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Stroke Jul 2024The mitochondrial unfolded protein response (UPR) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic...
BACKGROUND
The mitochondrial unfolded protein response (UPR) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPR may be a potential therapeutic target for ischemic stroke.
METHODS
We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPR. We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro.
RESULTS
Inducing UPR with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPR could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPR with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPR in vivo, which reduced infarction and improved neurological outcomes.
CONCLUSIONS
These findings suggest that the UPR is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPR mechanism may provide a new therapeutic avenue for ischemic stroke.
Topics: Animals; Neurons; Mice; Glucose; Unfolded Protein Response; Mitochondria; Brain Ischemia; Male; Infarction, Middle Cerebral Artery; Oxygen; Mice, Inbred C57BL; Cells, Cultured; Neuroprotective Agents
PubMed: 38913800
DOI: 10.1161/STROKEAHA.123.045550 -
Chemistry (Weinheim An Der Bergstrasse,... Jun 2024In this study, protonation constant values and liquid chromatographic behaviors of hydrophobic cyclizine, chlorcyclizine, hydroxyzine, cinnarizine, cetirizine,...
In this study, protonation constant values and liquid chromatographic behaviors of hydrophobic cyclizine, chlorcyclizine, hydroxyzine, cinnarizine, cetirizine, meclizine, and buclizine in some water-organic solvent binary mixtures were examined for the first time using classical and green reverse phase liquid chromatography methods. In the isocratic study, the relationship of the retention time and mobile phase pH in water-organic solvent binary mixtures containing acetonitrile (45, 50, 55, 60, 65%, v/v), methanol (60, 65, 70, 75%, v/v) and ethanol (45, 50, 55, 56, 59, 60, 62, 65%, v/v) were determined at 37 °C. In the study, XBridge C18 and Gemini NX C18 columns suitable for the chemical properties of basic compounds were used. The obtained liquid chromatographic data were analyzed using the linear solvation energy relationship methodology and the SOLVER program. The aqueous protonation constant values of the investigated compounds were calculated using the linear relationship between the protonation constant data calculated in studied binary mixtures and some macroscopic constant values of the solvents used. The greenness of methods developed using three different solvents was evaluated with the Analytical Greenness Metric Approach, the Green Analytical Procedures Index, and the Green Solvent Selection Tool approaches.
PubMed: 38632089
DOI: 10.1002/chem.202400649 -
The Journal of Neuroscience : the... Apr 2024
Erratum: Shannonhouse et al., "Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy".
PubMed: 38594070
DOI: 10.1523/JNEUROSCI.0541-24.2024 -
Stroke May 2024Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However,...
BACKGROUND
Mild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney. Here, we examine the mechanism of action of meclizine and report the efficacy and improved safety of the ) enantiomer.
METHODS
We determined the anoxic depolarization latency, tissue and neurological outcomes, and glucose uptake using micro-positron emission tomography after transient middle cerebral artery occlusion in mice pretreated (-17 and -3 hours) with either vehicle or meclizine. To exclude a direct effect on tissue excitability, we also examined spreading depression susceptibility. Furthermore, we accomplished the chiral synthesis of )- and )-meclizine and compared their effects on oxygen consumption and histamine H1 receptor binding along with their brain concentrations.
RESULTS
Micro-positron emission tomography showed meclizine increases glucose uptake in the ischemic penumbra, providing the first in vivo evidence that the neuroprotective effect of meclizine indeed stems from its ability to toggle metabolism toward glycolysis. Consistent with reduced reliance on oxidative phosphorylation to sustain the metabolism, meclizine delayed anoxic depolarization onset after middle cerebral artery occlusion. Moreover, the ) enantiomer showed reduced H1 receptor binding, a dose-limiting side effect for the racemate, but retained its effect on mitochondrial respiration. )-meclizine was at least as efficacious as the racemate in delaying anoxic depolarization onset and decreasing infarct volumes after middle cerebral artery occlusion.
CONCLUSIONS
Our data identify )-meclizine as a promising new drug candidate with high translational potential as a chemical preconditioning agent for preemptive prophylaxis in patients with high imminent stroke or myocardial infarction risk.
PubMed: 38572656
DOI: 10.1161/STROKEAHA.123.044397 -
Endocrine Journal Apr 2024Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the...
Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.
PubMed: 38569854
DOI: 10.1507/endocrj.EJ24-0109 -
JBMR Plus Apr 2024Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor...
Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Activated FGFR3, which is a negative regulator of bone elongation, impairs the growth of long bones and the spinal arch by inhibiting chondrocyte proliferation and differentiation. Most patients with ACH have spinal canal stenosis in addition to short stature. Meclozine has been found to inhibit FGFR3 via drug repurposing. A 10-d treatment with meclozine promoted long-bone growth in a mouse model of ACH ( mice). This study aimed to evaluate the effects of long-term meclozine administration on promoting bone growth and the spinal canal in mice. Meclozine (2 mg/kg/d) was orally administered to mice for 5 d per wk from the age of 7 d to 56 d. Meclozine (2 mg/kg/d) significantly reduced the rate of death or paralysis and improved the length of the body, cranium, and long bones in male and female mice. Micro-computed tomography analysis revealed that meclozine ameliorated kyphotic deformities and trabecular parameters, including BMD, bone volume/tissue volume, trabecular thickness, and trabecular number at distal femur of mice in both sexes. Histological analyses revealed that the hypertrophic zone in the growth plate was restored in mice following meclozine treatment, suggesting upregulation of endochondral ossification. Skeletal preparations demonstrated that meclozine restored the spinal canal diameter in mice in addition to improving the length of each bone. The 2 mg/kg/d dose of meclozine reduced the rate of spinal paralysis caused by spinal canal stenosis, maintained the growth plate structure, and recovered the bone quality and growth of axial and appendicular skeletons of mice in both sexes. Long-term meclozine administration has the potential to ameliorate spinal paralysis and bone growth in patients with ACH.
PubMed: 38544920
DOI: 10.1093/jbmrpl/ziae018 -
American Journal of Obstetrics and... Jul 2024Adenomyosis is one of the structural causes of abnormal uterine bleeding, which often presents as heavy menstrual bleeding. Mostly because of the poor understanding of...
BACKGROUND
Adenomyosis is one of the structural causes of abnormal uterine bleeding, which often presents as heavy menstrual bleeding. Mostly because of the poor understanding of its pathophysiology, medical management of adenomyosis-induced heavy menstrual bleeding is still a challenge. We have previously reported that glycolysis is crucial to endometrial repair following menstruation and that suppressed glycolysis can cause heavy menstrual bleeding.
OBJECTIVE
This study aimed to test the hypothesis that meclizine, a drug with an excellent safety profile, alleviates heavy menstrual bleeding in mice with induced adenomyosis using a simulated menstruation model.
STUDY DESIGN
Adenomyosis was induced in 36 female C57BL/6 mice using endometrial-myometrial interface disruption. Three months after induction, the mice were randomly divided into the following 3 groups: low-dose meclizine, high-dose meclizine, and controls. Treatment with meclizine or vehicle started shortly before the simulated menstruation procedure and ended before progesterone withdrawal. The amount of blood loss was quantified and uterine tissue was harvested for histologic evaluation of the grade of endometrial repair. We performed immunohistochemistry analysis of 4 proteins critically involved in glycolysis: Glut1 (glucose transporter 1), Hk2 (hexokinase 2), Pfkfb3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3), and Pkm2 (pyruvate kinase M2). The extent of tissue fibrosis in both ectopic and eutopic endometria was evaluated using Masson trichrome staining.
RESULTS
In mice with induced adenomyosis, meclizine accelerated endometrial repair in a dose-dependent manner and reduced the amount of menstrual bleeding. Meclizine administration raised endometrial immunoexpression of Hk2 and Pfkfb3 but not of Glut1 or Pkm2. The extent of endometrial fibrosis was reduced following the meclizine administration. Remarkably, these favorable changes were accompanied by the suppression of lesional progression, as evidenced by the dose-dependent reduction in the extent of fibrosis (a surrogate for lesional progression).
CONCLUSION
These encouraging results, taken together, suggest that glycolysis may be a promising therapeutic target and that meclizine may hold therapeutic potential as a nonhormonal treatment for adenomyosis-induced heavy menstrual bleeding without exacerbating the disease.
Topics: Animals; Female; Endometrium; Adenomyosis; Mice; Meclizine; Mice, Inbred C57BL; Glycolysis; Disease Models, Animal; Menorrhagia; Pyruvate Kinase; Glucose Transporter Type 1
PubMed: 38367751
DOI: 10.1016/j.ajog.2024.02.016 -
ACS Omega Jan 2024In this work, we demonstrate a sensitive high-performance liquid chromatography (HPLC) method for the determination of piperazine antihistamine drugs employing...
In this work, we demonstrate a sensitive high-performance liquid chromatography (HPLC) method for the determination of piperazine antihistamine drugs employing innovative electrochemical detection based on a spark-generated nickel oxide nanoparticle-modified carbon fiber microelectrode built into a miniaturized electrochemical detector. The direct carbon fiber-to-nickel plate electrode spark discharge, carried at 0.8 kV DC, with the nickel electrode connected to the negative pole of the high-voltage power supply, provides extremely fast (1 s) in situ tailoring of the carbon fiber microelectrode surface by nickel oxide nanoparticles. It has been found that nickel oxide nanoparticles exhibit an electrocatalytic effect toward the piperazine moiety electrooxidation process, as confirmed by voltammetric experiments, revealing the shift in the peak potential from 1.25 to 1.09 V versus Ag/AgCl. Cetirizine, cyclizine, chlorcyclizine, flunarizine, meclizine, and buclizine were selected as sample piperazine antihistamine drugs, while diclofenac served as an internal standard. The isocratic reversed-phase separation of the above set was achieved within 15 min using an ARION-CN 3 μm column with a binary mobile phase consisting of 50 mM phosphate buffer (pH 3) and methanol (45/55, v/v). The limits of detection (LOD) were within the range of 3.8-120 nM (for cyclizine and buclizine) at = +1500 mV (vs Ag/AgCl), while the response was linear within the concentration range measured up to 5 μmol L. The method was successfully applied to the determination of piperazine antihistamine drugs in spiked plasma samples.
PubMed: 38313503
DOI: 10.1021/acsomega.3c09474 -
Frontiers in Pharmacology 2023The medicines information service, SafeMotherMedicine, regularly receives inquiries from breastfeeding women asking about antiemetics for nausea and vomiting during...
The medicines information service, SafeMotherMedicine, regularly receives inquiries from breastfeeding women asking about antiemetics for nausea and vomiting during pregnancy (NVP) or hyperemesis gravidarum (HG). However, treatment guidelines for NVP or HG do not address the use of antiemetics in women who are breastfeeding while becoming pregnant again. Our objective was to characterize inquiries to describe the need for lactation risk information among women with NVP or HG and also to raise awareness of this topic. We conducted a review of inquiries to the Norwegian web-based medicines information service, SafeMotherMedicine. In total, 97 inquiries addressing the use of antiemetics for NVP or HG during breastfeeding were identified. The following medications were addressed in the inquiries ( = 97): meclizine (51%), metoclopramide (33%), promethazine (16%), ondansetron (9%), and others (6%). The breastfed child was older than 6 months and 1 year in 96% and 71% of the inquiries, respectively. There was a preponderance of general inquiries (unclear motivation/double checking) (64%); however, one-third of the inquiries were generated by restrictive information from sources such as product information. Based on our small review of spontaneous inquiries, there seems to be an information need about the use of antiemetics during lactation among women breastfeeding an older infant whilst suffering from NVP or HG. Addressing such use in guidelines for NVP and HG and/or other easily available information sources may be considered in order to balance out the restrictive information provided by the manufacturers. This could avoid potential unnecessary weaning of breastfeeding in an otherwise challenging situation.
PubMed: 38094894
DOI: 10.3389/fphar.2023.1238875