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Journal of Biochemical and Molecular... Mar 2024Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on... (Review)
Review
Phenothiazines (PTZs) are an emerging group of molecules showing effectiveness toward redox signaling and reduction of oxidative injury to cells, via the activation on Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Nrf2). Although several electrophilic and indirect Nrf2 activators have been reported, the risk of "off-target" effect due to the complexity of their molecular mechanisms of action, has aroused research interest toward non-electrophilic and direct modulators of Nrf2 pathway, such as PTZs. This review represents the first overview on the roles of PTZs as non-electrophilic Nrf2 activator and free radical scavengers, as well as on their potential therapeutic effects in oxidative stress-mediated diseases. Here, we provide a collective and comprehensive information on the PTZs ability to scavenge free radicals and activate the Nrf2 signaling pathway, with the aim to broaden the knowledge of their therapeutic potentials and to stimulate innovative research ideas.
Topics: Antioxidants; Free Radical Scavengers; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Phenothiazines
PubMed: 38369721
DOI: 10.1002/jbt.23661 -
Toxicology Jun 2023The current review focuses on the effect of phenothiazine derivatives, tested in vitro, on necrosis and necroptosis, the latter constitutes one of the kinds of... (Review)
Review
The current review focuses on the effect of phenothiazine derivatives, tested in vitro, on necrosis and necroptosis, the latter constitutes one of the kinds of programmed cell death. Necroptosis is a necrotic and inflammatory type of programmed cell death. Phenothiazines are D1 and D2-like family receptor antagonists, which are used in the treatment of schizophrenia. Necroptosis begins from TNF-α, whose synthesis is stimulated by dopamine receptors, thus it can be concluded that phenothiazine derivatives may modulate necroptosis. We identified 19 papers reporting in vitro assays of necroptosis and necrosis in which phenothiazine derivatives, and both normal and cancer cell lines were used. Chlorpromazine, fluphenazine, levomepromazine, perphenazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate necroptosis and necrosis. The type of a drug, concentration and a cell line have an impact on the ultimate effect. Unfortunately, the authors confirmed both processes on the basis of TNF-α and ATP levels as well as the final steps of necrosis/necroptosis related to membrane permeability (PI staining, LDH release, and HMGB1 amount), which makes it impossible to understand the complete mechanism of phenothiazines impact on necroptosis and necrosis. Studies analyzing the effect of phenothiazines on RIPK1, RIPK3, or MLKL has not been performed yet. Only the analysis of the expression of those proteins as well as necrosis and necroptosis inhibitors can help us to comprehend how phenothiazine derivatives act, and how to improve their therapeutic potential.
Topics: Humans; Tumor Necrosis Factor-alpha; Necroptosis; Phenothiazines; Antipsychotic Agents; Necrosis
PubMed: 37127180
DOI: 10.1016/j.tox.2023.153528 -
Anticancer Research Nov 2017Phenothiazines have been used in many areas of medicine, mainly in psychopharmacology. These compounds are able to effectively inhibit dopamine, histamine, serotonin,... (Review)
Review
Phenothiazines have been used in many areas of medicine, mainly in psychopharmacology. These compounds are able to effectively inhibit dopamine, histamine, serotonin, acetylcholine, and α-adrenergic receptors; thus, their effect and side-effect profiles are extremely diverse. Besides their antipsychotic activity, phenothiazines have a significant antimicrobial effect as well, since they can enhance the bactericidal function of macrophages and inhibit efflux pumps. They are also able to eliminate bacterial resistance plasmids and destroy bacteria by their membrane-destabilizing effect. Their antiviral, antiprotozoal, antifungal, and antiprion activities have also been described. Phenothiazines have also been proven to destroy cancer cells and sensitize them to chemotherapy. Anti-angiogenesis and anticancer stem cell activities have also been reported, and they might be applied as adjuvants in the treatment of infections and tumors in the future. Finally, phenothiazines can also be effective in the treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Antipsychotic Agents; Humans; Infections; Mental Disorders; Neoplasms; Phenothiazines
PubMed: 29061777
DOI: 10.21873/anticanres.12045 -
Experimental Neurology Nov 2023Neuroprotective effects have been the main focus of new treatment modalities for ischemic stroke. Phenothiazines, or chlorpromazine plus promethazine (C + P), are...
BACKGROUND
Neuroprotective effects have been the main focus of new treatment modalities for ischemic stroke. Phenothiazines, or chlorpromazine plus promethazine (C + P), are known to prevent the generation of free radicals and uptake of Ca by plasma membrane; they have a potential as a treatment for acute ischemic stroke (AIS). This study aims to investigate the role of endoplasmic reticulum (ER) stress-associated PERK-eIF2α pathway underlying the phenothiazine-induced neuroprotective effects after cerebral ischemia/reperfusion (I/R) injury.
METHODS
A total of 49 male Sprague Dawley rats (280-320 g) were randomly divided into 4 groups (n = 7 per group): (1) sham, (2) I/R that received 2 h of middle cerebral artery occlusion (MCAO), followed by 6 or 24 h of reperfusion, (3) MCAO treated by C + P without temperature control and (4) MCAO treated by C + P with temperature control. Human neuroblastoma (SH-SY5Y) cells were used in 5 groups: (1) control, (2) oxygen-glucose deprivation (OGD) for 2 h followed by reoxygenation (OGD/R), (3) OGD/R with C + P; (4) OGD/R with PERK inhibitor, GSK2656157, and (5) OGD/R with C + P and GSK2656157. The molecules of ER stress, unfolded protein response (UPR) (Bip, PERK, p-PERK, p-PERK/PERK, eIF2α, p-eIF2α, p-eIF2α/eIF2α), autophagy (ATG12, LC3II/I), and apoptosis (BAX, Bcl-XL) were measured at mRNA levels by real time PCR and protein levels by Western blotting.
RESULTS
In ischemic rats followed by reperfusion, expression of Bip, p-PERK/PERK, p-eIF2α/eIF2α, ATG12, and LC3II/I, as well as BAX were all significantly increased. These markers were significantly reduced by C + P at both 6 and 24 h of reperfusion. Anti-apoptotic Bcl-XL expression was increased, while pro-apoptotic BAX expression was decreased by C + P. In SH-SY5Y cell lines, both C + P and GSK2656157 significantly reduced the level of autophagy and apoptosis after I/R, respectively. The combination of GSK2656157 and C + P did not promote the same effect, suggesting that C + P did not induce any neuroprotective effect by inhibiting autophagy and apoptosis through the PERK-eIF2α pathway when this pathway was already blocked by GSK2656157. In general, the reduction in body temperature by phenothiazines was associated with better neuroprotection but it did not reach significant levels.
CONCLUSION
The combined treatment of C + P plays a crucial role in stroke therapy by inhibiting ER stress-mediated autophagy, thereby leading to reduced apoptosis and increased neuroprotection. Our findings highlight the PERK-eIF2α pathway as a central mechanism through which C + P exerts its beneficial effects. The results from this study may pave the way for the development of more targeted and effective treatments for stroke patients.
Topics: Animals; Humans; Male; Rats; Apoptosis; Autophagy; bcl-2-Associated X Protein; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Infarction, Middle Cerebral Artery; Ischemic Stroke; Neuroblastoma; Neuroprotective Agents; Phenothiazines; Rats, Sprague-Dawley; Reperfusion Injury
PubMed: 37673390
DOI: 10.1016/j.expneurol.2023.114524 -
Methods in Molecular Biology (Clifton,... 2023The ommochrome and porphyrin body pigments that give freshwater planarians their brown color are produced by specialized dendritic cells located just beneath the...
The ommochrome and porphyrin body pigments that give freshwater planarians their brown color are produced by specialized dendritic cells located just beneath the epidermis. During embryonic development and regeneration, differentiation of new pigment cells gradually darkens newly formed tissue. Conversely, prolonged light exposure ablates pigment cells through a porphyrin-based mechanism similar to the one that causes light sensitivity in rare human disorders called porphyrias. Here, we describe a novel program using image-processing algorithms to quantify relative pigment levels in live animals and apply this program to analyze changes in bodily pigmentation induced by light exposure. This tool will facilitate further characterization of genetic pathways that affect pigment cell differentiation, ommochrome and porphyrin biosynthesis, and porphyrin-based photosensitivity.
Topics: Animals; Humans; Planarians; Pigmentation; Phenothiazines; Porphyrins
PubMed: 37428383
DOI: 10.1007/978-1-0716-3275-8_16 -
FEMS Microbiology Reviews Nov 2019Antibiotic resistance is a global health concern; the rise of drug-resistant bacterial infections is compromising the medical advances that resulted from the... (Review)
Review
Antibiotic resistance is a global health concern; the rise of drug-resistant bacterial infections is compromising the medical advances that resulted from the introduction of antibiotics at the beginning of the 20th century. Considering that the presence of mutations within individuals in a bacterial population may allow a subsection to survive and propagate in response to selective pressure, as long as antibiotics are used in the treatment of bacterial infections, development of resistance is an inevitable evolutionary outcome. This, combined with the lack of novel antibiotics being released to the clinical market, means the need to develop alternative strategies to treat these resistant infections is critical. We discuss how the use of antibiotic adjuvants can minimise the appearance and impact of resistance. To this effect, several phenothiazine-derived drugs have been shown to potentiate the activities of antibiotics used to treat infections caused by Gram-positive and Gram-negative bacteria. Outside of their role as antipsychotic medications, we review the evidence to suggest that phenothiazines possess inherent antibacterial and efflux inhibitory properties enabling them to potentially combat drug resistance. We also discuss that understanding their mode of action is essential to facilitate the design of new phenothiazine derivatives or novel agents for use as antibiotic adjuvants.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Biological Transport; Drug Resistance, Multiple, Bacterial; Humans; Phenothiazines
PubMed: 31216574
DOI: 10.1093/femsre/fuz017 -
The Cochrane Database of Systematic... Oct 2018Schizophrenia is a severe mental disorder with a prevalence of about 1% among the general population. It is listed among the top 10 causes of disability-adjusted life... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Schizophrenia is a severe mental disorder with a prevalence of about 1% among the general population. It is listed among the top 10 causes of disability-adjusted life years (DALYs) worldwide. Antipsychotics are the mainstay treatment. Piperacetazine has been reported to be as clinically effective as chlorpromazine, a well established 'benchmark' antipsychotic, for people with schizophrenia. However, the side effect profiles of these antipsychotics differ and it is important that an evidence base is available comparing the benefits, and potential harms of these two antipsychotics.
OBJECTIVES
To assess the clinical and side effects of chlorpromazine for people with schizophrenia and schizophrenia-like psychoses in comparison with piperacetazine.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Trials Register (6 June 2015 and 8 October 2018) which is based on regular searches of CINAHL, CENTRAL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO and registries of clinical trials. There are no language, date, document type, or publication status limitations for inclusion of records in the register.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) focusing on chlorpromazine versus piperacetazine for people with schizophrenia, reporting useable data.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.
MAIN RESULTS
We found 12 records referring to six trials. We included five trials, all from the 1970s, randomising 343 participants. We excluded one trial. The overall methodology and data reporting by the trials was poor. Only short-term data were available.Results from the included trials found that, in terms of global state improvement, when rated by a psychiatrist, there was no clear difference between chlorpromazine and piperacetazine (RR 0.90, 95% CI 0.80 to 1.02; participants = 208; studies = 2; very low-quality evidence). One trial reported change scores on the mental state scale Brief Psychiatric Rating Scale (BPRS); no clear difference was observed (MD -0.40, 95% CI -1.41 to 0.61; participants = 182; studies = 1; very low-quality evidence). Chlorpromazine appears no worse or better than piperacetazine regarding adverse effects. In both treatment groups, around 60% of participants experienced some sort of adverse effect (RR 1.00, 95% CI 0.75 to 1.33; participants = 74; studies = 3; very low-quality evidence), with approximately 40% of these participants experiencing some parkinsonism-type movement disorder (RR 0.95, CI 0.61 to 1.49; participants = 106; studies = 3; very low-quality evidence). No clear difference in numbers of participants leaving the study early for any reason was observed (RR 0.50, 95% CI 0.10 to 2.56; participants = 256; studies = 4; very low-quality evidence). No trial reported data for change in negative symptoms or economic costs.
AUTHORS' CONCLUSIONS
The results of this review show chlorpromazine and piperacetazine may have similar clinical efficacy, but data are based on very small numbers of participants and the evidence is very low quality. We can not make firm conclusions based on such data. Currently, should clinicians and people with schizophrenia need to choose between chlorpromazine and piperacetazine they should be aware there is no good quality evidence to base decisions. More high quality research is needed.
Topics: Adult; Antipsychotic Agents; Chlorpromazine; Female; Humans; Male; Phenothiazines; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome
PubMed: 30378678
DOI: 10.1002/14651858.CD011709.pub2 -
Contact Dermatitis Jul 2020In Europe, contact photosensitivity to phenothiazines is well-known, particularly in southern countries. Topical phenothiazines are widely used and sold over-the-counter...
BACKGROUND
In Europe, contact photosensitivity to phenothiazines is well-known, particularly in southern countries. Topical phenothiazines are widely used and sold over-the-counter (OTC) for the treatment of mosquito bites and pruritus in France.
OBJECTIVE
To report a series of cases with photodermatitis following use of topical phenothiazines.
METHOD
A retrospective study of cases of contact dermatitis from phenothiazines seen in French photodermatology centers was performed.
RESULTS
In all, 14 patients with a diagnosis of contact dermatitis from phenothiazines were included. These patients developed eczema on the application sites, and in 13 the eruption spread to photodistributed sites. Topical products containing isothipendyl were the most common cause of photodermatitis. One patient had photoaggravated eczema due to promethazine cream. All patients stopped using topical phenothiazines and were treated successfully with topical corticosteroids. One patient relapsed and developed persistent light eruption. In all of the nine cases tested, photopatch testing to the topical phenothiazine used "as is" was positive. Isothipendyl, chlorproethazine, and the excipients were not tested. Photopatch tests to chlorpromazine and promethazine were positive in 8 of 12 and 7 of 13 tested, respectively.
CONCLUSION
Use of isothipendyl and promethazine as OTC (or even prescribed) drugs needs to be limited due to severe reactions and sensitization to other phenothiazines that consequently will have to be avoided.
Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Chlorpromazine; Dermatitis, Photoallergic; Female; Histamine Antagonists; Humans; Male; Middle Aged; Phenothiazines; Promethazine; Thiazines
PubMed: 32124458
DOI: 10.1111/cod.13509 -
Bioorganic & Medicinal Chemistry Oct 2015The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP,...
The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Dibenzazepines; Heterocyclic Compounds, 3-Ring; Humans; Mice; Neoplasms; Phenothiazines; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Transplantation, Heterologous; Vesicular Monoamine Transport Proteins
PubMed: 26372073
DOI: 10.1016/j.bmc.2015.07.007 -
Chemistry (Weinheim An Der Bergstrasse,... Sep 2020Cyclic RGD peptides are well-known ligands of integrins. The integrins α β and α β are involved in angiogenesis, and integrin α β is abundantly present on cancer...
Cyclic RGD peptides are well-known ligands of integrins. The integrins α β and α β are involved in angiogenesis, and integrin α β is abundantly present on cancer cells, thus representing a therapeutic target. Hence, synthetic and biophysical studies continuously are being directed towards the understanding of ligand-integrin interaction. In this context, the development of versatile synthetic strategies to obtain fluorescent building blocks that can add molecular diversity and modular spectral characteristics while not compromising binding affinity or selectivity is a relevant task. An on-resin intramolecular Suzuki-Miyaura cross-coupling (SMC) between l- or d-7-bromotryptophan (7BrTrp) and a phenothiazine (Ptz) boronic acid affords fluorescent cyclic RGD pseudopeptides, c(RGD(W/w)Ptz). Ring closure by SMC establishes a phenothiazine-indole moiety with axial chirality. An array of eight novel compounds has been synthesized, among them one fluorescent compound with good affinity to integrin α β . The fluorescence properties of the analogues can be efficiently tuned depending on the substituents in Ptz moiety even for fluorescence emission in the visible (red) spectral range.
Topics: Fluorescence; Integrin alphaVbeta3; Ligands; Oligopeptides; Phenothiazines
PubMed: 32297686
DOI: 10.1002/chem.202001312