergetic state. Receptor-binding studies showed that 35b did not act with high affinity at 50 classical receptors, channels, or transporters. Thus, 35b shows none of the typical physiologic actions associated with TRH, but possesses neuroprotective actions in vivo and in vitro, and appears to attenuate both necrotic and apoptotic cell death.

Animals↗
PubMed1999

Theoretical electroencephalogram stationary spectrum for a white-noise-driven cortex: evidence for a general anesthetic-induced phase transition.

We present a model for the dynamics of a cerebral cortex in which inputs to neuronal assemblies are treated as random Gaussian fluctuations about a mean value. We incorporate the effect of general anesthetic agents on the cortex as a modulation of the inhibitory neurotransmitter rate constant. Stochastic differential equations are derived for the state variable h(e), the average excitatory soma potential, coherent fluctuations of which are believed to be the source of scalp-measured electroencephalogram (EEG) signals. Using this stochastic approach we derive a stationary (long-time limit) fluctuation spectrum for h(e). The model predicts that there will be three distinct stationary (equilibrium) regimes for cortical activity. In region I ("coma"), corresponding to a strong inhibitory anesthetic effect, h(e) is single valued, large, and negative, so that neuronal firing rates are suppressed. In region II for a zero or small anesthetic effect, h(e) can take on three values, two of which are stable; we label the stable solutions as "active" (enhanced firing) and "quiescent" (suppressed firing). For region III, corresponding to negative anesthetic (i.e., analeptic) effect, h(e) again becomes single valued, but is now small and negative, resulting in strongly elevated firing rates ("seizure"). If we identify region II as associated with the conscious state of the cortex, then the model predicts that there will be a rapid transit between the active-conscious and comatose unconscious states at a critical value of anesthetic concentration, suggesting the existence of phase transitions in the cortex. The low-frequency spectral power in the h(e) signal should increase strongly during the initial stage of anesthesia induction, before collapsing to much lower values after the transition into comatose-unconsciousness. These qualitative predictions are consistent with clinical measurements by Bührer et al. [Anaesthesiology 77, 226 (1992)], MacIver et al. [ibid. 84, 1411 (1996)], and Kuizenga et al. [Br. J. Anaesthesia 80, 725 (1998)]. This strong increase in EEG spectral power in the vicinity of the critical point is similar to the divergences observed during thermodynamic phase transitions. We show that the divergence in low-frequency power in our model is a natural consequence of the existence of turning points in the trajectory of stationary states for the cortex.

Action Potentials↗