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1.
Cholinesterase Inhibitors Stabilize Alzheimer Disease 总被引:6,自引:0,他引:6
Giacobini E 《Neurochemical research》2000,25(9-10):1185-1190
During the last decade, a systematic effort to develop a pharmacological treatment for Alzheimer disease (AD) has resulted into three drugs being registered for the first time in USA and Europe for this specific indication. All three are cholinesterase inhibitors (ChEI). The major therapeutic effect of ChEI on AD patients is to maintain cognitive function at a constant level during a 6 months to one year period of treatment as compared to placebo. Additional drug effects might be slowing cognitive deterioration and improving behavioral and daily living conditions. Comparison of clinical effects of 6 ChEI demonstrates a rather similar magnitude of improvement in cognitive measures. For some drugs. this may represent an upper limit while for other it may still be possible to increase further the benefit. In order to maximize and prolong positive drug effects it is important to start early and adjust dosage during the treatment. Recent studies show that in many patients the stabilization effect produced by ChEI can be prolonged for as long as a 24 month period. In order to explain the stabilizing effect of ChEI, a mechanism other than AChE inhibition, based on beta-amyloid metabolism, is postulated. 相似文献
2.
Kapai NA Bukanova JV Solntseva EI Skrebitsky VG 《Cellular and molecular neurobiology》2012,32(2):219-226
Acetylcholinesterase (AChE) inhibitor donepezil is widely used for the treatment of Alzheimer’s disease (AD). The mechanisms
of therapeutic effects of the drug are not well understood. The ability of donepezil to reverse a known pathogenic effect
of β-amyloid peptide (Abeta), namely, the impairment of hippocampal long-term potentiation (LTP), was not studied yet. The
goal of the present study was to study the influence of donepezil in 0.1–10 μM concentrations on control and Abeta-impaired
hippocampal LTP. Possible involvement of N-methyl-d-aspartate receptors (NMDARs) into mechanisms of donepezil action was also studied. LTP of population spike (PS) was studied
in the CA1 region of rat hippocampal slices. Change of LTP by donepezil treatment had a bell-shaped dose–response curve. The
drug in concentrations of 0.1 and 1 μM did not change LTP while in concentration of 0.5 μM significantly increased it, and
in concentration of 5 and 10 μM suppressed LTP partially or completely. Abeta (200 nM) markedly suppressed LTP. Addition of
0.1, 0.5 or 1 μM donepezil to Abeta solution caused a restoration of LTP. N-methyl-d-aspartate (NMDA) currents were studied in acutely isolated pyramidal neurons from CA1 region of rat hippocampus. Neither
Abeta, nor 0.5 μM donepezil were found to change NMDA currents, while 10 μM donepezil rapidly and reversibly depressed it.
Results suggest that donepezil augments control and impaired by Abeta hippocampal LTP in NMDAR-independent manner. In general,
our findings extend the understanding of mechanisms of therapeutic action of donepezil, especially at an early stage of AD,
and maybe taken into account while considering the possibility of donepezil overdose. 相似文献
3.
Pei-Hsuan Weng Jen-Hau Chen Ta-Fu Chen Yu Sun Li-Li Wen Ping-Keung Yip Yi-Min Chu Yen-Ching Chen 《PloS one》2013,8(12)
Background
CHRNA7 encodes the α7 nicotinic acetylcholine receptor subunit, which is important to Alzheimer''s disease (AD) pathogenesis and cholinergic neurotransmission. Previously, CHRNA7 polymorphisms have not been related to cholinesterase inhibitors (ChEI) response.Methods
Mild to moderate AD patients received ChEIs were recruited from the neurology clinics of three teaching hospitals from 2007 to 2010 (n = 204). Nine haplotype-tagging single nucleotide polymorphisms of CHRNA7 were genotyped. Cognitive responders were those showing improvement in the Mini-Mental State Examination score ≧2 between baseline and 6 months after ChEI treatment.Results
AD women carrying rs8024987 variants [GG+GC vs. CC: adjusted odds ratio (AOR) = 3.62, 95% confidence interval (CI) = 1.47–8.89] and GG haplotype in block1 (AOR = 3.34, 95% CI = 1.38–8.06) had significantly better response to ChEIs (false discovery rate <0.05). These variant carriers using galantamine were 11 times more likely to be responders than female non-carriers using donepezil or rivastigmine.Conclusion
For the first time, this study found a significant association between CHRNA7 polymorphisms and better ChEI response. If confirmed by further studies, CHRNA7 polymorphisms may aid in predicting ChEI response and refining treatment choice. 相似文献4.
Cholinesterases: New Roles in Brain Function and in Alzheimer's Disease 总被引:15,自引:0,他引:15
Giacobini E 《Neurochemical research》2003,28(3-4):515-522
The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission–experimental or pathological, such as in AD–leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on -amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine. 相似文献
5.
The effect of ammonia onl-glutamate (L-GLU) uptake was examined in cultured astrocytes. Acute ammonia treatment (5–10 mM) enhanced L-[3H]GLU uptake by 20–42% by increasing the Vmax; this persisted for 2 days and then started to decline. Ammonia, however, did not affect the uptake ofd-[3H]aspartate (D-ASP), a non-metabolizable analog of L-GLU, that uses the same transport carrier as L-GLU. Also, L-GLU uptake
was not affected during the first 2 min of the assay. Thus, ammonia did not have an acute effect on L-GLU transport (translocation);
rather, ammonia enhanced the accumulation or “trapping” of L-GLU or its by-products. Chronic ammonia treatment, on the other
hand, inhibited L-GLU transport in astrocytes by ∼30–45% and this was due to a decrease in Vmax, suggesting that the number of L-GLU transporters was decreased. This inhibitory effect was observed after 1 day of treatment
and persisted for at least 7 days. The inhibition of L-GLU transport was partially reversible following removal of ammonia.
The effects of ammonia on L-GLU transport and uptake may explain the abnormal L-GLU neurotransmission observed in hyperammonemia/hepatic
encephalopathy, and the brain swelling associated with fulminant hepatic failure. 相似文献
6.
Adventitious root formation in Malus ‘Jork 9’ stem discs was studied through temporarily blocking DNA synthesis by application
of aphidicolin (AD). Higher number of roots per disc (8.4) after 21 days of cultivation were formed after a 24-h pulse of
15 μM AD, compared to control without AD application (6.7), with significantly more roots (3.7) already appearing at day 7,
compared to 1.5 roots on the control. The promotive effect of AD on rooting was lower at 5 μM, while a concentration of 30 μM
was slightly inhibitory. Results show that DNA synthesis is effectively blocked by AD, and this blockage is overcome after
AD withdrawal. The data indicate that AD treatment influences cell divisions, thereby, might synchronise root initiation.
The effects of different treatments with and without AD were studied at the cellular level by visualising DNA replication
through BrdU-labelling. BrdU labelling further revealed temporal changes in the competence of the explants to respond to applied
IBA. Thus, it is shown that the proportion of replicating nuclei present during 28–32 h is significantly increased in the
split IBA treatment (0–4 h and 28–32 h; treatment C3), compared with a single IBA application during 0–8 h (treatment C3.1).
An erratum to this article can be found at 相似文献
7.
Long-term treatment of l-dopa for Parkinson’s disease (PD) patients induces adverse effects, including dyskinesia, on–off and wearing-off symptoms.
However, the cause of these side effects has not been established to date. In the present study, therefore, 3-O-methyldopa (3-OMD), which is a major metabolite of l-dopa, was tested to determine whether it plays a role in the aforementioned adverse effects. The effects of 3-OMD on the
dopaminergic nervous system in the brain were investigated, by examining behavioral, biochemical, and cellular changes in
male Sprague–Dawley rats and catecholamine-producing PC12 neuronal cells. The results revealed that the intracerebroventricular
(icv) injection of 1 μmol of 3-OMD impaired locomotor activities by decreasing movement time (MT), total distance (TD), and
the number of movement (NM) by 70, 74 and 61%, respectively. The biochemical analysis results showed that a single administration
of 1 μmole of 3-OMD decreased the dopamine turnover rate (DOPAC/DA) by 40.0% in the rat striatum. 3-OMD inhibited dopamine
transporter and uptake in rat brain striatal membranes and PC12 cells. The subacute administration of 3-OMD (5 days, icv)
also significantly impaired the locomotor activities and catecholamine levels. 3-OMD induced cytotoxic effects via oxidative
stress and decreased mitochondrial membrane potential in PC12 cells, indicating that 3-OMD can damage neuronal cells. Furthermore,
3-OMD potentiated l-dopa toxicity and these toxic effects induced by both 3-OMD and l-dopa were blocked by vitamin E (α-tocopherol) in PC12 cells, indicating that 3-OMD may increase the toxic effects of l-dopa to some extent by oxidative stress. Therefore, the present study reveals that 3-OMD accumulation from long-term l-dopa treatment may be involved in the adverse effects of l-dopa therapy. Moreover, l-dopa treatment might accelerate the progression of PD, at least in part, by 3-OMD. 相似文献
8.
Amyloid β peptides appear to play a role in physiological processes; however, they are also involved in the pathogenesis of
Alzheimer disease. Their actions under normal conditions are probably mediated by soluble monomeric l-isoforms at low concentrations, perhaps via highly specific interactions. On the contrary, toxic effects of aggregated natural
l-isoforms/synthetic d-isoforms on membranes are very similar, but synthetic reverse/random l-isoforms without pronounced aggregation properties are not toxic. Our previous work reported interactions of non-aggregated/aggregated
l-isoforms of amyloid β peptides 1–40/1–42 with racemic 24-hydroxycholesterol. In this study, stereospecificity in the interactions
of natural 24(S)hydroxycholesterol (cerebrosterol) or synthetic 24(R)hydroxycholesterol with soluble fragment 1–40 was evaluated
by means of an in vitro test based on increased vulnerability of the hemicholinium-3 sensitive high-affinity choline uptake
system in rat hippocampal cholesterol-depleted synaptosomes to the actions of amyloid β; computational simulations were also
performed. Our results suggest that: (1) 24(S)hydroxycholesterol interacts with l-peptide 1–40 but not with the reverse l-peptide 40–1, (2) 24(R)hydroxycholesterol does not interact with l-peptide 1–40 or reverse 40–1, and (3) both enantiomers can probably interact with d-peptide 1–40. Therefore, the binding of 24(S)hydroxycholesterol is not fully stereospecific and the interaction could not
reflect a physiological mechanism. Data from the computational simulation indicate that the hydrophobic core of the amyloid
β molecule interacts with the hydrophobic part of 24(S)hydroxycholesterol, but no hydrogen bonds with high stability were
found. Using this procedure, globular amyloid β could retain 24(S)hydroxycholesterol and thus contribute to its pathological
accumulation in the brains of patients with Alzheimer disease. 相似文献
9.
《Journal of Physiology》1998,92(3-4):283-287
Cholinesterase inhibitors (ChEI) represent the drug of choice for Alzheimer's disease (AD) treatment. They produce significant improvement on cognitive as well as non-cognitive function for a period up to 1 year during the first 3 years following clinical diagnosis. The magnitude of cognitive improvements is similar for different ChEI, however, differences are seen with regard to incidence and severity of side effects, optimal ChE inhibition, pharmacokinetic properties and mode of administration. 相似文献
10.
Francesco Cilurzo Francesca Selmin Paola Minghetti Luisa Montanari 《AAPS PharmSciTech》2008,9(4):1136-1142
This study aimed to design methyprednisolone (MP)-loaded poly(d,l lactide-co-glycolide) (PLGA) microspheres (MS) intended for intra-articular administration. MP was encapsulated in four different
types of PLGA by using an S/O/W technique. The effects of β-irradiation at the dose of 25 kGy were evaluated on the chemical
and physicochemical properties of MS and the drug release profiles. The S/O/W technique with hydroxypropylmethylcellulose
(HPMC) as surfactant allowed obtaining MS in the tolerability size (7–50 μm) for intra-articular administration. The MP encapsulation
efficiency ranged 56–60%. HPMC traces were evidenced in the loaded and placebo MS by attenuated total reflectance Fourier
transform infrared spectroscopy. MS made of the capped PLGA DL5050 2M (MS 2M) and uncapped PLGA DL5050 3A (MS 3A) prolonged
the release of MP over a 2- to 3-month period with a triphasic (burst release–dormant period–second release pulse) and biphasic
release pattern, respectively. The β-irradiation did not significantly alter the morphology, chemical, and physicochemical
properties of MS. The only variation was evidenced in the drug release for MS 2M in term of shorting of the dormant period.
The minimal variations in the properties of irradiated PLGA MS, which are in disagreement with literature data, may be attributed
to a radioprotecting effect exerted by HPMC. 相似文献
11.
d-kyotorphin (d-Kyo) is a synthetic analogue of the neuropeptide kyotorphin and produces naloxone reversible analgesia. Stress-induced analgesia
(SIA) is an in-built mammalian pain-suppression response that occurs during or following exposure to a stressful stimulus.
The periaqueductal gray (PAG) is implicated as a critical site for processing strategies for coping with different types of
stress and pain and NO affects its activity. The objectives of the present study were twofold: (1) to examine the effects
of d-Kyo (5 mg/kg) on acute immobilization SIA; (2) to investigate the effect of peptide on NO activity in rat PAG after the stress
procedure mentioned above. All drugs were injected intraperitoneally in male Wistar rats. The nociception was measured by
the paw pressure and hot plate tests. A histochemical procedure for nicotinamide adenine dinucleotide phosphate–diaphorase
(NADPH-d)-reactive neurons was used as indirect marker of NO activity. Our results revealed that d-Kyo has modulating effects on acute immobilization stress-induced analgesia in rats may be by opioid and non-opioid systems.
Although d-Kyo is incapable of crossing the blood–brain barrier it showed an increased number of NADPH-d reactive neurons in dorsolateral
periaqueductal gray (dlPAG) in control but not in stressed groups. We may speculate that the effect of d-Kyo in the brain is due to structural and functional interaction between opioidergic and NO-ergic systems or d-Kyo appears itself as a stressor. Further studies are needed to clarify the exact mechanisms of its action. 相似文献
12.
Marianna Trebunova Eva Slaba Viera Habalova Zuzana Gdovinova 《Central European Journal of Biology》2008,3(1):49-54
Angiotensin-converting enzyme (ACE) has been reported to show altered activity in patients with neurological diseases. The
recent studies found that a 287 bp insertion/deletion (I/D) polymorphism of the ACE gene may be associated with susceptibility
to Alzheimer’s disease (AD) but the results have been heterogenous between studies in Europe. In the present study we examined
for the first time the association of ACE I/D polymorphism along with APOE genotype in 70 sporadic AD and 126 control subjects
in Slovak Caucasians (Central Europe). An increased risk for AD was observed in subjects with at least one APOE*E4 allele
(OR=3.99, 95% CI=1.97–8.08). No significant differences for the genotype distribution or the allele frequency were revealed
comparing controls and patients for ACE gene. Gene-gene interaction analysis showed increase of the risk to develop AD in
subjects carrying both the ACE DD genotype and the APOE*E4 allele (OR=10.32, 95% C.I. 2.67–39.81). 相似文献
13.
Evidence for NO-dependent vasodilation in the trout (Oncorhynchus mykiss ) coronary system 总被引:1,自引:0,他引:1
T. Mustafa C. Agnisola J. K. Hansen 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1997,167(2):98-104
The effects of l-arginine, and its analogues N
ω-nitro-l-arginine methyl ester and N
ω-nitro-l-arginine on vascular resistance were investigated in the intact coronary system of an isolated non-working trout heart preparation.
l-Arginine, at 10–8 mol · l–1induced a slight vasodilatory effect (max 10%). N
ω-nitro-l-arginine methyl ester and N
ω-Nitro-l-arginine in the range 10–8–10–4 mol · l–1 caused dose-dependent increases in coronary resistance. The vasodilatory action of l-arginine was abolished when the preparation was pretreated with 10–4 mol · l–1
N
ω-nitro-l-arginine or N
ω-nitro-l-arginine methyl ester. Nitroprusside alone at 1 mmol · l–1 induced a maximum vasodilation (30%) of the coronary system. Methylene blue a known inhibitor of guanylate cyclase, induced
a strong vasoconstriction (already significant at 10–5 mol · l–1) and was able to overcome the vasodilative effect of nitroprusside. The endothelial nitric oxide agonists acetylcholine and
serotonin, established in mammalian vessels, also mediate vasodilation in trout coronary system. In 50% of preparations, acetylcholine
induced a biphasic response with vasodilation at low concentration (max 15% at 10–8 mol · l–1). Serotonin displayed a dose-response vasodilation in the range 10–8–10–4 mol · l–1 (max 20%). These vasodilative effects were reduced or abolished by 10–4 mol · l–1
l-NA. These data support the existence of NO-mediated vasodilation mechanisms in the trout coronary system.
Accepted: 1 July 1996 相似文献
14.
Juhász A Rimanóczy A Boda K Vincze G Szlávik G Zana M Bjelik A Pákáski M Bódi N Palotás A Janka Z Kálmán J 《Neurochemical research》2005,30(8):943-948
Multiple genetic and environmental factors regulate the susceptibility to Alzheimer’s disease (AD). Recently, several independent
studies have reported that a locus on chromosome 14q32.1, where a gene encoding a cholesterol degrading enzyme of the brain,
called 24-hydroxylase (CYP46A1) is located, has been linked with AD. The single nucleotide polymorphism (T/C) in intron 2
of CYP46 gene has been found to confer the risk for AD. The water soluble 24(S)-hydroxysterol is the product of the CYP46A1, and elevated plasma and cerebrospinal fluid hydroxysterol concentrations have
been found in AD, reflecting increased brain cholesterol turnover or cellular degradation, due to the neurodegenerative process.
A case–control study was performed on 125 AD and 102 age- and gender-matched control subjects (CNT) from Hungary, to test
the association of CYP46 T/C and apolipoprotein E (ApoE) gene polymorphisms in AD. The frequency of the CYP46 C allele was
similar (χ2=0.647, df=1, P=0.421, exact P=0.466, OR=0.845; 95% CI: 0.561–1.274) in both groups (CNT: 27%; 95% CI: 21.3–33.4; AD 30%; 95% CI: 25.0–36.3). The ApoE ɛ4
allele was significantly over-represented (χ2=11.029, df=2, P=0.004) in the AD population (23.2%; 95% CI: 18.2–29.0) when compared with the CNT (11.3%; 95% CI: 7.4–16.6). The presence
or absence of one or two CYP46C alleles together with the ApoE ɛ4 allele did not increase the risk of AD (OR=3.492; 95% CI:
1.401–8.707; P<0.007 and OR=3.714; 95% CI: 1.549–8.908; P<0.003, respectively). Our results indicate that the intron 2 T/C polymorphism of CYP46 gene (neither alone, nor together
with the ɛ4 allele) does not increase the susceptibility to late-onset sporadic AD in the Hungarian population. 相似文献
15.
Somatic embryogenesis and in vitro rosmarinic acid accumulation in Salvia officinalis and S. fruticosa leaf callus cultures 总被引:1,自引:0,他引:1
The effect of explant age, plant growth regulators and culture conditions on somatic embryogenesis and rosmarinic acid production
from leaf explants of Salvia officinalis and S. fruticosa plants collected in Greece was investigated. Embryogenic callus with numerous spherical somatic embryos could be induced
on explants derived from both species and cultured for 3 weeks on a Murashige and Skoog (MS) medium supplemented with 1.8–18
μm 2,4-dichlorophenoxyacetic acid (2,4-D) and kinetin (Kin) or 10.5–21 μm 1-naphthalenacetic acid and 6-benzyladenine. Only explants from young plants (with six to eight leaves) responded to the
culture treatments and, in general, low light intensities (50 μmol m–2 s–1) favoured callus formation and induction of somatic embryos. Somatic embryos were further developed on the same medium. Heart-
and torpedo-shaped embryos (1–2 mm long) were subcultured on a growth-regulator-free MS medium for maturation. Maximum rosmarinic
acid accumulation in S. officinalis and S. fruticosa callus cultured on 4.5 μm 2,4-D and 4.5 μm Kin was 25.9 and 29.0 g/l, respectively.
Received: 17 January 1997 / Revision received: 26 May 1997 / Accepted: 30 June 1997 相似文献
16.
Inhibition of large-conductance calcium-activated potassium channel by 2-methoxyestradiol in cultured vascular endothelial (HUV-EC-C) cells 总被引:4,自引:0,他引:4
2-Methoxyestradiol, an endogenous metabolite of 17β-estradiol, is known to have antitumor and antiangiogenic actions. The
effects of 2-methoxyestradiol on ionic currents were investigated in an endothelial cell line (HUV-EC-C) originally derived
from human umbilical vein. In the whole-cell patch-clamp configuration, 2-methoxyestradiol (0.3–30 μm) reversibly suppressed the amplitude of K+ outward currents. The IC
50 value of the 2-methoxyestradiol-induced decrease in outward current was 3 μm. Evans blue (30 μm) or niflumic acid (30 μm), but not diazoxide (30 μm), reversed the 2-methoxyestradiol-induced decrease in outward current. In the inside-out configuration, application of 2-methoxyestradiol
(3 μm) to the bath did not modify the single-channel conductance of large-conductance Ca2+-activated K+ (BKCa) channels; however, it did suppress the channel activity. 2-Methoxyestradiol (3 μm) produced a shift in the activation curve of BKCa channels to more positive potentials. Kinetic studies showed that the 2-methoxyestradiol-induced inhibition of BKCa channels is primarily mediated by a decrease in the number of long-lived openings. 2-Methoxyestradiol-induced inhibition
of the channel activity was potentiated by membrane stretch. In contrast, neither 17β-estradiol (10 μm) nor estriol (10 μm) affected BKCa channel activity, whereas 2-hydroxyestradiol (10 μm) slightly suppressed it. Under current-clamp condition, 2-methoxyestradiol (10 μm) caused membrane depolarization and Evans blue (30 μm) reversed 2-methoxyestradiol-induced depolarization. The present study provides evidence that 2-methoxyestradiol can suppress
the activity of BKCa channels in endothelial cells. These effects of 2-methoxyestradiol on ionic currents may contribute to its effects on functional
activity of endothelial cells.
Received: 27 November 2000/Revised: 13 April 2001 相似文献
17.
Antidepressants, such as traditional tricyclic antidepressants (TCAs), are the first-line treatment for various pain syndromes.
Available evidence indicates that TCAs may target Na+ channels for their analgesic action. In this report, we examined the effects of contemporary antidepressants sertraline and
paroxetine on (1) neuronal Na+ channels expressed in GH3 cells and (2) muscle rNav1.4 Na+ channels heterologously expressed in Hek293t cells. Our results showed that both antidepressants blocked Na+ channels in a highly state-dependent manner. The 50% inhibitory concentrations (IC50) for sertraline and paroxetine ranged ∼18–28 μm for resting block and ∼2–8 μm for inactivated block of neuronal and rNav1.4 Na+ channels. Surprisingly, the IC50 values for both drugs were about 0.6–0.7 μm for the open channel block of persistent late Na+ currents generated through inactivation-deficient rNav1.4 mutant Na+ channels. For comparison, the open channel block in neuronal hNav1.7 counterparts yielded IC50 values around 0.3–0.4 μm for both drugs. Receptor mapping using fast inactivation-deficient rNav1.4-F1579A/K mutants with reduced affinities toward
local anesthetics (LAs) and TCAs indicated that the F1579 residue is not involved in the binding of sertraline and paroxetine.
Thus, sertraline and paroxetine are potent open channel blockers that target persistent late Na+ currents preferentially, but their block is not mediated via the phenylalanine residue at the known LA/TCA receptor site. 相似文献
18.
In the present investigation, nutritional requirements for induction of a high frequency of well formed somatic embryos (SEs)
from zygotic embryos (ZEs) of sunflower were assessed. Variables like genotype, embryo size (0.5–10 mm), sucrose concentration
(30–240 g l−1), carbohydrate source (sucrose, glucose, maltose), agar strength (0.2–1.0%), basal media (MS, Gamborg, Nitsch, White), photoperiod
(light/dark) and temperature (20–36°C) were tested. All these variables except photoperiod had significant effect on the frequency
of embryogenesis. Highest frequency of embryogenesis was facilitated by Gamborg basal salt media, 120–210 g l−1 sucrose, 0.8–1.0% agar, smaller sized embryos (0.5–2 mm) and incubation temperature of 28–32°C. In addition to these, growth
regulator combinations (2,4-D, 2,4-D+kinetin, BA+NAA) in varying concentrations were tried. Media supplemented with 2,4-D promoted direct embryogenesis, BA+NAA facilitated formation of single/multiple shoots while there was no response on 2,4-D+kinetin supplemented media. Zygotic embryos with well differentiated embryos were transferred to growth regulator free half
strength MS medium for whole plantlet development.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
19.
Shao YX Zhao P Li Z Liu M Liu P Huang M Luo HB 《European biophysics journal : EBJ》2012,41(3):297-306
In our previous kinetics studies the natural products oroxylin and wogonin were shown to have strong biological affinity for,
and inhibitory effects against, human cytochrome P450 1A2, with IC50 values of 579 and 248 nM, respectively; this might lead to the occurrence of drug–drug interactions when co-administered clinically. However, their
inhibitory mechanisms against 1A2 remain elusive. In this study, molecular docking and molecular dynamics simulations were
performed to better understand the molecular basis of their inhibitory mechanisms towards 1A2. Structural analysis revealed
that oroxylin has a different binding pattern from wogonin and another very strongly binding inhibitor α-naphthoflavone (ANF,
IC50 = 49 nM). The O7 atom of oroxylin forms hydrogen bonds with the OD1/OD2 atoms of Asp313, which is not observed in the 1A2–wogonin complex.
Because of energetically unfavorable repulsions with the methoxy group at the 6 position of the oroxylin ring, significant
conformational changes were observed for the sidechain of Thr118 in the MD simulated model. As a result, the larger and much
more open binding-site architecture of the 1A2–oroxylin complex may account for its weaker inhibitory effect relative to the
1A2–ANF complex. Energy analysis indicated that oroxylin has a less negative predicted binding free energy of −19.8 kcal/mol
than wogonin (−21.1 kcal/mol), which is consistent with our experimental assays. Additionally, our energy results suggest
that van der Waals/hydrophobic and hydrogen-bonding interactions are important in the inhibitory mechanisms of oroxylin whereas
the former is the underlying force responsible for strong inhibition by ANF and wogonin. 相似文献
20.
Chuanqin Fang Jinbo Yin Zhiqiang Xu Yanjiang Wang Haiwei Xu Huadong Zhou Changyue Gao 《Cell biochemistry and biophysics》2011,59(1):49-56
In order to examine the acute effects of l-DOPA treatment following 6-hydroxydopamine (6-OHDA) injection into rat medial forebrain bundle (MFB). Sprague–Dawley rats
(n = 48) received either 6-OHDA, via intracranial unilateral injection, into the MFB (experimental group) or saline 0.9% (control
group). Administration of l-DOPA or saline 0.9% began 1 month after the 6-OHDA injection for 10 consecutive days. Within 3 days, an increase in the density
of striatal tyrosine hydroxylase (TH) immunoreactive fibers within the striatum, when compared to the control group was observed.
There was no difference in the loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons between. The greater
density of TH fibers in the striatum following l-DOPA may be related to recovery of the DA phenotype and/or sprouting of TH axon terminals. Only animals with severe cell
loss in the SNpc experienced abnormal involuntary movements (AIMs) or “dyskinesias” in response to l-DOPA, which did not correlate with striatal TH fiber density, suggesting that induction of TH-positive fibers does not contribute
to the occurrence of dyskinesia. The relationship between cell loss, fiber density and AIM to the abundance of markers of
microglial activation were also examined. Iba-1, a microglial marker, immunoreactivity was not affected by l-DOPA treatment, was not correlated with the severity of AIM indicating that microglial activation does not contribute to
dyskinetic phenomena. 相似文献