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EBioMedicine Sep 2022Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with heterogeneous aetiology and a complex genetic background. Effective therapies are therefore likely to act on convergent pathways such as dysregulated energy metabolism, linked to multiple neurodegenerative diseases including ALS.
METHODS
Activity of the glycolysis enzyme phosphoglycerate kinase 1 (PGK1) was increased genetically or pharmacologically using terazosin in zebrafish, mouse and ESC-derived motor neuron models of ALS. Multiple disease phenotypes were assessed to determine the therapeutic potential of this approach, including axon growth and motor behaviour, survival and cell death following oxidative stress.
FINDINGS
We have found that targeting a single bioenergetic protein, PGK1, modulates motor neuron vulnerability in vivo. In zebrafish models of ALS, overexpression of PGK1 rescued motor axon phenotypes and improved motor behaviour. Treatment with terazosin, an FDA-approved compound with a known non-canonical action of increasing PGK1 activity, also improved these phenotypes. Terazosin treatment extended survival, improved motor phenotypes and increased motor neuron number in Thy1-hTDP-43 mice. In ESC-derived motor neurons expressing TDP-43, terazosin protected against oxidative stress-induced cell death and increased basal glycolysis rates, while rescuing stress granule assembly.
INTERPRETATION
Our data demonstrate that terazosin protects motor neurons via multiple pathways, including upregulating glycolysis and rescuing stress granule formation. Repurposing terazosin therefore has the potential to increase the limited therapeutic options across all forms of ALS, irrespective of disease cause.
FUNDING
This work was supported by project grant funding from MND Scotland, the My Name'5 Doddie Foundation, Medical Research Council Doctoral Student Training Fellowship [Ref: BST0010Z] and Academy of Medical Sciences grant [SGL023\1100].
Topics: Amyotrophic Lateral Sclerosis; Animals; DNA-Binding Proteins; Humans; Mice; Motor Neurons; Phenotype; Phosphoglycerate Kinase; Prazosin; Zebrafish
PubMed: 35963713
DOI: 10.1016/j.ebiom.2022.104202 -
Cell Reports Jul 2020Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens...
Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers.
Topics: Animals; Antigens; Antineoplastic Agents; Biological Transport; Cross-Priming; Cytosol; Dendritic Cells; Endoplasmic Reticulum-Associated Degradation; Endosomes; Immunity; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms; Permeability; Prazosin; Quinazolines; Small Molecule Libraries; Tamoxifen; beta-Lactamases
PubMed: 32668257
DOI: 10.1016/j.celrep.2020.107905 -
Psychopharmacology Jun 2018The role of norepinephrine (NE) in the development of alcohol use disorder (AUD) has been studied over the past several decades. However, the NE system has been largely... (Review)
Review
The role of norepinephrine (NE) in the development of alcohol use disorder (AUD) has been studied over the past several decades. However, the NE system has been largely ignored for many years as a potential target for medication development for AUD. More recently, preclinical and clinical studies have demonstrated the potential value of targeting NE signaling for developing new pharmacological treatments for AUD. This review contributes to a special issue of Psychopharmacology focused on promising targets for alcohol addiction. Specifically, this review coalesces preclinical and clinical neuroscience that re-evaluate the noradrenergic system, and in particular the alpha-1 receptor, as a potential target for AUD.
Topics: Adrenergic Neurons; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Agonists; Adrenergic beta-Antagonists; Alcoholism; Clonidine; Drug Delivery Systems; Humans; Norepinephrine; Prazosin; Propranolol; Receptors, Adrenergic
PubMed: 29460163
DOI: 10.1007/s00213-018-4843-6 -
Indian Journal of Medical Ethics 2023I have been practising medicine in an under-served rural setting since 1976, and have published around 109 papers in PubMed-indexed journals - including The Lancet, BMJ,...
I have been practising medicine in an under-served rural setting since 1976, and have published around 109 papers in PubMed-indexed journals - including The Lancet, BMJ, NEJM and several tropical medicine journals - on scorpion and snakebite cases causing acute life-threatening conditions. I have researched in detail, with restricted resources, the acute clinical effects of envenomation and management of scorpion and snakebite cases [1, 2]. In Mahad, the fatality rate due to refractory heart failure arising from autonomic storm evoked by scorpion venom was previously 30% [3]. Since the advent of prazosin and scorpion antivenom, it has dropped to less than 1% [4]. Similarly, fatalities due to snakebite poisoning have been reduced from 18% to 5.
Topics: Animals; Humans; Snake Bites; Scorpion Stings; Prazosin; Antivenins; Scorpion Venoms; Scorpions
PubMed: 36420604
DOI: 10.20529/IJME.2022.068 -
International Journal of Molecular... Sep 2021To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed....
To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were recorded. The ratios of the frequency and amplitude of the sIPSCs and sEPSCs following the introduction of naftopidil compared with baseline, and after the application of naftopidil, serotonin (5-HT), and prazosin, compared with noradrenaline (NA) were evaluated. First, the sIPSC analysis indicated that SG neurons reached their full response ratio for NA at 50 μM. Second, they responded to 5-HT (50 μM) with a response ratio similar to that for NA, but prazosin (10 μM) did not change the sEPSCs and sIPSCs. Third, the highest concentration of naftopidil (100 μM) led to two types of response in the SG neurons, which corresponded with the reactions to 5-HT and prazosin. These results indicate that not all neurons were necessarily activated by naftopidil, and that the micturition reflex may be regulated in a sophisticated manner by inhibitory mechanisms in these interneurons.
Topics: Adrenergic alpha-Antagonists; Animals; Excitatory Postsynaptic Potentials; Inhibitory Postsynaptic Potentials; Male; Membrane Potentials; Naphthalenes; Neurons; Norepinephrine; Patch-Clamp Techniques; Piperazines; Prazosin; Rats, Sprague-Dawley; Serotonin; Substantia Gelatinosa; Synaptic Transmission; Rats
PubMed: 34502543
DOI: 10.3390/ijms22179636 -
Neuroscience Letters Jan 2021The emission of 50 kHz frequency-modulated ultrasonic vocalizations (FM USVs) in rats has been associated with positive affective states, while a decrease in FM USVs has...
The emission of 50 kHz frequency-modulated ultrasonic vocalizations (FM USVs) in rats has been associated with positive affective states, while a decrease in FM USVs has been associated with anxiety-like states. We tested the hypothesis in male Sprague-Dawley rats that FM USVs would complement measures of aversive memories (decrease in FM USVs) in a conditioned fear task in which we examined extinction or reconsolidation disruption. In Experiment 1, rats were fear conditioned using low-level footshock followed by extinction while monitoring freezing and FM USVs. In Experiment 2, rats were fear conditioned, the alpha-1 antagonist prazosin was used to disrupt reconsolidation of memory, and freezing and FM USVs were measured. Rats fear conditioned with low-level shock showed minimal freezing that rapidly extinguished, despite a persistent decrease in FM USVs throughout extinction. Prazosin reduced freezing in a memory reactivation-dependent manner as expected, but the reduction in FM USVs after fear conditioning remained decreased, suggesting that an affective component of memory was not impacted by prazosin. These findings indicate that FM USVs may be used as an index of fear- or anxiety-like memory, and their measurement could benefit pre-clinical animal models for assessing reduction of aversive memories.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Avoidance Learning; Conditioning, Classical; Electroshock; Extinction, Psychological; Fear; Male; Memory; Memory Consolidation; Prazosin; Rats, Sprague-Dawley; Ultrasonics; Vocalization, Animal; Rats
PubMed: 33166637
DOI: 10.1016/j.neulet.2020.135458 -
Urology Annals 2023The present retrospective study evaluates the effectiveness and tolerability of alpha-blockers as monotherapy in patients with benign prostatic hyperplasia associated...
Electronic medical records-based retrospective, longitudinal, observational study to understand the patient management of benign prostatic hyperplasia with alpha-blockers monotherapy in Indian population.
OBJECTIVE
The present retrospective study evaluates the effectiveness and tolerability of alpha-blockers as monotherapy in patients with benign prostatic hyperplasia associated with lower urinary tract symptoms (LUTS).
MATERIALS AND METHODS
A total of 335 male patients >50 years were categorized into four groups (Alfuzosin: 166, Silodosin: 67, Tamsulosin: 70, Prazosin: 32). The efficacy evaluated as a change in International Prostate Symptom Score (IPSS), peak flow rate (Qmax), residual urine volume, and relief from LUTS, and tolerability of the various alpha-blockers was assessed across the study group.
RESULTS
At baseline, most of the patients in alfuzosin (60%), silodosin (77%), and tamsulosin (90%) groups presented with severe IPSS (20-35), whereas patients in the prazosin group (69%) presented with a moderate score. At the end of the study, the mean IPSS gradually improved to moderate (41%, 62%, 66%, and 28%) and mild (59%, 38%, 28%, and 72%) in the alfuzosin, silodosin, tamsulosin, and prazosin groups, respectively ( = 0.004), with improvement in mean change in residual urine volume and complete relief from LUTS symptoms with no surgical or radiological interventions. Overall, 194 adverse events (AEs) were observed in 38.8% of patients. Of the total AEs, patients in the alfuzosin, silodosin, tamsulosin, and prazosin groups experienced 21%, 22%, 39%, and 18% of AEs, respectively.
CONCLUSION
The nonselective alpha-adrenergic receptor antagonist, alfuzosin, emerged as noninferior in effectiveness and superior in tolerability than other selective alpha-blockers, silodosin, tamsulosin, and prazosin.
PubMed: 37304518
DOI: 10.4103/ua.ua_114_21 -
Current Opinion in Psychiatry Jul 2019The aim of this study was to provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past 2 years) human... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past 2 years) human studies that evaluated medications' effects on alcohol-related outcomes.
RECENT FINDINGS
Forty-five publications were found suitable for this review. A variety of compounds have been tested in the past 2 years as potential pharmacological options for AUD, including medications that act on multiple targets (topiramate, aripiprazole, quetiapine), calcium channels (gabapentin), gamma-Aminobutyric acid receptors (baclofen, diazepam), glutamate receptors (ifenprodil, memantine, glycine), nicotinic acetylcholine receptors (varenicline, mecamylamine), α1 adrenergic receptors (prazosin, doxazosin), neuroendocrine pathways (oxytocin, a vasopressin receptor 1b antagonist, a ghrelin receptor inverse agonist) and others (samidorphan, ibudilast, N-acetylcysteine, citoline). Important findings and limitations regarding the effects of these medications on alcohol-related outcomes are discussed.
SUMMARY
There is a critical need to increase the armamentarium of medications for AUD. Human laboratory studies may help screen and prioritize promising targets and compounds before running large clinical trials. Given the complexity of AUD and the heterogeneity of afflicted patients, future studies should also investigate potential moderators and predictors of response to each pharmacological intervention.
Topics: Adrenergic alpha-1 Receptor Antagonists; Alcohol-Related Disorders; Cholinergic Agonists; GABA Modulators; GABA-B Receptor Agonists; Humans; Nicotinic Agonists; Treatment Outcome
PubMed: 31107292
DOI: 10.1097/YCO.0000000000000519 -
International Journal of Molecular... Apr 2022In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal...
In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal growth factor receptor (EGFR) in isolated endothelium-denuded rat aortas. Additionally, we aimed to elucidate the associated underlying cellular mechanisms. The effects of the alpha-2 adrenoceptor inhibitor rauwolscine, EGFR tyrosine kinase inhibitor AG1478, Src kinase inhibitors PP1 and PP2, and matrix metalloproteinase inhibitor GM6001 on EGFR tyrosine phosphorylation and c-Jun NH-terminal kinase (JNK) phosphorylation induced by dexmedetomidine in rat aortic smooth muscles were examined. In addition, the effects of these inhibitors on dexmedetomidine-induced contraction in isolated endothelium-denuded rat aorta were examined. Dexmedetomidine-induced contraction was inhibited by the alpha-1 adrenoceptor inhibitor prazosin, rauwolscine, AG1478, PP1, PP2, and GM6001 alone or by a combined treatment with prazosin and AG1478. AG1478 (3 × 10 M) inhibited dexmedetomidine-induced contraction in isolated endothelium-denuded rat aortas pretreated with rauwolscine. Dexmedetomidine-induced EGFR tyrosine and JNK phosphorylation were inhibited by rauwolscine, PP1, PP2, GM6001, and AG1478. Furthermore, dexmedetomidine-induced JNK phosphorylation reduced upon EGFR siRNA treatment. Therefore, these results suggested that the transactivation of EGFR associated with dexmedetomidine-induced contraction, mediated by the alpha-2 adrenoceptor, Src kinase, and matrix metalloproteinase, caused JNK phosphorylation and increased calcium levels.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Aorta; Dexmedetomidine; ErbB Receptors; Muscle, Smooth, Vascular; Phosphorylation; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Transcriptional Activation; Tyrosine; Yohimbine; src-Family Kinases
PubMed: 35457136
DOI: 10.3390/ijms23084320 -
Frontiers in Pharmacology 2021(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the...
Aqueous Tuber Extracts of (Kotschy ex Schweinf.) Torre and Hillc. (Fabaceae). Possess Significant Antidiarrheal Activity and Spasmolytic Effect Possibly Mediated by Modulation of Nitrous Oxide System, Voltage-Gated Calcium Channels, and Muscarinic Receptors.
(TFG) is used as an antidiarrheal traditional medicine in Western Kenya. This study aimed to investigate the antidiarrheal activity of its aqueous extracts and the putative mechanism (s) of action using Sprague-Dawley rats and New Zealand white rabbits respectively. The antidiarrheal effects of the extract were evaluated in castor oil-induced diarrhea, the castor oil-induced enteropooling, and phenol red gastric motility tests. On the other hand, isolated rabbit's jejunal segments were used to evaluate the spasmolytic effect of TFG on spontaneous contraction, in acetylcholine-induced contraction, in presence of 80mMK, calcium chloride-induced contraction as well as in presence of the following antagonists: naloxone, methylene blue, L-NAME, prazosin, and propranolol in the studies. The data were express as Mean ± S.E.M and analyzed by one-way ANOVA and Tukey's post hoc test in cases of significance which was set at < 0.05. The extract was phytochemically characterized using Liquid chromatography Mass spectroscopy (LC-MS).The extract possessed significant inhibitory effect in the experiments. The extract exhibited significant spasmolytic effect on both spontaneous contraction and in jejunal segment pre-contracted acetylcholine as well as in presence of 80mMK solution. It also attenuated the spasmogenic effect of various concentration of calcium chloride. The extract's spasmolytic effect was, however, significantly attenuated in presence of several antagonists (methylene blue and L-NAME) but the adrenergic blockers (prazosin and propranolol) had no significant effect in the LC-MS identified thirty compounds where Proathocyanidin (11.54%), Syringic acid (7.30%), and 4-Hydroxybenzoic acid (6.19%) had the highest percentage abundance. In conclusion, the results obtained in this study partially validate the traditional uses of the tubers of this plant species as an antidiarrheal. These antidiarrheal effects are probably mediated via modulation of nitrous oxide pathway, voltage gated calcium channels, and muscarinic receptors.
PubMed: 33796023
DOI: 10.3389/fphar.2021.636879