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Journal of Pharmacological Sciences Sep 2021Schizophrenia is one of the foremost psychological illness around the world, and recent evidence shows that inflammation and oxidative stress may play a critical role in...
Schizophrenia is one of the foremost psychological illness around the world, and recent evidence shows that inflammation and oxidative stress may play a critical role in the etiology of schizophrenia. Andrographolide is a diterpenoid lactone from Andrographis paniculate, which has shown anti-inflammation and anti-oxidative effects. In this study, we explored whether andrographolide can improve schizophrenia-like behaviors through its inhibition of inflammation and oxidative stress in Phencyclidine (PCP)-induced mouse model of schizophrenia. We found that abnormal behavioral including locomotor activity, forced swimming and novel object recognition were ameliorated following andrographolide administration (5 mg/kg and 10 mg/kg). Andrographolide inhibited PCP-induced production of inflammatory cytokines, decreased p-p65, p-IκBα, p-p38 and p-ERK1/2 in the prefrontal cortex. Andrographolide significantly declined the level of MDA and GSH, as well as elevated the activity of SOD, CAT and GCH-px. In addition, andrographolide increased expression of NRF-2, HO-1 and NQO-1, promoted nuclear translocation of NRF-2 through blocking the interaction between NRF-2 and KEAP1, which may be associated with directly binding to NRF-2. Furthermore, antioxidative effects and anti-schizophrenia-like behaviors of andrographolide were compromised by the application of NRF-2 inhibitor ML385. In conclusion, these results suggested that andrographolide improved oxidative stress and schizophrenia-like behaviors induced by PCP through increasing NRF-2 pathway.
Topics: Andrographis paniculata; Animals; Anti-Inflammatory Agents; Antioxidants; Disease Models, Animal; Diterpenes; Epistasis, Genetic; Inflammation; Kelch-Like ECH-Associated Protein 1; Male; Mice, Inbred ICR; NF-E2-Related Factor 2; Oxidative Stress; Phencyclidine; Phytotherapy; Schizophrenia; Signal Transduction; Mice
PubMed: 34294378
DOI: 10.1016/j.jphs.2021.05.007 -
World Journal of Clinical Cases Nov 2021Capillary leak syndrome (CLS) is characterized by the leakage of large amounts of fluid and plasma proteins into the interstitial space, resulting in hypoalbuminemia,...
BACKGROUND
Capillary leak syndrome (CLS) is characterized by the leakage of large amounts of fluid and plasma proteins into the interstitial space, resulting in hypoalbuminemia, hypovolemic shock, elevated blood concentration, systemic progressive edema, and multiple serosal cavity effusion. Clinical syndromes such as cavity effusion pose a grave threat to the life and health of the patient.
CASE SUMMARY
A 58-year-old female patient was admitted to the hospital after being in a coma for 6 h following accidental ingestion of a pesticide. She was treated with phencyclidine hydrochloride and pralidoxime iodide for detoxification, mechanical ventilation to maintain oxygen supply, continuous renal replacement therapy to maintain the internal environment, and hemoperfusion to promote the excretion of toxins. She also received a transfusion of red blood cells and massive fluid resuscitation. However, her blood pressure was not maintained. The patient was diagnosed with CLS due to pesticide poisoning. Oxygenation was difficult to maintain under full ventilator support; therefore, veno-venous-extracorporeal membrane oxygenation (VV-ECMO) treatment was given 13 h after admission. Her oxygenation level improved, but a large amount of ascites and pleural effusion soon became apparent. We continued drainage with an indwelling drainage tube, and the ECMO flow stabilized. The leakage gradually decreased, and ECMO was discontinued 3 d later. On the 6 day, the patient recovered from unconsciousness, but on gastroscopic evaluation, severe erosions were found in her entire stomach. With the family's consent, treatment was stopped, and the patient was discharged from the hospital on the 7 day.
CONCLUSION
ECMO, liquid resuscitation and management, and improvement in plasma colloidal osmotic pressure, circulation, and tissue oxygen supply are crucial in treating CLS.
PubMed: 34904099
DOI: 10.12998/wjcc.v9.i33.10273 -
Behavioural Brain Research Apr 2021Reversal learning, a component of executive functioning, is commonly impaired among schizophrenia patients and is lacking effective treatment. N-methyl-ᴅ-aspartate...
Reversal learning, a component of executive functioning, is commonly impaired among schizophrenia patients and is lacking effective treatment. N-methyl-ᴅ-aspartate (NMDA) receptor antagonists, such as phencyclidine (PCP), impair reversal learning of rodents. Touchscreen-based pairwise visual discrimination and reversal test is a translational tool to assess reversal learning in rodents. However, to fully exploit this task in testing of novel compounds, it is necessary to perform several reversal learning experiments with trained animals. Firstly, we assessed whether PCP-induced deficits in visual reversal learning in rats would be detectable with a short (5 sessions) reversal learning phase, and whether the short reversal phases could be repeated with novel stimulus pairs. Secondly, we assessed whether the PCP-induced deficits in reversal learning could be seen upon repeated PCP challenges with the same animals. Finally, we tested the effect of a novel compound, a selective α adrenoceptor antagonist, ORM-13070, to reverse PCP-induced cognitive deficits in this model. A 4-day PCP treatment at a dose of 1.5 mg/kg/day impaired early reversal learning in male Lister Hooded rats without inducing non-specific behavioral effects. We repeated the reversal learning experiment four times using different stimulus pairs with the same animals, and the PCP-induced impairment was evident in every single experiment. The α adrenoceptor antagonist ameliorated the PCP-induced cognitive deficits. Our results suggest that repeated PCP challenges in the touchscreen set-up induce schizophrenia-like cognitive deficits in visual reversal learning, improve throughput of the test and provide a protocol for testing novel drugs.
Topics: Animals; Cognitive Dysfunction; Discrimination Learning; Male; Phencyclidine; Photic Stimulation; Rats; Receptors, N-Methyl-D-Aspartate; Reversal Learning
PubMed: 33316322
DOI: 10.1016/j.bbr.2020.113057 -
Analytical Chemistry Dec 2023The market for illicit drugs has been reshaped by the emergence of more than 1100 new psychoactive substances (NPS) over the past decade, posing a major challenge to the...
The market for illicit drugs has been reshaped by the emergence of more than 1100 new psychoactive substances (NPS) over the past decade, posing a major challenge to the forensic and toxicological laboratories tasked with detecting and identifying them. Tandem mass spectrometry (MS/MS) is the primary method used to screen for NPS within seized materials or biological samples. The most contemporary workflows necessitate labor-intensive and expensive MS/MS reference standards, which may not be available for recently emerged NPS on the illicit market. Here, we present NPS-MS, a deep learning method capable of accurately predicting the MS/MS spectra of known and hypothesized NPS from their chemical structures alone. NPS-MS is trained by transfer learning from a generic MS/MS prediction model on a large data set of MS/MS spectra. We show that this approach enables a more accurate identification of NPS from experimentally acquired MS/MS spectra than any existing method. We demonstrate the application of NPS-MS to identify a novel derivative of phencyclidine (PCP) within an unknown powder seized in Denmark without the use of any reference standards. We anticipate that NPS-MS will allow forensic laboratories to identify more rapidly both known and newly emerging NPS. NPS-MS is available as a web server at https://nps-ms.ca/, which provides MS/MS spectra prediction capabilities for given NPS compounds. Additionally, it offers MS/MS spectra identification against a vast database comprising approximately 8.7 million predicted NPS compounds from DarkNPS and 24.5 million predicted ESI-QToF-MS/MS spectra for these compounds.
Topics: Tandem Mass Spectrometry; Deep Learning; Psychotropic Drugs; Illicit Drugs; Spectrometry, Mass, Electrospray Ionization
PubMed: 38048435
DOI: 10.1021/acs.analchem.3c02413 -
Neurobiology of Disease Jan 2023Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is...
Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.
Topics: Mice; Animals; Cannabinoids; Cyclin-Dependent Kinase 5; Psychotic Disorders; Schizophrenia; Phencyclidine; Cannabinoid Receptor Agonists; Disks Large Homolog 4 Protein
PubMed: 36473591
DOI: 10.1016/j.nbd.2022.105942 -
Science Advances Jan 2024Metabotropic glutamate receptor 2 (mGlu) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways...
Metabotropic glutamate receptor 2 (mGlu) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu partners, including the neurotrophin receptor TrkB. The later interaction was confirmed both in cultured cells and prefrontal cortex. mGlu activation triggers phosphorylation of TrkB on Tyr in primary cortical neurons and prefrontal cortex. Reciprocally, TrkB stimulation enhances mGlu-operated G protein activation. Furthermore, TrkB inhibition prevents the rescue of behavioral deficits by glutamatergic antipsychotics in phencyclidine-treated mice. Collectively, these results reveal a cross-talk between TrkB and mGlu, which is key to the behavioral response to glutamatergic antipsychotics.
Topics: Mice; Animals; Antipsychotic Agents; Receptor, trkB; Prefrontal Cortex; Cells, Cultured; Neurons
PubMed: 38277461
DOI: 10.1126/sciadv.adg1679 -
Annals of Indian Academy of Neurology 2019Saccadic intrusions such as opsoclonus and ocular flutter are often due to a paraneoplastic or a parainfectious condition. Toxins/drugs may rarely cause them. Herein, we...
Saccadic intrusions such as opsoclonus and ocular flutter are often due to a paraneoplastic or a parainfectious condition. Toxins/drugs may rarely cause them. Herein, we report a rare case of ocular flutter/opsoclonus due to phencyclidine (PCP) toxicity. Our patient is a 21-year-old male who presented with a 3-day history of headache, generalized ill health, and aggressive behavior. He was admitted with reduced level of consciousness following generalized seizures. He had features of sympathetic overactivity with ocular flutter and opsoclonus. Urine toxicology was positive for PCP. Despite supportive care, he succumbed to complications of rhabdomyolysis. Several drugs including cocaine, phenytoin, lithium, and amitriptyline are known to cause ocular flutter/opsoclonus rarely. It is poorly described with PCP. This case highlights PCP as a rare cause of toxin-induced saccadic intrusions and attempts to postulate its pathogenesis. Moreover, our report is the first case of PCP intoxication in Sri Lanka and one of the few documented reports in the South Asian region. Therefore, it represents a significant worrisome alarm about the spread of this substance in this region.
PubMed: 31736584
DOI: 10.4103/aian.AIAN_174_18 -
Journal of Medicinal Chemistry Sep 2021In line with recent clinical trials demonstrating that ondansetron, a 5-HT receptor (5-HTR) antagonist, ameliorates cognitive deficits of schizophrenia and the known...
In line with recent clinical trials demonstrating that ondansetron, a 5-HT receptor (5-HTR) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT receptor (5-HTR) antagonists, we applied the hybridization strategy to design dual-acting 5-HT/5-HTR antagonists. We identified the first-in-class compound , which behaves as a 5-HTR antagonist and a neutral antagonist 5-HTR of the Gs pathway. shows selectivity over 87 targets and decent brain penetration. Likewise, inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to , neither 5-HTR inverse agonist SB399885 nor neutral 5-HTR antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HTR antagonism and 5-HTR antagonism, exemplified by , contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT/5-HT receptors and encourage further studies on dual-acting 5-HT/5-HTR antagonists for the treatment of psychiatric disorders.
Topics: Animals; Antipsychotic Agents; Cognitive Dysfunction; Drug Combinations; Guinea Pigs; Humans; Male; Microsomes, Liver; Molecular Structure; Nootropic Agents; Ondansetron; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Structure-Activity Relationship; Sulfonamides
PubMed: 34467765
DOI: 10.1021/acs.jmedchem.1c00224 -
Fa Yi Xue Za Zhi Aug 2021Objective To establish an ion chromatography method for the salt form determination of new psychoactive substances (NPS). Methods The method of conducting...
Objective To establish an ion chromatography method for the salt form determination of new psychoactive substances (NPS). Methods The method of conducting qualitative and quantitative analysis of six types of organic acid ions (acetate ion, tartrate ion, maleate ion, oxalate ion, fumarate ion, citrate ion) and five types of inorganic anions (fluoride ion, chloride ion, nitrate ion, sulfate ion, phosphate ion) in NPS sample by ion chromatography was developed. The salt forms of 222 seized NPS samples (103 samples with synthetic cannabinoids, 81 samples with cathinones, 44 samples with phenylethylamines, 12 samples with tryptamines, 7 samples with phencyclidines, 6 samples with piperazines, 2 samples with aminoindenes, 26 samples with fentanyls and 43 samples with other types of NPS) were analyzed by this method. Results Each anion had good linearity in the corresponding linear range, the correlation coefficients () were greater than 0.999, the limits of detection were 0.01-0.05 mg/L, and the limits of quantitative were 0.1-0.5 mg/L. Except that 5F-BEPIRAPIM was hydrochloride, the salt forms of the other 102 synthetic cannabinoids were all base. The salt form of 81 cathinone samples, 44 phenylethylamine samples, 7 phencyclidine samples and 2 aminoindene samples were all hydrochloride. The salt forms of tryptamine samples included base, hydrochloride, fumarate and oxalate. The salt forms of piperazine samples included base and hydrochloride. The salt forms of fentanyl samples and samples of other types included base, hydrochloride and citrate. Conclusion Ion chromatography is a simple, accurate and efficient method for determining the salt form of NPS samples, which makes the qualitative and quantitative conclusions of NPS more scientific and rigorous.
Topics: Chromatography, Liquid; Gas Chromatography-Mass Spectrometry; Ions; Psychotropic Drugs
PubMed: 34726002
DOI: 10.12116/j.issn.1004-5619.2021.310402 -
Arhiv Za Higijenu Rada I Toksikologiju Dec 2021Lysergic acid diethylamide (LSD) is a classic hallucinogen, widely abused for decades, while phencyclidine (PCP) has increased in popularity in recent years, especially...
Lysergic acid diethylamide (LSD) is a classic hallucinogen, widely abused for decades, while phencyclidine (PCP) has increased in popularity in recent years, especially among the adolescents. Very little is known about the general toxicity of these compounds, especially about their possible neurotoxic effects at the cell level. The aim of this study was to address these gaps by assessing the toxic effects of 24-hour exposure to LSD and PCP in the concentration range of 0.39-100 μmol/L in the human neuroblastoma SH-SY5Y cell line. After cell viability was established, cells treated with concentrations that reduced their viability up to 30 % were further subjected to the alkaline comet assay and biochemical assays that enable estimation of oxidative stress-related effects. Treatment with LSD at 6.25 μmol/L and with PCP at 3.13 μmol/L resulted with 88.06±2.05 and 84.17±3.19 % of viable cells, respectively, and led to a significant increase in primary DNA damage compared to negative control. LSD also caused a significant increase in malondialdehyde level, reactive oxygen species (ROS) production, and glutathione (GSH) level, PCP significantly increased ROS but lowered GSH compared to control. Treatment with LSD significantly increased the activities of all antioxidant enzymes, while PCP treatment significantly increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) but decreased catalase (CAT) activity compared to control. Our findings suggest that LSD has a greater DNA damaging potential and stronger oxidative activity than PCP in SH-SY5Y cells.
Topics: Adolescent; Cell Line; Cell Line, Tumor; DNA Damage; Humans; Lysergic Acid Diethylamide; Neuroblastoma; Oxidative Stress; Phencyclidine; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 34985843
DOI: 10.2478/aiht-2021-72-3604