Tolfenamic Acid Research Articles

Repurposing Tolfenamic Acid to Anchor the Uncharacterized Pocket of the PUB Domain for Proteolysis of the Atypical E3 Ligase HOIP.

The E3 ligase HOIP is vital for the NF-κB pathway and is implicated in cancer and immunity. However, it remains challenging to achieve high selectivity by directly targeting the conserved catalytic RBR domain of HOIP. Herein, we identified four low-molecular-weight compounds that bind to an uncharacterized pocket of the HOIP PUB domain (HOIPPUB). The complex structure facilitated the discovery of the first single-digit micromolar ligand of HOIPPUB, tolfenamic acid, which exhibited over 30-fold selectivity due to the low sequence identity of the uncharacterized pocket of HOIPPUB. Although tolfenamic acid did not block the substrate recognition and linear ubiquitination activity of HOIP, a ligand of the uncharacterized PUB pocket of HOIP (LUPH), by chemical linking pomalidomide with tolfenamic acid, degraded HOIP, reduced NEMO ubiquitination and p65 phosphorylation, and eventually inhibited NF-κB activation and breast cancer cell proliferation. Our work proposes an alternative strategy to target the nonfunctional pocket of the PUB domain with high sequence diversity to promote HOIP degradation, rather than targeting the conserved RBR domain to block the catalytic function of HOIP.

Pharmacokinetics of tolfenamic acid in ducks (Anas platyrhynchos domestica) after different administration routes

ABSTRACT 1. The objective of this research was to compare the pharmacokinetics and bioavailability of tolfenamic acid, analgesic, antipyretic and anti-inflammatory compound, after administration through different routes to Pekin ducks. The investigation was carried out over four time periods using a randomised cross-pharmacokinetic design. 2. Tolfenamic acid was administered to ducks intravenously, intramuscularly, subcutaneously and orally at a dose of 2 mg/kg. Tolfenamic acid analysis was performed using HPLC-UV and pharmacokinetic data were conducted by non-compartmental analysis. 3. The total clearance, volume of distribution at steady state and terminal elimination half‐life after intravenous administration were 0.14 l/h/kg, 0.29 l/kg and 1.80 h, respectively. The peak plasma concentration and bioavailability for intramuscular, subcutaneous and oral administration were 4.59, 3.55 and 2.23 μg/ml and 93.62, 74.30 and 43.43%, respectively. 4. Tolfenamic acid was absorbed rapidly, eliminated quickly and exhibited a small distribution volume in Pekin ducks. Pharmacokinetic parameters, including maximum concentration, area under the plasma concentration – time curve and bioavailability, were found to be different in ducks from other bird species.

Determination of some NSAIDs content in meat by liquid chromatography with tandem mass spectrometry (LC-MS/MS)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used group of drugs worldwide for pain relief, anti-inflammation, blood clot prevention, and fever reduction, but they can cause some side effects bad for health if used incorrectly. NSAIDs are on the list of drugs that must be monitored according to Council Directive 96/23/EC. The fact that NSAIDs are also used in animals for anti-inflammation, fever reduction, and pain relief raises concerns that animal products such as meat, eggs, and milk may be contaminated with NSAIDs, affecting human health if consumed like eating right. Therefore, developing a method to analyze NSAIDs in meat products is necessary, contributing to assessing the quality of meat products currently circulating on the market. In this study, 4 common substances in the NSAIDs group were studied and identified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) using a Symmetry C18 chromatographic column with an ESI (+) positive electron spray ionization source and multiple reaction monitoring (MRM) mode. The validity of the method was confirmed according to the guidelines of the Association of Official Analytical Chemists (AOAC). The results showed that the method has good specificity, the linearity range from 5.0 to 100 µg/kg, the detection limit of 1.5 µg/kg, the quantification limit of 5.0 µg/kg; precision and accuracy with relative standard deviation (RSD) less than 11% and recoveries ranging from 81.1 to 111%, meeting AOAC requirements. The method was used to analyze the content of NSAIDs in 15 meat samples in Hanoi. The results showed that 7 samples showed tolfenamic acid exceeding the quantitative limit of the method.

Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss).

Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2mg/kg in rainbow trout at 13±0.5°C. The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2mg/kg. Blood samples were taken at 13 different sampling times until the 72h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. The elimination half-life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09L/kg and 0.03L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.

Excision of prolapsed vaginal fibroma in a Golden Retriever dog

Vaginal fibromas are a type of neoplasm that is commonly found in dogs. This report describes a case involving a 13-year-old female Golden Retriever (intact) that presented with pain during urination and a visible mass protruding from the vagina. On physical examination, the dog was found to be in shock with vaginal pain. An oval-shaped, hard texture, white mass measuring 9.3 cm x 5.5 cm, covered with blood, was observed. Hematological analysis revealed leukocytosis, lymphocytosis, granulopenia, hyperchromic microcytic anemia, and thrombocytopenia. The tumor mass was excised, and the vaginal wall was repositioned and sutured. Premedication included atropine sulfate and xylazine, and anesthesia was administered using ketamine and isoflurane. Postoperative care consisted of tolfenamic acid, vitamin K1, amoxicillin, meloxicam, and Sangobion® supplements. Histopathological examination using hematoxylin-eosin staining revealed fusiform fibroma cells. Seven days post-excision, the sutures were removed, and the vaginal condition returned to normal.

Antiseizure properties of fenamate NSAIDs determined in mature human stem-cell derived neuroglial circuits.

Repeated and uncontrolled seizures in epilepsy result in brain cell loss and neural inflammation. Current anticonvulsants primarily target ion channels and receptors implicated in seizure activity. Identification of neurotherapeutics that can inhibit epileptiform activity and reduce inflammation in the brain may offer significant benefits in the long-term management of epilepsy. Fenamates are unique because they are both non-steroidal anti-inflammatory drugs (NSAIDs) and highly subunit selective modulators of GABAA receptors. In the current study we have investigated the hypothesis that fenamates have antiseizure properties using mature human stem cell-derived neuro-glia cell cultures, maintained in long-term culture, and previously shown to be sensitive to first, second and third generation antiepileptics. Mefenamic acid, flufenamic acid, meclofenamic acid, niflumic acid, and tolfenamic acid (each tested at 10-100μM) attenuated 4-aminopyridine (4-AP, 100μM) evoked epileptiform activity in a dose-dependent fashion. These actions were as effective diazepam (3-30μM) and up to 200 times more potent than phenobarbital (300-1,000μM). The low (micromolar) concentrations of fenamates that inhibited 4-AP evoked epileptiform activity correspond to those reported to potentiate GABAA receptor function. In contrast, the fenamates had no effect on neural spike amplitudes, indicating that their antiseizure actions did not result from inhibition of sodium-channels. The antiseizure actions of fenamates were also not replicated by either of the two non-fenamate NSAIDs, ibuprofen (10-100μM) or indomethacin (10-100μM), indicating that inhibition of cyclooxygenases is not the mechanism through which fenamates have anticonvulsant properties. This study therefore shows for the first time, using functionally mature human stem cell-derived neuroglial circuits, that fenamate NSAIDs have powerful antiseizure actions independent of, and in addition to their well-established anti-inflammatory properties, suggesting these drugs may provide a novel insight and new approach to the treatment of epilepsy in the future.

Equilibrium Solubility and Density Functional Theory Study of Tolfenamic Acid in Several Neat Solvents from 283.15 to 323.15 K

Equilibrium Solubility and Density Functional Theory Study of Tolfenamic Acid in Several Neat Solvents from 283.15 to 323.15 K

HAEMOBARTONELLOSIS IN DOMESTIC SHORT HAIR CATS

Haemobartonellosis is a disease caused by Mycoplasma haemofelis, previously called Haemobartonella felis, causing lethargy, fever, pale mucosa, and anemia of varying severity in cats. M. haemofelis is a small, gram-negative bacterium without cell walls that lives on the edge or surface (epicellular) of erythrocytes. The animal used as a case report is a domestic short-haired cat, ± 9 months old, an unsterilized female with a body weight of 3.3 kg. The results of the clinical examination and praesens status showed that the case cat experienced vomiting, loss of appetite, lethargy, mild ectoparasite infestation, pale mucosa, a CRT of more than two seconds, and increased respiratory frequency and body temperature. Routine hematological examination on the first day showed normochromic normocytic anemia, leukopenia, neutropenia, monocytopenia, and thrombocytopenia. Blood biochemical examination on the first day showed hypophosphatemia, hyponatremia, and hyperglycemia. A blood smear examination shows a round or ring-shaped formation on the edge or surface of the erythrocytes, which is morphologically identified as M. haemofelis. Based on the history, physical examination, and supporting examinations, the case cat was diagnosed as having haemobartonellosis. The case cat was treated for five days, and then on the sixth day, the case cat was sent home and underwent outpatient therapy because it showed an improving condition. Causative therapy for M. haemofelis is given oxytetracycline antibiotics for five days, followed by doxycycline antibiotics for 28 days during outpatient therapy. Frontline Plus® antiparasitic is given once to treat ectoparasites. The symptomatic therapy given is tolfenamic acid, once administered. The supportive therapy given is Lactate Ringer's infusion fluid therapy for 5 days and multivitamin, mineral, and hematopoietic supplements, namely Hematodin® by injection for five days, followed by Caviplex Syrup® for 28 days. Therapy for vulnus morsum is enrofloxacin for 8 days. After 28 days of outpatient therapy, the case cat showed clinical improvement and was actively playing.

Irradiation Behavior of Analgesic and Nonsteroidal Anti-Inflammatory Drug-Loaded UHMWPE for Joint Replacement.

Local delivery of pain medication can be a beneficial strategy to address pain management after joint replacement, as it can decrease systemic opioid usage, leading to less side and long-term effects. In this study, we used ultrahigh molecular weight polyethylene (UHMWPE), commonly employed as a bearing material for joint implants, to deliver a wide set of analgesics and the nonsteroidal anti-inflammatory drug tolfenamic acid. We blended the drugs with UHMWPE and processed the blend by compression molding and sterilization by low-dose gamma irradiation. We studied the chemical stability of the eluted drugs, drug elution, tensile properties, and wear resistance of the polymer blends before and after sterilization. The incorporation of bupivacaine hydrochloride and tolfenamic acid in UHMWPE resulted in either single- or dual-drug loaded materials that can be sterilized by gamma irradiation. These compositions were found to be promising for the development of clinically relevant drug-eluting implants for joint replacement.

Analysis of Tolfenamic Acid using a Simple, Rapid, and Stability-indicating Validated HPLC Method.

Tolfenamic acid (TA) belongs to the fenamates class of nonsteroidal anti-inflammatory drugs. Insufficient information is available regarding the availability of a reliable and validated stability-indicating method for the assay of TA. A relatively simple, rapid, accurate, precise, economical, robust, and stabilityindicating RP-HPLC method has been developed to determine TA in pure and tablet dosage forms. The method was validated according to the ICH guideline, and parameters like linearity, range, selectivity, accuracy, precision, robustness, specificity, and solution stability were determined. TLC and FTIR spectrometry were used to ascertain the purity of TA. The specificity was determined with known impurities and after performing forced degradation, while the robustness was established by Plackett-Burman's experimental design. The mobile phase used for the analysis was acetonitrile and water (90:10, v/v) at pH 2.5. The detection of the active drug was made at 280 nm using a C18 column (tR = 4.3 min.). The method's applicability was also checked for the yellow polymorphic form of TA. The results indicated that the method is highly accurate (99.39-100.80%), precise (<1.5% RSD), robust (<2% RSD), and statistically comparable to the British Pharmacopoeia method with better sensitivity and specificity. It was observed that the stress degradation studies do not affect the method's accuracy and specificity. Hence the proposed method can be used to assay TA and its tablet dosage form.

Design, Synthesis and Evaluation of Antioxidant and NSAID Derivatives with Antioxidant, Anti-Inflammatory and Plasma Lipid Lowering Effects.

Amides containing methyl esters of γ-aminobutyric acid (GABA), L-proline and L-tyrosine, and esters containing 3-(pyridin-3-yl)propan-1-ol were synthesized by conjugation with 3,5-di-tert-butyl-4-hydroxybenzoic, an NSAID (tolfenamic acid), or 3-phenylacrylic (cinnamic, (E)-3-(3,4-dimethoxyphenyl)acrylic and caffeic) acids. The rationale for the conjugation of such moieties was based on the design of structures with two or more molecular characteristics. The novel compounds were tested for their antioxidant, anti-inflammatory and hypolipidemic properties. Several compounds were potent antioxidants, comparable to the well-known antioxidant, Trolox. In addition, the radical scavenging activity of compound 6 reached levels that were slightly better than that of Trolox. All the tested compounds demonstrated remarkable activity in the reduction in carrageenan-induced rat paw edema, up to 59% (compound 2, a dual antioxidant and anti-inflammatory molecule, with almost 2.5-times higher activity in this experiment than the parent NSAID). Additionally, the compounds caused a significant decrease in the plasma lipidemic indices in Triton-induced hyperlipidemic rats. Compound 2 decreased total cholesterol by 75.1% and compound 3 decreased triglycerides by 79.3% at 150 μmol/kg (i.p.). The hypocholesterolemic effect of the compounds was comparable to that of simvastatin, a well-known hypocholesterolemic drug. Additionally, all compounds lowered blood triglycerides. The synthesized compounds with multiple activities, as designed, may be useful as potential candidates for conditions involving inflammation, lipidemic deregulation and oxygen toxicity.

ENUCLEATION OF BULBUS OCULI PROLAPSUS IN TERRIER MIX

An 8-year-old female Chihuahua mix terrier breed with a body weight of 3.3 kg was brought to the Teaching Animal Hospital, Faculty of Veterinary Medicine, Udayana University. The dog was brought in with a complaint of the right eye coming out of the eye socket after fighting with a large breed dog. The purpose of this article is to find out the process of lifting the eyeball using the trans-conjunctival enucleation method. The results of the physical examination showed damage and no response to the case dog's right eye. Based on history and physical examination, the dog was diagnosed with bulbus oculi prolapse. Premedication was carried out by administering 0.3 ml of atropine sulfate and induced anesthesia with 0.2 ml and 0.3 ml of xylazine and ketamine respectively. The postoperative care given was e-collar fitting, giving cefadroxil monohydrate 22mg/kgBB q12h for 5 days, giving anti-inflammatory tolfenamic acid injection 0.3 mg/kgBW and continued with giving meloxicam 1 mg/kgBBq12h for 5 days, and ointment. Bioplacenton® skin is given sufficiently until the wound dries. On the seventh day after surgery, the case dog was declared cured with the surgical wound closed on the right eye after routine postoperative care.

Docking and molecular dynamic simulations of Mithramycin-A and Tolfenamic acid against Sp1 and survivin

Therapeutic targeting of Sp1 transcription factor and survivin, are studied in various cancers due to their consistent overexpression. These markers result in poorer cancer prognoses and their downregulation has been investigated as an effective treatment approach. Mithramycin-A and Tolfenamic acid are two drugs with innate anti-cancer properties and are suggested to be able to target Sp1 through GC/GT DNA binding interference, however in-depth binding and mechanistic studies are lacking. Through docking analysis, we investigated Mithramycin-A and Tolfenamic acid in terms of their specific binding interactions with Sp1 and survivin. Through further molecular dynamics simulations including Root Mean Square (RMS) Fluctuation and RMS Deviation, rGYr, and H-bond analysis, we identified critical residues involved in drug interactions with each protein in question. We show Mithramycin-A as the superior binding candidate to each protein and found that it exhibited stronger binding with Sp1, and then survivin. Subsequent molecular dynamics simulations followed the same trend as initial binding energy calculations and showed crucial amino acids involved in each Mithramycin-A-protein complex. Our findings warrant further investigation into Mithramycin-A and its specific interaction with Sp1 and their downstream targets giving a better understanding of Mithramycin-A and its potential as an effective cancer treatment.

TREATMENT OF BULBUS OCULI DEXTRA PROLAPSE IN MIX POM DOGS

Prolapse of the bulbus oculi is a condition where the eyeball protrudes from the eye socket, which occurs due to impact, blunt trauma, fights or tumors. A Mix Pom purebred dog, named Koko, male, 7 years old, 5.21 kg body weight and brown hair color, complained of the right eyeball protruding from the eye socket since two days. The purpose of writing this case report is to describe the process of lifting the eyeball by cutting the tissue and the nerves inside it using the enucleation technique. From physical examination and clinical signs, the case dog was diagnosed with prolapse of the dextra bulbus oculi with a fausta prognosis. Case dogs were treated with bulbus oculi enucleation surgery, which is a surgical procedure by lifting the eyeball from the eye socket. The surgery was performed under a combination of xylazine and ketamine general anesthesia. Postoperative case dogs were given cefotaxime antibiotics at a dose of 20 mg/kg body weight for two days and followed by oral antibiotic cefixime trihydrate at a dose of 10 mg/kg body weight for five days. Anti-inflammatory in the form of tolfenamic acid with a dose of 4 mg/kg body weight intramuscularly for two days and followed by oral anti-inflammatory dexamethasone tablets 0.25 mg/kg body weight (2 x daily) for five days. The results of the operation showed wound healing on the 10th day, which was indicated by the stitches that had dried and merged, and the dog was active again. Advice that can be given is that a dog suffering from bulbus oculi prolapse must be immediately acted upon, so as not to worsen the dog's condition and to prevent various complications, one of which is miasis.

Photolysis of tolfenamic acid in aqueous and organic solvents: a kinetic study.

Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug that was studied for its photodegradation in aqueous (pH 2.0-12.0) and organic solvents (acetonitrile, methanol, ethanol, 1-propanol, 1-butanol). TA follows first-order kinetics for its photodegradation, and the apparent first-order rate constants (k obs) are in the range of 0.65 (pH 12.0) to 6.94 × 10-2 (pH 3.0) min-1 in aqueous solution and 3.28 (1-butanol) to 7.69 × 10-4 (acetonitrile) min-1 in organic solvents. The rate-pH profile for TA photodegradation is an inverted V (∧) or V-top shape, indicating that the cationic form is more susceptible to acid hydrolysis than the anionic form of TA, which is less susceptible to alkaline hydrolysis. The fluorescence behavior of TA also exhibits a V-top-shaped curve, indicating maximum fluorescence intensity at pH 3.0. TA is highly stable at a pH range of 5.0-7.0, making it suitable for formulation development. In organic solvents, the photodegradation rate of TA increases with the solvent's dielectric constant and solvent acceptor number, indicating solute-solvent interactions. The values of k obs decreased with increased viscosity of the solvents due to diffusion-controlled processes. The correlation between k obs versus ionization potential and solvent density has also been established. A total of 17 photoproducts have been identified through LC-MS, of which nine have been reported for the first time. It has been confirmed through electron spin resonance (ESR) spectrometry that the excited singlet state of TA is converted into an excited triplet state through intersystem crossing, which results in an increased rate of photodegradation in acetonitrile.

Coordination compounds of cobalt(II) with carboxylate non-steroidal anti-inflammatory drugs: structure and biological profile.

Fourteen cobalt(II) complexes with the non-steroidal anti-inflammatory drugs sodium meclofenamate, tolfenamic acid, mefenamic acid, naproxen, sodium diclofenac, and diflunisal were prepared in the presence or absence of a series of nitrogen-donors (namely imidazole, pyridine, 3-aminopyridine, neocuproine, 2,2'-bipyridine, 1,10-phenanthroline and 2,2'-bipyridylamine) as co-ligands and were characterised by spectroscopic and physicochemical techniques. Single-crystal X-ray crystallography was employed to determine the crystal structure of eight complexes. The biological profile of the complexes was investigated regarding their interaction with serum albumins and DNA, and their antioxidant potency. The interaction of the compounds with calf-thymus DNA takes place via intercalation. The ability of the complexes to cleave pBR322 plasmid DNA at the concentration of 500 μM is rather low. The complexes demonstrated tight and reversible binding to human and bovine serum albumins and the binding site of bovine serum albumin was also examined. In order to assess the antioxidant activity of the compounds, the in vitro scavenging activity towards free radicals, namely 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), and their ability to reduce H2O2 were studied.

Influence of the crystallisation solution environment on the structural pathway from solute solvation to the polymorphic forms of tolfenamic acid

Multi-scale (molecular, cluster, crystallographic) modelling together with solvent-dependent polymorphic screening examines the influence of solution environment on TFA crystallisation.

Free Radical Scavenging and Antioxidant effects of Tolfenamic Acid in L-NAME-Induced Hypertensive Rats

Objectives: The aim of this study was to determine the antioxidant and free radical scavenging properties of tolfenamic acid (TA) against N-Nitro-L-arginine methyl ester hydrochloride (L-NAME) induced hypertension.&#x0D; Materials and Methods: The rats were divided into five groups at random: Group I (control rats), Group II (control TA), Group III (L-NAME), Group IV (L-NAME+TA), and Group V (L-NAME+Enalapril). For four weeks, rats were given L-NAME (40mg/kg body weight) dissolved in drinking water to induce hypertension. Intraperitoneal injections of TA (50mg/kg body weight) and enalapril (0.7 mg/kg body weight) were given to rats.&#x0D; Results: The results showed that the In vitro free radical scavenging effect of TA on DPPH and ABTS was concentration dependent. In vivo studies with L-NAME resulted in increases in blood pressure, lipid hydroperoxides (LOOH), and thiobarbituric acid reactive substances (TBARS). In addition, the level of the non-enzymatic antioxidant reduced glutathione (GSH) and other enzyme antioxidant activities in the heart and aorta, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx), are reduced. The level of nitric oxide metabolism in the erythrocyte aorta of L-NAME rats was increased.&#x0D; Conclusions: These findings imply that tolfenamic acid acts as an antihypertensive and antioxidant agent in L-NAME-induced hypertension.

Tolfenamic acid negatively regulates YAP and TAZ expression in human cancer cells.

Several diseases are associated with improper regulation of the Hippo pathway, which plays an important role in cell proliferation and cancer metastasis. Overactivation of the YAP and TAZ proteins accelerates cell proliferation, invasion, and migration during tumorigenesis. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits activity against various types of cancer. In this study, we observed that TA decreased YAP and TAZ protein levels in cancer cells. TA increased the phosphorylation of YAP and TAZ, leading to the degradation of YAP and TAZ in the cytoplasm and nucleus. TA predominantly affected multiple phosphodegron sites in the YAP and TAZ and lowered 14-3-3β protein expression, causing YAP and TAZ to enter the ubiquitination pathway. Proteins that affect YAP and TAZ regulation, such as NAG-1 and several YAP/TAZ E3 ligases, were not involved in TA-mediated YAP/TAZ degradation. In summary, our results indicate that TA affects phosphodegron sites on YAP/TAZ, demonstrating a novel effect of TA in tumorigenesis.

Exploring the Potential of Fenamate NSAID Analogs for the Treatment of Alzheimer’s Disease

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia, and its prevalence continues to increase with absence of available interventions. Drug repurposing accelerates the drug discovery process as therapeutics with known safety and toxicology profiles are considered. Although the blood‐brain barrier (BBB) prevents uptake of most pharmaceuticals, our laboratory previously showed that tolfenamic acid (TA), a fenamate non‐steroidal anti‐inflammatory drug (NSAID) with known anti‐cancer effects, can cross the BBB and slow the progression of AD (Zawia et al, 2018).MethodIn the present study, we test 2‐(2‐Cyanophenylthio) benzoic acid (CBA) and Niflumic acid (NA), small molecule analogs of TA that showed better safety and efficacy at targeting neurodegenerative pathways in vitro, and a similar mechanism of action to TA. We aimed to examine the effects of the analogs on in mice using proteomic and transcriptomic analyses.Single dose study of TA, CBA, and NA was carried out in C57BL/6 mice following oral administration at 100 mg/kg. Differential expression of genes and proteomic biomarkers in mice cortices were analyzed between each treatment group and a corresponding control group.ResultsAnalysis of the number of perturbed genes revealed that the drugs demonstrate limited off‐target effects. Bioinformatic analyses revealed that the therapeutics targeted cancer and neurodegenerative pathways including autophagy, inflammation, and neuronal trafficking. CBA and NA shared common downstream targets and pathways suggesting that they may have a similar mode of action.ConclusionWe found a set of differentially expressed genes that have been linked to processes involved in AD pathogenesis such as the production and clearance of neurotoxic Aβ peptides, tau phosphorylation, regulation of oxidative stress, and inflammatory processes. These results suggest that the drugs may influence pathways related to the pathogenesis of AD and support the potential of drug repurposing of fenamate NSAIDs such as TA, and its analogs CBA and NA, as a strategy for cancer and neurodegenerative disease therapy. Further research is needed to confirm the effect of the analogs on AD biomarkers and their efficacy as therapeutics for AD.