- Differential impairment of short working and spatial memories in a rat model of progressive Parkinson's disease onset: a focus on the prodromal stage. [Journal Article]
- BRBrain Res Bull 2019 Jun 19
- Studying the non-motor disorders of the prodromal phase of Parkinson's disease (PD) is of great importance because of their negative impact on patient's quality of life. Classical neurotoxic animal m…
Studying the non-motor disorders of the prodromal phase of Parkinson's disease (PD) is of great importance because of their negative impact on patient's quality of life. Classical neurotoxic animal models of PD generally unable the exploration of the progression of the non-motor phase of the prodromal stage of the disease. The aim of this study is to assess the evolution of two types of memory alteration namely; short working and spatial memories at different stages of the prodromal phase of a rat model of PD, using repetitive reserpine administration at low dose. The study was carried out in rat with repeated i.p reserpine administration (0.2 mg/kg/day) during 13 days. Working memory was assessed by the Novel Object Recognition test (NOR) and the T-maze, while spatial memory was assessed by Morris Water maze (MWM) at to stages (7days and 13days) of prodromal phase of the disease. By means of immunohistochemistry, the serotonergic innervation of the Baso-Lateral Amygdala nucleus (BLA) as well as the morphological changes of astroglia within hippocampus (using anti-GFAP marker) were examined at the latest stage (13days) of the disease. Our data show a differential deterioration of short-term working memory without the long-term spatial memory being changed which was accompanied by a significant decrease in serotonin innervation of the BLA and a striking change in both density and morphology of the astrocyte at the level of the hippocampus. The present study has brought evidence of an early deficit of short working memory rather than spatial memory deficit which seems to be intact even at the latest stage of the prodromal phase of PD. Such deficit could arise from the loss of 5-HT innervation in BLA and/or the astroglial morpho-functional changes within the hippocampus leading to possible neurophysiological disturbances of the different neighboring neuronal populations involved in short working memory.
- Epoxide-derived mixed-mode chromatographic stationary phases for separation of active substances in fixed-dose combination drugs. [Journal Article]
- JSJ Sep Sci 2019 Jun 20
- A method for preparation of novel mixed-mode reversed-phase/strong cation exchange stationary phase for the separation of fixed-dose combination drugs has been developed. An epoxysilane bonded silica…
A method for preparation of novel mixed-mode reversed-phase/strong cation exchange stationary phase for the separation of fixed-dose combination drugs has been developed. An epoxysilane bonded silica prepared by vapor phase deposition was used as starting material to produce diol, octadecyl, sulfonate and mixed octadecyl/sulfonate groups bonded silica phases. The chemical structure and surface coverage of the functional groups on these synthesized phases were confirmed by fourier-transform infrared and solid-state 13 C NMR spectroscopy and elemental analysis. Alkylbenzene homologs, basic drugs, nucleobases and alkylaniline homologs were used as probes to demonstrate the reversed-phase, ion exchange, hydrophilic interaction and mixed-mode retention behaviors of these stationary phases. The octadecyl/sulfonate bonded silica exhibits pronounced mixed-mode retention behavior and superior retentivity and selectivity for alkylaniline homologs. The mixed-mode retention is affected by either ionic or solvent strength in the mobile phase, permiting optimization of a separation by fine tuning these parameters. The mixed-mode stationary phase was applied to separate two fixed-dose combination drugs: compound reserpine tablets and compound methoxyphenamine capsules. The results show that simultaneous separation of multiple substances in the compound dosage can be achieved on the mixed-mode phase, which makes multi-cycles of analysis for multiple components obsolete. This article is protected by copyright. All rights reserved.
- The search of potential inhibitors of the AcrAB-TolC system of multidrug-resistant Escherichia coli: an in silico approach. [Journal Article]
- AMAppl Microbiol Biotechnol 2019 Jun 17
- The number of infections caused by multidrug antibiotic resistance (MDR) species is increasing globally. The efflux pump system, AcrAB-TolC, confers Escherichia coli resistance to many antibiotics an…
The number of infections caused by multidrug antibiotic resistance (MDR) species is increasing globally. The efflux pump system, AcrAB-TolC, confers Escherichia coli resistance to many antibiotics and results in poor treatment outcomes. Different rational drug design techniques were employed to search for a safe and effective AcrAB-TolC system inhibitor. Ligand docking was performed to analyze the binding of different ArcB substrates and/or inhibitors in the different AcrAB crystal structure binding sites. The validated docking site using the established docking preferences was used to perform virtual high-throughput screening on a large library of compounds. Domperidone, a known and safe over-the-counter antiemetic drug, was proposed as an effective ArcB inhibitor. Microbiological studies confirmed the computational results and domperidone reversed the resistance to the antibiotics: levofloxacin and ciprofloxacin in the MDR E. coli stains with an effect that surpassed the effect of the known efflux pump inhibitor, reserpine. In addition, it was able to increase both antibiotic effects on susceptible strains. This finding suggests that the antibiotic-domperidone combination can be used clinically to treat infections caused by multidrug-resistant E. coli strains.
- Lacidipine attenuates reserpine-induced depression-like behavior and oxido-nitrosative stress in mice. [Journal Article]
- NSNaunyn Schmiedebergs Arch Pharmacol 2019 Jun 11
- Depression is a serious medical illness displaying high lifetime prevalence, early-age onset that adversely affects socio-economic status. The bidirectional association between oxidative stress and c…
Depression is a serious medical illness displaying high lifetime prevalence, early-age onset that adversely affects socio-economic status. The bidirectional association between oxidative stress and calcium-signaling adversely affects the monoaminergic neuron functions that instigate the pathogenesis of depression. The present study investigates the effect of lacidipine (LCD), L-type Ca2+-channel blocker, on reserpine-induced depression in mice. Separate groups of mice (Swiss albino, 18-25 g) were administered lacidipine (0.3, 1 and 3 mg/kg, i.p.) daily for 14 days and reserpine (5 mg/kg, i.p.) was injected on day 14. Rectal temperature, catalepsy, and tail-suspension test (TST) were performed 18 h and ptosis scores at 60, 120, 240, 360 min post-reserpine treatment. Whole-brain TBARS, GSH, nitrite, and superoxide dismutase (SOD) and catalase activities were estimated. Reserpine elevated the catalepsy, ptosis, hypothermia, and immobility period in TST owing to the marked increase in oxidative-nitrosative stress in the brain of mice. LCD attenuated the reserpine triggered the rise in catalepsy, ptosis scores, hypothermia, and immobility period in mice. LCD pretreatment attenuated the increase in TBARS and nitrite levels, and the decline of GSH, SOD, and catalase activities in the brain of reserpine injected mice. Bay-K8644 (0.5 mg/kg, i.p.), Ca2+-channel agonist, attenuated these effects of LCD (3 mg/kg) in reserpine-treated mice. It can be inferred that lacidipine (Ca2+ channel antagonist) attenuates depression-like symptoms in reserpine-treated mice. Furthermore, the abrogation of antidepressant-like effects of LCD by Bay-K8644 revealed that modulation of Ca2+-channels might present a potential strategy in the management of depression.
- Blockade of spinal α5-GABAA receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats. [Journal Article]
- EJEur J Pharmacol 2019 Jun 07; :172443
- The role of spinal α5 subunit-containing GABAA (α5-GABAA) receptors in chronic pain is controversial. The purpose of this study was to investigate the participation of spinal α5-GABAA receptors in th…
The role of spinal α5 subunit-containing GABAA (α5-GABAA) receptors in chronic pain is controversial. The purpose of this study was to investigate the participation of spinal α5-GABAA receptors in the reserpine-induced pain model. Reserpine administration induced tactile allodynia and muscle hyperalgesia in female and male rats. Intrathecal injection of L-655,708 and TB 21007 (7 days after the last reserpine injection) decreased tactile allodynia and, at a lesser extent, muscle hyperalgesia in female rats. The effects of these drugs produced a lower antiallodynic and antihyperalgesic effect in male than in female rats. Contrariwise, these drugs produced tactile allodynia and muscle hyperalgesia in naïve rats and these effects were lower in naïve male than female rats. Intrathecal L-838,417 prevented or reversed L-655,708-induced antiallodynia in reserpine-treated female rats. Repeated treatment with α5-GABAA receptor small interfering RNA (siRNA), but not scramble, siRNA reduced reserpine-induced allodynia in female rats. Accordingly, α5-GABAA receptor siRNA induced nociceptive hypersensitivity in naïve female rats. Reserpine enhanced α5-GABAA receptors expression in spinal cord and DRG, while it increased CD11b (OX-42) and glial fibrillary acidic protein (GFAP) fluorescence intensity in the lumbar spinal cord. In contrast, reserpine diminished K+-Cl- co-transporter 2 (KCC2) protein in the lumbar spinal cord. Data suggest that spinal α5-GABAA receptors play a sex-dependent proallodynic effect in reserpine-treated rats. In contrast, these receptors have a sex-dependent antiallodynic role in naïve rats.
- Boosting the Sensitivity and Selectivity of a Miniature Mass Spectrometer Using a Hybrid Ion Funnel. [Journal Article]
- ACAnal Chem 2019 Jun 07
- Besides high portability, high analytical performances are also crucial concerns for a miniature mass spectrometer to meet the demands in in situ analysis. As a continuous effort in improving analyti…
Besides high portability, high analytical performances are also crucial concerns for a miniature mass spectrometer to meet the demands in in situ analysis. As a continuous effort in improving analytical performances of the miniature mass spectrometer with continuous atmospheric pressure interface, a hybrid ion funnel was developed and coupled into the system in this study. The hybrid ion funnel consisted of a rectangular ion funnel region and a planar quadrupole field region, which were fabricated by the printed circuit board technology. After systematic optimization, a limit of detection of 1 ng/mL was obtained, which was improved by 10 folds relative to that of 10 ng/mL previously reported for the miniature mass spectrometer. Besides improved ion transmission efficiency, this hybrid ion funnel was also capable of filtering ions according to their mobilities, thus improving the system selectivity. This capability was demonstrated by separation and selective transmission of protein ions at different charge states, reserpine in PEG background and isobaric peptide ions. Resolution of this system was also tested by analyzing isotopic peaks of reserpine. The ppb-level detection sensitivity and isotope resolving capability achieved in this work would greatly expand the application range of miniature mass spectrometers.
- Developmental neurotoxicity of reserpine exposure in zebrafish larvae (Danio rerio). [Journal Article]
- CBComp Biochem Physiol C Toxicol Pharmacol 2019 May 22; 223:115-123
- Reserpine is widely used for treatment of hypertension and schizophrenia. As a specific inhibitor of monoamine transporters, reserpine is known to deplete monoamine neurotransmitters and cause decrea…
Reserpine is widely used for treatment of hypertension and schizophrenia. As a specific inhibitor of monoamine transporters, reserpine is known to deplete monoamine neurotransmitters and cause decreased movement symptoms. However, how zebrafish larvae respond to reserpine treatment is not well studied. Here we show that swimming distance and average velocity are significantly reduced after reserpine exposure under various stimulatory conditions. Using liquid chromatograph-mass spectrometer analysis, decreased levels of monoamines (e.g. dopamine, noradrenaline, and serotonin) were detected in reserpine-treated larvae. Moreover, reserpine treatment significantly reduced the number of dopaminergic neurons, which was identified with th (Tyrosine Hydroxylase) in situ hybridization in the preoptic area. Interestingly, dopaminergic neuron development-associated genes, such as otpa, otpb, wnt1, wnt3, wnt5 and manf, were downregulated in reserpine treated larvae. Our data indicates that 2 mg/L reserpine exposure induces dopaminergic neuron damage in the brain, demonstrating a chemical induced depression-like model in zebrafish larvae for future drug development.
- Coresistance to Benzalkonium Chloride Disinfectant and Heavy Metal Ions in Listeria monocytogenes and Listeria innocua Swine Isolates from China. [Journal Article]
- FPFoodborne Pathog Dis 2019 May 22
- The development of coresistance to disinfectants and heavy metals contributes to the fitness of Listeria spp. in foods or food processing environments, where life-threatening Listeria monocytogenes c…
The development of coresistance to disinfectants and heavy metals contributes to the fitness of Listeria spp. in foods or food processing environments, where life-threatening Listeria monocytogenes coexist and coevolve with other Listeria spp. Despite extensive research on L. monocytogenes, coresistance to disinfectants and heavy metals is less documented for other Listeria spp. In this study, we screened 30 L. monocytogenes and 27 Listeria innocua isolates recovered from 273 swine samples for resistance to quaternary ammonium compound benzalkonium chloride (BC) and to heavy metals cadmium (Cd) and arsenic (As). Moreover, we evaluated the potential mechanisms of resistance by detecting the efflux pump activity in BC resistance and the presence of resistance determinants. The average minimum inhibitory concentrations of BC in L. innocua (10.7 ± 2.0) were significantly higher than that in L. monocytogenes (6.9 ± 3.7) (p < 0.05). Resistance to BC and heavy metals was correlated, where all BC-resistant L. innocua and As-resistant L. monocytogenes isolates were coresistant to BC and Cd. Twenty percent and 66.7% of BC resistance in L. monocytogenes and L. innocua were related to reserpine-associated efflux pumps, whereas all cases of BC resistance were related to carbonyl cyanide 3-chlorophenylhydrazone-associated efflux pumps. The cadA1 and cadA2 genes were present in Cd-resistant isolates but not in Cd-sensitive isolates, and cadA3 was undetectable in all isolates examined. cadA4 conferring lower level of Cd resistance was copresent with arsA1 and arsA2 in the Cd-resistant and As-susceptible L. monocytogenes isolate LM3. Our findings suggest that swine serves as a reservoir for developing resistance to disinfectant and heavy metals in L. monocytogenes and L. innocua, which share common resistance mechanisms such as efflux pumps and resistance genes. This work provides new insight into the coresistance events of other Listeria as a potential contributor of the resistance in L. monocytogenes.
- Repeated treatment with a low dose of reserpine as a progressive model of Parkinson's dementia. [Journal Article]
- PJPak J Pharm Sci 2019; 32(2):555-562
- Present study was designed to monitor the cognitive profile of the animals upon repeated administration of reserpine, so as to determine that whether these animals should be used as animal models of …
Present study was designed to monitor the cognitive profile of the animals upon repeated administration of reserpine, so as to determine that whether these animals should be used as animal models of Parkinson's dementia. In the present study, reserpine was injected daily (once a day for three weeks) at the dose of 0.1mg/kg. Short- and long term memories were assessed using a Morris water maze, on weekly basis. Novel object recognition test was performed after completion of the treatment (day 21). Animals were decapitated on day 21 and brain samples were stored at -70ºC until neurochemical analysis by HPLC-EC. Impairment of short- and long term activities (as monitored in Morris water maze) were not observed until after first week. Long term memory was found to be impaired earlier than the short term memory. Novel object recognition test also exhibited reserpine-induced impairment of working memory. Neurochemical analysis of the whole brain samples by HPLC-EC method showed that repeated administration of reserpine significantly increased DOPAC/ DA ratio (p<0.01). While 5-HIAA/ 5-HT ratio was found to be decreased (p<0.05) in reserpine injected animals. This further confirmed that these neurochemical deficits to be the underlying reason in memory impairment. In conclusion, present study provides evidence that repeated administration of reserpine can be used as a 'progressive' animal model of Parkinson's dementia. Results could be beneficial for face validity and screening of the drugs for the treatment of dementia secondary to Parkinson's and related disorders.
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- Ameliorative effect of imperatorin in chemically induced fibromyalgia: Role of NMDA/NFkB mediated downstream signaling. [Journal Article]
- BPBiochem Pharmacol 2019 May 07; 166:56-69
- Fibromyalgia (FM) is a chronic pain syndrome involving complex interplay of biogenic amines and NMDA receptor mediated hypersensitization of nociceptive pathways. Clinical management of FM is poorly …
Fibromyalgia (FM) is a chronic pain syndrome involving complex interplay of biogenic amines and NMDA receptor mediated hypersensitization of nociceptive pathways. Clinical management of FM is poorly addressed with only a few available therapeutic options. Coumarins are active phenolic molecules of natural origin found to have broad pharmacological activities. Current investigation explores the role of naturally occurring coumarin, imperatorin in mouse model of fibromyalgia. Administration of reserpine (0.5 mg/kg, s.c.) thrice at 24 h intervals induced behavioral and neurochemical alterations characteristic of fibromyalgia. Reserpine was found to induce allodynia quantified using electronic von Frey (e-VF) and pressure application measurement (PAM) test, depression as indicated by an increased duration of immobility in forced swim test (FST), decreased motor coordination and locomotor activity in inclined plane test (IPT) and open field test (OFT) respectively. Cognitive deficits were evident by an increased latency to locate hidden platform in Morris water maze (MWM) and passive avoidance test (PAT). Reserpine treatment was found to cause an increased anxiety as revealed by increased time spent in closed arm of the elevated plus maze (EPM). Furthermore, an up- regulation in NMDA and NFκB expression in the brain and spinal cord was observed in reserpine treated groups. Administration of imperatorin (10 mg/kg, i.p) for a period of 5 days ameliorated all behavioral deficits, biochemical changes and decreased expression of NMDA and NFκB in the brain and spinal cord of treated mice. These findings indicate an interplay of NMDA/NFκB modulation by imperatorin in the reserpine induced fibromyalgia in mice.