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JPMA. the Journal of the Pakistan... May 2024
Topics: Humans; Ondansetron; Long QT Syndrome; Antiemetics
PubMed: 38783462
DOI: 10.47391/JPMA.10825 -
BMJ Case Reports May 2024We report the case of a man in his mid-80s with diabetes mellitus who presented to the emergency department with a 1-day history of right-sided choreiform movements and...
We report the case of a man in his mid-80s with diabetes mellitus who presented to the emergency department with a 1-day history of right-sided choreiform movements and falls. Laboratory tests revealed blood glucose of 597 mg/dL. Non-contrast CT imaging of his head demonstrated a faint hyperdensity involving the left lentiform nucleus and brain MRI showed a hyperintensity in the left basal ganglia on T1-weighted images. These lesions are typical of diabetic striatopathy. Symptoms of hemichorea/hemiballismus did not resolve with glycaemic control and several pharmacological agents were tried with eventual improvement with risperidone. He was discharged to a rehabilitation facility and had mild persistent arm chorea at 6-month follow-up.
Topics: Humans; Male; Chorea; Dyskinesias; Aged, 80 and over; Risperidone; Magnetic Resonance Imaging; Antipsychotic Agents; Diabetes Complications; Diabetes Mellitus, Type 2; Tomography, X-Ray Computed
PubMed: 38782432
DOI: 10.1136/bcr-2023-259046 -
Behavioural Brain Research Jul 2024Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or...
Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HTR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HTR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[I]iodophenyl)-nortropane ([I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HTR inhibition and 5-HTR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.
Topics: Animals; Dopamine Plasma Membrane Transport Proteins; Male; Recognition, Psychology; Exploratory Behavior; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Motor Activity; Brain; Emotions; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Rats, Wistar
PubMed: 38777263
DOI: 10.1016/j.bbr.2024.115051 -
BMC Complementary Medicine and Therapies May 2024Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that...
BACKGROUND
Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model.
METHODS
A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT receptor antagonist.
RESULTS
Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5 µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration.
CONCLUSION
This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT receptor, one of the serotonin receptors, to produce analgesia.
Topics: Animals; Mice; Drugs, Chinese Herbal; Disease Models, Animal; Male; Pain, Postoperative; Analgesics; Serotonin; Receptor, Serotonin, 5-HT1A; Administration, Oral; Mice, Inbred ICR
PubMed: 38773460
DOI: 10.1186/s12906-024-04501-6 -
Scientific Reports May 2024Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed...
Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo efficacy assay in rats which could support chemogenetic drug discovery by providing a quick, simple and reliable animal model. Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts 1-3 h post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments. We also hypothesize based on our results that universal LH silencing with existing and human translatable genetic neuroengineering techniques might be a viable strategy to affect food intake and influence obesity.
Topics: Animals; Clozapine; Rats; Eating; Hypothalamic Area, Lateral; Dependovirus; Male; Proof of Concept Study; Exenatide; Humans
PubMed: 38762561
DOI: 10.1038/s41598-024-62014-1 -
Biomedicine & Pharmacotherapy =... Jun 2024Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine...
BACKGROUND
Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system.
METHODS
Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA.
RESULTS
Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5' regulatory region of the Aqp4 gene (-1096 bp to -1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment.
CONCLUSIONS
Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal.
Topics: Animals; Ketamine; Astrocytes; Cognitive Dysfunction; Mice; Male; Hippocampus; Glymphatic System; Proto-Oncogene Proteins c-akt; Aquaporin 4; Receptor, Serotonin, 5-HT2C; Mice, Inbred C57BL; Cells, Cultured; Proto-Oncogene Proteins c-fos; PTEN Phosphohydrolase
PubMed: 38759288
DOI: 10.1016/j.biopha.2024.116739 -
Cureus Apr 2024Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer's-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed. As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.
PubMed: 38756263
DOI: 10.7759/cureus.58416 -
Scientific Reports May 2024Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with...
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R-CHOP) is one of the standard regimens. Given that R-CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R-CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Cyclophosphamide; Male; Female; Middle Aged; Vincristine; Nausea; Vomiting; Rituximab; Prednisone; Aged; Palonosetron; Adult; Prospective Studies; Antiemetics; Pyridines; Treatment Outcome; Drug Combinations; Isoquinolines; Quinuclidines
PubMed: 38755279
DOI: 10.1038/s41598-024-62057-4 -
BioRxiv : the Preprint Server For... May 2024Islet transplantation can cure type 1 diabetes, but peri-transplant beta cell death limits this procedure to those with low insulin requirements. Improving human beta...
UNLABELLED
Islet transplantation can cure type 1 diabetes, but peri-transplant beta cell death limits this procedure to those with low insulin requirements. Improving human beta cell survival or proliferation may make islet transplantation a possibility for more type 1 patients. To identify novel regulators of beta cell survival and proliferation, we conducted a pooled small hairpin RNA (shRNA) screen in primary human beta cells transplanted into immunocompromised mice. shRNAs targeting several cyclin dependent kinase inhibitors were enriched after transplant. Here, we focused on the Gi/o-coupled GPCR, serotonin 1F receptor ( 5-HT ) which our screen identified as a negative regulator of beta cell numbers after transplant. , 5-HT knockdown induced human beta cell proliferation but only when combined with harmine and exendin-4. , knockdown of 5-HT reduced beta cell death during transplant. To demonstrate the feasibility of targeting 5-HT in islet transplant, we identified and validated a small molecule 5-HT antagonist. This antagonist increased glucose stimulated insulin secretion from primary human islets and cAMP accumulation in primary human beta cells. Finally, the 5-HT antagonist improved glycemia in marginal mass, human islet transplants into immunocompromised mice. We identify 5-HT as a novel druggable target to improve human beta cell survival in the setting of islet transplantation.
ONE SENTENCE SUMMARY
Serotonin 1F receptor (5-HT ) negatively regulates insulin secretion and beta cell survival during transplant.
PubMed: 38746433
DOI: 10.1101/2024.05.01.591950 -
International Journal of Molecular... Apr 2024Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) and total hip arthroplasty (THA) is a prevalent complication of joint replacement surgery which... (Review)
Review
Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) and total hip arthroplasty (THA) is a prevalent complication of joint replacement surgery which has the potential to decrease patient satisfaction, increase financial burden, and lead to long-term disability. The identification of risk factors for CPSP following TKA and THA is challenging but essential for targeted preventative therapy. Recent meta-analyses and individual studies highlight associations between elevated state anxiety, depression scores, preoperative pain, diabetes, sleep disturbances, and various other factors with an increased risk of CPSP, with differences observed in prevalence between TKA and THA. While the etiology of CPSP is not fully understood, several factors such as chronic inflammation and preoperative central sensitization have been identified. Other potential mechanisms include genetic factors (e.g., catechol-O-methyltransferase (COMT) and potassium inwardly rectifying channel subfamily J member 6 (KCNJ6) genes), lipid markers, and psychological risk factors (anxiety and depression). With regards to therapeutics and prevention, multimodal pharmacological analgesia, emphasizing nonopioid analgesics like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), has gained prominence over epidural analgesia. Nerve blocks and local infiltrative anesthesia have shown mixed results in preventing CPSP. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, exhibits antihyperalgesic properties, but its efficacy in reducing CPSP is inconclusive. Lidocaine, an amide-type local anesthetic, shows tentative positive effects on CPSP. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have mixed results, while gabapentinoids, like gabapentin and pregabalin, present hopeful data but require further research, especially in the context of TKA and THA, to justify their use for CPSP prevention.
Topics: Humans; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Pain, Postoperative; Chronic Pain; Risk Factors; Pain Management; Analgesics
PubMed: 38731944
DOI: 10.3390/ijms25094722