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Synthetic analgesics and other phenylpiperidines: effects on uptake and storage of dopamine and other monoamines mouse forebrain tissue.

The neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce degeneration of dopamine (DA) and other central monoamine neur … take of NE than of DA. MPP+ was also more potent than MPTP in releasing endogenous DA from striatal synaptosomes (EC50 = 3 vs. 30 microM), but did not release the cytoplasmic markers tyrosine hydroxylase and lactate dehydrogenase (LDH). In contrast to MPTP, synthetic phenylpiperidine analgesics, their potential metabolites and the experimental neuroleptic agen …

The synaptic membrane D2-protein in amniotic fluid from pregnancies with fetal neural tube defects.

The D2-protein is a neuronal membrane protein which has an immunochemically detectable soluble derivative in cerebrospinal fluid. We used rocket-on-line immunoelectrophoresis with an antiserum against rat synaptosomal membranes for demonstration of the human D2-protein in fetal cerebrospinal fluid and in amniotic fluids from pregnancies with fetal neural tube defects. D2 was neither found in normal amniotic fluids nor in cases of amniotic fluids from pregnancies with other malformations. Analysis of D2 in amniotic fluids may thus have a future role in the antenatal diagnosis of fetal neural tu

Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models.

BACKGROUND AND OBJECTIVES: Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selectiv

Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.

Methamphetamine (METH) is a highly abused psychostimulant that is neurotoxic to dopaminergic (DAergic) nerve terminals in the striatum and increases the risk of developing Parkinson's disease (PD). In vivo, METH-mediated DA release, followed by DA-mediated oxidative stress and mitochondrial dysfunction in pre- and postsynaptic neurons, mediates METH neurotoxicity. METH-triggered oxidative stress damages parkin, a neuroprotective protein involved in PD etiology via its involvement in the maintenance of mitochondria. It is not known whether METH itself contributes to mitochondrial dysfunction an

Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment.

Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients' daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairment

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… Synaptosome isolation and mitochondrial bioenergetics analysis Synaptosomes were isolated as previously described [ 11 ]. Briefly, one hemisphere of the brain was homogenized (10% w / v ) into 0.32 M sucrose solution in HEPES buffer using a glass Dounce homogenizer. … Results are expressed as mean ± SEM; * P < 0.05 ACY-1083 reverses cisplatin-induced impairment in synaptosomal mitochondrial morphology and bioenergetics Synaptosomal mitochondrial dysfunction is a key player in cisplatin-induced cognitive impairment [ 11 ]. …

Characterization of Am IT, an anti-insect β-toxin isolated from the venom of scorpion Androctonus mauretanicus.

In the present study, a 'novel' toxin, called Am IT from the venom of scorpion Androctonus mauretanicus is isolated and characterized. A det … ect. The toxin competed with radio-labeled β-toxin Css IV by binding to Na(+) channels of rat brain synaptosomes. Analysis of toxin amino acid sequences showed that Am IT shares high structural identity (92%) with AaH IT4. In conclusion, Am IT not only reveals an anti-insect compound properties secreted by 'Old World' scorpions, paralyzing insect larvae by bin …

Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington's disease.

A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's disease (HD), a neurodegenerative disorder. HD patients have ox … ce had elevated NOX activity at 3 months of age and a further rise at 6 and 12 months compared with synaptosomes of age-matched wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons of HD(140Q/140Q) mice correlated with more ROS and neurite swellings. These features and neuronal cell death were markedly reduced by treatment with NOX i …

Volatile anesthetics selectively inhibit the Ca(2+)-transporting ATPase in neuronal and erythrocyte plasma membranes.

BACKGROUND: The activity of the plasma membrane Ca(2+)-transporting adenosine triphosphatase (PMCA) is inhibited by volatile anesthetics at clinical concentrations. The goal of the current study was to determine whether the inhibition is selective as compared to other adenosine triphosphatases (ATPases) and another group of general anesthetics, barbiturates. In addition, the authors determined whether the response to anesthetics of the enzymes in neuronal membranes is similar to that in erythrocyte membranes. METHODS: The effects of halothane, isoflurane, and sodium pentobarbital on four diff

SNX-325, a novel calcium antagonist from the spider Segestria florentina.

A novel selective calcium channel antagonist peptide, SNX-325, has been isolated from the venom of the spider Segestria florentina. The peptide was isolated using as bioassays the displacement of radioiodinated omega-conopeptide SNX-230 (MVIIC) from rat brain synaptosomal membranes, as well as the inhibition of the barium current through cloned expressed calcium channels in oocytes. The primary sequence of SNX-325 is GSCIESGKSCTHSRSMKNGLCCPKSRCNCRQIQHRHDYLGKRKYSCRCS, which is a novel amino acid sequence. Solid-phase synthesis resulted in a peptide that is chromatographically identical with the

Aβ/tau oligomer interplay at human synapses supports shifting therapeutic targets for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is characterized by progressive cognitive decline due to accumulating synaptic insults by toxic oligome … t each other's binding dynamics. METHODS: Binding of labeled, pre-formed Aβ and tau oligomers onto synaptosomes isolated from the hippocampus and frontal cortex of mouse and postmortem cognitively intact elderly human brains was evaluated using flow-cytometry and western blot analyses. Binding of labeled, pre-formed Aβ and tau oligomers onto mouse primary neu …

Early life stress induces hyperactivity but not increased anxiety-like behavior or ethanol drinking in outbred heterogeneous stock rats.

Early life stress is known to impact vulnerability to psychopathological disorders in adulthood, including anxiety and alcohol use disorder … ncentrations. Furthermore, while ASI in Long-Evans rats resulted in decreased SK2 expression in vHC synaptosomes, no differences were seen in vHC synaptosomes for SK2 or GluA1 in HS rats. These results demonstrate that HS rats are protected against many of the negative effects previously seen in response to ASI, namely anxiety-like behavior and increased ethan …

Effects of chlorpromazine HCl on the structural parameters of bovine brain membranes.

Fluorescence probes located in different membrane regions were used to evaluate the effects of chlorpromazine .HCl on structural parameters (transbilayer lateral mobility, annular lipid fluidity, protein distribution, and lipid bilayer thickness) of synaptosomal plasma membrane vesicles (SPMVs) isolated from bovine cerebral cortex. The experimental procedure was based on the selective quenching of 1,3-di(1-pyrenyl)propane (Py-3-Py) by trinitrophenyl groups, radiationless energy transfer from the tryptophan of membrane proteins to Py-3-Py, and energy transfer from Py-3-Py monomers to 1-anilinon

Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease.

Adrenergic systems regulate both cognitive function and immune function. The primary source of adrenergic signaling in the brain is norepine … e and APP mice. Given the induction of markers of phagocytosis in vivo, we examined phagocytosis of synaptosomes in an in vitro primary microglia culture and showed that beta-blockers enhanced whereas beta-adrenergic agonists inhibited phagocytosis of synaptosomes. In conclusion, beta-blockers potentiated inflammation peripherally in a systemic model of inflam …

Role of glycine-33 and methionine-35 in Alzheimer's amyloid beta-peptide 1-42-associated oxidative stress and neurotoxicity.

Recent theoretical calculations predicted that Gly33 of one molecule of amyloid beta-peptide (1-42) (Abeta(1-42)) is attacked by a putative … a(1-42) on protein oxidation and neurotoxicity of hippocampal neurons and free radical formation in synaptosomes and in solution. Gly33 of Abeta(1-42) was substituted by Val (Abeta(1-42G33V)). The substituted peptide showed almost no neuronal toxicity compared to the native Abeta(1-42) as well as significantly lowered levels of oxidized proteins. In addition, …

Inhibition of neuronal high voltage-activated calcium channels by insect peptides: a comparison with the actions of omega-conotoxin GVIA.

The whole cell variant of the patch clamp technique was used to investigate the actions of two novel insect peptides on high voltage-activat … s. The electrophysiological data are supported by studies on 45Ca2+ influx into rat cerebrocortical synaptosomes. Both PMP-D2 (10 microM), PMP-C (10 microM) and omega-CgTx GVIA (1 microM) attenuated a proportion of 45Ca2+ influx into the synaptosomes, but additive effects of these peptides were not observed. We conclude that these naturally occurring peptides …

Changes in benzodiazepine receptors by acute stress: different effect of chronic diazepam or RO 15-1788 treatment.

In rats submitted to acute stress by forced swimming there was an immediate sharp decline in the binding of [3H]flunitrazepam and of [3H]ethyl-beta-carboline-3-carboxylate in synaptosomal membranes of the cerebral cortex and hippocampus. This was followed by a rebound increase in benzodiazepine receptors after 60 min, specially in the hippocampal formation. These two changes were blocked by chronic treatment with diazepam for 14 days (4 mg/kg/day). On the other hand, long-term treatment with the antagonist RO 15-1788 did not modify the changes caused by the acute stress. These findings are dis

Small Fluorogenic Amino Acids for Peptide-Guided Background-Free Imaging.

The multiple applications of super-resolution microscopy have prompted the need for minimally invasive labeling strategies for peptide-guide … d their application in peptide-PAINT imaging of postsynaptic density protein-95 nanoclusters in the synaptosomes from mouse brain tissues.

Tx3-4 a toxin from the venom of spider Phoneutria nigriventer blocks calcium channels associated with exocytosis.

The purpose of the present work was to investigate the pharmacological action of a calcium channel-blocking toxin from the venom of the spid … r of calcium channels involved in the KCl-induced exocytosis of synaptic vesicles in brain cortical synaptosomes.

Structural and functional comparison of toxins from the venom of the scorpions Centruroides infamatus infamatus, Centruroides limpidus limpidus and Centruroides noxius.

Two novel toxins containing 66 amino acid residues each were isolated from the venom of the scorpions Centruroides infamatus infamatus and Centruroides limpidus limpidus, respectively. Their full amino acid sequences were determined. Comparison of primary structures showed that they share 97% similarity among themselves and 83% to that of toxin 2 from Centruroides noxius. The three toxins studied compete with each other for the same binding sites on membranes prepared from rat brain synaptosomes, suggesting that they are all beta-scorpion toxins. Toxin action was assayed into the microI-2 rat …

Differential effects of sedative and anticonvulsant barbiturates on specific [3H]GABA binding to membrane preparations from rat brain cortex.

The sensitivity to barbiturates of [3H]GABA binding to synaptosomal membrane fractions from rat cortex has been examined. We show that a range of anaesthetic/sedative barbiturates enhance GABA binding in the presence of chloride or other ions that interact with the associated ionophore. Furthermore, picrotoxinin and the anticonvulsant barbiturate phenobarbital antagonise the enhancement produced by pentobarbital. These effects are therefore comparable to those observed at benzodiazepine receptors and may be mediated through the chloride ionophore component of the receptor complex. Other classe