Abstract:
:Focusing on development of novel drug candidates for the treatment of neurodegenerative diseases, we developed and synthesized a new compound, 2-(cyclohexylamino)-1-(4-cyclopentylpiperazin-1-yl)-2-methylpropan-1-one (amido-piperizine 1). The compound demonstrated robust neuroprotective properties after both glutamate excitotoxicity and peroxide induced oxidative stress in primary cortical cultures. Furthermore, amido-piperizine 1 was found to significantly induce neurite outgrowth in vitro which could suggest central reparative and regenerative potential of the compound. With these potential beneficial effects in CNS, the ability of the amido-piperizine 1 to penetrate the blood-brain barrier was tested using MDR1-MDCK cells. Amido-piperizine 1 was found not to be a P-gp substrate and to have a high blood-brain barrier penetration potential, indicating excellent availability to the CNS. Moreover, amido-piperizine 1 had a fast metabolic clearance rate in vitro, suggesting that parenteral in vivo administration seems preferable. As an attempt to elucidate a possible mechanism of action, we found that amido-piperizine 1 bound in nano-molar range to the sigma-1 receptor, which could explain the observed neuroprotective and neurotrophic properties, and with a 100-fold lower affinity to the sigma-2 receptor. These results propose that amido-piperizine 1 may hold promise as a drug candidate for the treatment of stroke/traumatic brain injury or other neurodegenerative diseases.
journal_name
Neurochem Intjournal_title
Neurochemistry internationalauthors
Elbrønd-Bek H,Wellejus A,Kelly NM,Weidner MS,Jørgensen SHdoi
10.1016/j.neuint.2011.08.003subject
Has Abstractpub_date
2011-11-01 00:00:00pages
821-9issue
6eissn
0197-0186issn
1872-9754pii
S0197-0186(11)00273-7journal_volume
59pub_type
杂志文章abstract::The effects of thyroid deficiency on the activity of glutamine synthetase (GS) and the number of glial fibrillary acidic (GFA) protein containing cells (the markers for astroglial cells) and on the 2?, 3?-cyclic nucleotide 3?-phosphohydrolase (CNPase) activity (the marker for oligodendroglial cells) were studied in th...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(89)90107-1
更新日期:1989-01-01 00:00:00
abstract::The effects of pretreatment of mice with some drugs which modify GABAergic neurotransmission on the convulsions and cerebellar cyclic nucelotide level changes induced by the subsequent intracerebroventricular administration of 4-isopropyl-2,6,7-trioxa-1-phosphabicyclo(2,2,2)octane-1-oxide (IPTBO) have been studied. Mu...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(84)90095-0
更新日期:1984-01-01 00:00:00
abstract::In this study, the properties of ischemic condition-induced and veratridine-evoked [3H]noradrenaline ([3H]NA) release from rat spinal cord slices were compared. It was expected that ischemia mimicked by oxygen and glucose deprivation results in the impairment of Na+/K+ -ATPase with a consequent elevation of the intrac...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/s0197-0186(00)00124-8
更新日期:2001-07-01 00:00:00
abstract::Phosphodiesterase-5 (PDE5) inhibitors act by competing with the substrate, cGMP, for the catalytic site of the enzyme. Two commercialized PDE5 inhibitors, sildenafil and vardenafil, are being used to treat erectile dysfunction. These two compounds differ in the heterocyclic ring system used to mimic the purine ring of...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2004.03.016
更新日期:2004-11-01 00:00:00
abstract::We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) neurofilament light chain (NFL) protein in the classification of patients with Alzheimer's disease (AD) and cognitively healthy control individuals (HCs) and patients with frontotemporal dementia (FTD) as comparisons. Particularly, we tested the performa...
journal_title:Neurochemistry international
pub_type: 杂志文章,多中心研究
doi:10.1016/j.neuint.2017.05.010
更新日期:2017-09-01 00:00:00
abstract::Oxidative stress-induced neuronal death plays a pivotal role in pathogenesis of neurodegenerative disorders. Recently, 7,8-dihydroxyflavone (7,8-DHF) has been shown to exert neuroprotective effects by acting as a selective tyrosine kinase receptor B (TrkB) agonist. In addition, the antioxidant action of 7,8-DHF may pr...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2013.10.018
更新日期:2014-01-01 00:00:00
abstract::Unveiling the roles of distinct cell types in brain response to insults is a partially unsolved challenge and a key issue for new neuroreparative approaches. In vivo models are not able to dissect the contribution of residential microglia and infiltrating blood-borne monocytes/macrophages, which are fundamentally undi...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2014.01.008
更新日期:2014-01-01 00:00:00
abstract::The aim of the present study was to investigate, whether dopamine D1 and/or D2 receptors are able to interfere with the ATP-induced increase of the intracellular Ca2+ concentration ([Ca2+]i) in cultured striatal neurons identified by their morphological characteristics and their [Ca2+]i transients in response to a hig...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2007.06.013
更新日期:2008-01-01 00:00:00
abstract::The effects of neonatal X-irradiation on cerebellar cathecholamine levels in rats were studied at different postnatal intervals. Since synaptogenesis in the cerebellar cortex is basically a postnatal phenomenon, changes in noradrenaline (NA) and dopamine (DA) levels induced by X-rays on the cerebella (CE) of adult rat...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(89)90081-8
更新日期:1989-01-01 00:00:00
abstract::Metabotropic glutamate receptors (mGluRs) are expressed in neural progenitor cells (NPCs) and may play important roles in the neurogenesis during embryonic development and adult brain repair following injuries. In the present study, we investigated the expression of metabotropic glutamate receptor 7 (mGluR7) and the p...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2010.04.004
更新日期:2010-08-01 00:00:00
abstract::Potassium bisperoxo(1,10-phenantroline)oxovanadate (V) [bpV(phen)] is a potent protein tyrocine phosphatase inhibitor which mediates a variety of biological effects. The aim of these studies was to examine the role(s) of mitogen activated protein kinase (MAPK) pathways in PC12 cell proliferation and toxicity by bpV(ph...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/s0197-0186(99)00018-2
更新日期:1999-04-01 00:00:00
abstract::The phosphorylation of proteins on tyrosine residues, initially believed to be primarily involved in cell growth and differentiation, is now recognized as having a critical role in regulating the function of mature cells. The brain exhibits one of the highest levels of tyrosine kinase activity in the adult animal and ...
journal_title:Neurochemistry international
pub_type: 杂志文章,评审
doi:10.1016/s0197-0186(97)00022-3
更新日期:1997-11-01 00:00:00
abstract::Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) affecting more than 2.5 million individuals worldwide. In the present study, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mice were treated with adenosine recept...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2019.104490
更新日期:2019-10-01 00:00:00
abstract::NADPH derived from glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, has been implicated not only to promote reduced glutathione (GSH) but also enhance oxidative stress in specific cellular conditions. In this study, the effects of G6PD antisense oligodeoxynucleotides...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2012.05.003
更新日期:2012-07-01 00:00:00
abstract::Free radicals have been implicated in the pathogenesis of vasogenic brain edema caused by ischemic or traumatic injury. It has been reported that in transgenic mice overexpressing the human CuZn-superoxide dismutase, brain edema is decreased in many cerebral disorders. To investigate the effects of free radicals on th...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(95)00120-4
更新日期:1996-08-01 00:00:00
abstract::In the present study we have investigated the relationship between serotonergic receptor(s) (5-HTR) and muscarinic cholinergic receptor (mAChR) activation, leading to the arachidonic acid (AA) release and inositol phosphates (IPs) formation in adult and aged brain cortex synaptoneurosomes. It was observed that seroton...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(95)00001-o
更新日期:1995-06-01 00:00:00
abstract::Stroke causes neuronal cell death and destruction of neuronal circuits in the brain and spinal cord. Injury to the brain tissue induces sterile inflammation triggered by the extracellular release of endogenous molecules, but cerebral inflammation after stroke is gradually resolved within several days. In this pro-reso...
journal_title:Neurochemistry international
pub_type: 杂志文章,评审
doi:10.1016/j.neuint.2018.10.013
更新日期:2019-11-01 00:00:00
abstract::Guanylate cyclase (GTP pyrophosphate-lyase (cyclizing); EC 4.6.1.2), in the crude synaptosomal soluble (P(2)-soluble) fraction obtained by hypo-osmotic treatment and subsequent centrifugation of crude synaptosomal (P(2)) fraction from the rat brain, showed a significantly high activity when assayed in the presence of ...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(81)90008-5
更新日期:1981-01-01 00:00:00
abstract::Structural analogues of ZAPA, Z-3-[(aminoiminomethyl)thio]prop-2-enoic acid, an isothiouronium analogue of GABA, are potent GABAA agonists as seen in the isolated guinea-pig ileum and in the facilitation of [3H]diazepam binding to rat brain membranes. Compounds with guanidino or amidine groups replacing the amino func...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/s0197-0186(96)00094-0
更新日期:1997-06-01 00:00:00
abstract::Endoplasmic reticulum (ER) stress is linked to several neurological disorders, and neuronal injury cascades initiated by excessive ER stress are mediated, in part, via mitochondrial dysfunction. In the present study, we identified FAM3A as an important regulator of ER stress-induced cell death in neuronal HT22 cells. ...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2016.02.010
更新日期:2016-03-01 00:00:00
abstract::In recent years there has been a great deal of research within the stem cell field which has led to the definition and classification of a range of stem cells from a plethora of tissues and organs. Stem cells, by classification, are considered to be pluri- or multipotent and have both self-renewal and multi-differenti...
journal_title:Neurochemistry international
pub_type: 杂志文章,评审
doi:10.1016/j.neuint.2016.08.001
更新日期:2017-06-01 00:00:00
abstract::Alzheimer's disease (AD) is characterized by memory decline, but is often associated with non-cognitive symptoms, including muscular dysfunction. In the majority of cases these motor disturbances are seen when other neuro-degenerative disorders such as Parkinson's disease overlap dementia, however these can also be di...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2013.10.014
更新日期:2014-01-01 00:00:00
abstract::D1 and D2 receptors are key mediators of dopaminergic signaling in the brain, and since the manifestations of pathologies related to dopamine are different in female and male patients, it is important to analyze if there are sex-related differences in dopaminergic markers. To contribute to the knowledge in this regard...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2016.09.001
更新日期:2016-11-01 00:00:00
abstract::Rapid eye movement sleep deprivation is associated with an increase in Na-K ATPase activity. In order to understand the possible biochemical mechanism of this increase, the kinetics of Na-K ATPase was studied. Although the enzyme activity increased after the deprivation, the catalytic efficiency of the enzyme remained...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/s0197-0186(99)00121-7
更新日期:2000-03-01 00:00:00
abstract::The 12/15-lipoxygenase (12/15-LOX) enzymes react with polyunsaturated fatty acids producing active lipid metabolites that are involved in plethora of human diseases including neurological disorders. A great many of elegant studies over the last decades have contributed to unraveling the mechanism how 12/15-lipoxygenas...
journal_title:Neurochemistry international
pub_type: 杂志文章,评审
doi:10.1016/j.neuint.2018.04.002
更新日期:2018-09-01 00:00:00
abstract::Gastrointestinal peptides and hormones are known to penetrate through the utero-placental barrier and regulate fetal development. In the present study, we tested permeation of maternal brain-derived neurotrophic factor (BDNF) to fetuses, using BDNF-gene deficient mice and exogenous BDNF administration. At embryonic da...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/j.neuint.2008.11.005
更新日期:2009-02-01 00:00:00
abstract::Two puromycin-sensitive aminopeptidase isozymes (PSA-I and PSA-II) were isolated from chicken brain cytosol by ammonium sulfate fractionation followed by column chromatography on Cellex D and AH-Sepharose 4B and separated on Bio-Gel HTP. Each was purified to homogeneity on Sephadex G-200, Arg-Tyr-AH-Sepharose, Bio-Gel...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(93)90039-8
更新日期:1993-05-01 00:00:00
abstract::Selective dopaminergic neurotoxicity induced by 1-methyl-4-phenylpyridine (MPP+) is believed to be due to the transmembrane uptake by the dopamine transporter and subsequent inhibition of mitochondrial complex I and/or production of free radicals. However, little is known about the molecular sequence of intracellular ...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/s0197-0186(99)00083-2
更新日期:1999-11-01 00:00:00
abstract::Immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) are detected in the serum of some patients with demyelinating diseases. These patients are known to show repeated clinical episodes of inflammatory demyelinating attacks in the central nervous system. Although the associated pathogenic...
journal_title:Neurochemistry international
pub_type: 杂志文章,评审
doi:10.1016/j.neuint.2018.10.016
更新日期:2019-11-01 00:00:00
abstract::The disposition of labelled [3H]GM1lactone, the inner ester of ganglioside GM1, was studied in the rat. After i.v. administration [3H]GM1lactone was quickly converted to its corresponding open form most likely by plasma esterases, and then displayed a pharmacokinetic profile identical to [3H]GM1. Following intramuscul...
journal_title:Neurochemistry international
pub_type: 杂志文章
doi:10.1016/0197-0186(92)90050-2
更新日期:1992-04-01 00:00:00