Design, Synthesis, In vitro and In vivo Evaluation of New Imidazo[1,2-a]pyridine Derivatives as Cyclooxygenase-2 Inhibitors.

BACKGROUND: Cyclooxygenase-2 (COX-2), the key enzyme in the arachidonic acid conversion to prostaglandins, is one of the enzymes associated with different pathophysiological conditions, such as inflammation, cancers, Alzheimer's, and Parkinson's disease. Therefore, COX-2 inhibitors have emerged as potential therapeutic agents in these diseases. OBJECTIVE: The objective of this study was to design and synthesize novel imidazo[1,2-a]pyridine derivatives utilizing rational design methods with the specific aim of developing new potent COX-2 inhibitors. Additionally, we sought to investigate the biological activities of these compounds, focusing on their COX-2 inhibitory effects, analgesic activity, and antiplatelet potential. We aimed to contribute to the development of selective COX-2 inhibitors with enhanced therapeutic benefits. METHODS: Docking investigations were carried out using AutoDock Vina software to analyze the interaction of designed compounds. A total of 15 synthesized derivatives were obtained through a series of five reaction steps. The COX-2 inhibitory activities were assessed using the fluorescent Cayman kit, while analgesic effects were determined through writing tests, and Born's method was employed to evaluate antiplatelet activities. RESULTS: The findings indicated that the majority of the tested compounds exhibited significant and specific inhibitory effects on COX-2, with a selectivity index ranging from 51.3 to 897.1 and IC50 values of 0.13 to 0.05 µM. Among the studied compounds, derivatives 5e, 5f, and 5j demonstrated the highest potency with IC50 value of 0.05 µM, while compound 5i exhibited the highest selectivity with a selectivity index of 897.19. In vivo analgesic activity of the most potent COX-2 inhibitors revealed that 3-(4-chlorophenoxy)-2-[4-(methylsulfonyl) phenyl] imidazo[1,2-a]pyridine (5j) possessed the most notable analgesic activity with ED50 value of 12.38 mg/kg. Moreover, evaluating the antiplatelet activity showed compound 5a as the most potent for inhibiting arachidonic acidinduced platelet aggregation. In molecular modeling studies, methylsulfonyl pharmacophore was found to be inserted in the secondary pocket of the COX-2 active site, where it formed hydrogen bonds with Arg-513 and His-90. CONCLUSION: The majority of the compounds examined demonstrated selectivity and potency as inhibitors of COX-2. Furthermore, the analgesic effects observed of potent compounds can be attributed to the inhibition of the cyclooxygenase enzyme.

Alpha-glucosidase inhibitory and hypoglycemic effects of imidazole-bearing thioquinoline derivatives with different substituents: In silico, in vitro, and in vivo evaluations.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by high blood sugar levels. It was shown that modulating the activity of α-glucosidase, an enzyme involved in carbohydrate digestion and absorption, can improve blood sugar control and overall metabolic health in individuals with T2DM. As a result, in the current study, a series of imidazole bearing different substituted thioquinolines were designed and synthesized as α-glucosidase inhibitors. All derivatives exhibited significantly better potency (IC50 = 12.1 ± 0.2 to 102.1 ± 4.9 µM) compared to the standard drug acarbose (IC50 = 750.0 ± 5.0 µM). 8g as the most potent analog, indicating a competitive inhibition with Ki = 9.66 µM. Also, the most potent derivative was subjected to molecular docking and molecular dynamic simulation against α-glucosidase to determine its mode of action in the enzyme and study the complex's behavior over time. In vivo studies showed that 8g did not cause acute toxicity at 2000 mg/kg doses. Additionally, in a diabetic rat model, treatment with 8g significantly reduced fasting blood glucose levels and decreased blood glucose levels following sucrose loading compared to acarbose, a standard drug used for blood sugar control. The findings suggest that the synthesized compound 8g holds promise as an α-glucosidase inhibitor for improving blood sugar control and metabolic health.

Protective effect of a standardized Allium jesdianum extract in an Alzheimer's disease induced rat model.

Alzheimer's disease (AD) is a complex disorder with multiple underlying mechanisms. Existing treatment options mostly address symptom management and are associated with numerous side effects. Therefore, exploring alternative therapeutic agents derived from medicinal plants, which contain various bioactive compounds with diverse pharmacological effects, holds promise for AD treatment. This study aims to assess the protective effects of the hydroalcoholic extract of Allium jesdianum on cognitive dysfunction, mitochondrial and cellular parameters, as well as genetic parameters in an intracerebroventricular Streptozotocin (icv-STZ) induced rat model of AD. Male Wistar rats were injected with a single dose of STZ (3 mg/kg, icv) to establish a sporadic AD model. A. jesdianum extract (100, 200, and 400 mg/kg/day) and donepezil (5 mg/kg/day) were orally administered for 14 days following model induction. Cognitive function was evaluated using the radial arm water maze test. Mitochondrial toxicity parameters in various brain regions (whole brain, frontal cortex, hippocampus, and cerebellum) were assessed. Gene expression analysis of miR-330, miR-132, Bax, and Bcl-2 in isolated rat brain neurons was performed using RT-qPCR. A. jesdianum extract significantly attenuated cognitive dysfunction and mitigated mitochondrial toxicity induced by icv-STZ administration. Following STZ injection, there was upregulation of Bax gene expression and downregulation of miR-330, miR-132, and Bcl-2 gene expression. Treatment with A. jesdianum extract resulted in the reversal of the expression of these microRNAs and genes, indicating its potential for improving AD and reducing neuronal apoptosis. This study demonstrates the neuroprotective capabilities of A. jesdianum against STZ-induced oxidative stress and cognitive impairment in rats, highlighting its therapeutic potential in the management of AD.

Synthesis and Radiolabeling of Glu-Urea-Lys with 99mTc-Tricarbonyl-Imidazole-Bathophenanthroline Disulfonate Chelation System and Biological Evaluation as Prostate-Specific Membrane Antigen Inhibitor.

Background: The Glu-Urea-Lys (EUK) pharmacophore as prostate-specific membrane antigen (PSMA)-targeted ligand was synthesized, radiolabeled with 99mTc-tricarbonyl-imidazole-BPS chelation system, and biological activities were evaluated. The strategy [2 + 1] ligand is applied for tricarbonyl labeling. (5-imidazole-1-yl)pentanoic acid as a monodentate ligand and bathophenanthroline disulfonate (BPS) as a bidentate ligand formed a chelate system with 99mTc-tricarbonyl. EUK-pentanoic acid-imidazole and EUK were evaluated for PSMA active site using AutoDock 4 software. Materials and Methods: EUK-pentanoic acid-imidazole was synthesized in two steps. BPS was radiolabeled with 99mTc-tricarbonyl at 100°C for 30 min. The purified 99mTc(CO)3(H2O)BPS was used to radiolabel EUK-pentanoic acid-imidazole at 100°C, 30 min. Radiochemical purity, Log P, and stability studies were carried out within 24 h. Affinity of 99mTc(CO)3BPS-imidazole-EUK was performed in the saturation binding studies using LNCaP cells at 37°C for 1 h with a range of 0.001-1000 nM radiolabeled compound range. Internalization studies were performed in LNCaP cells with 1000 nM radiolabeled compound incubated for (0-2) h at 37°C. Biodistribution was studied in normal male Balb/c mice. The artificial intelligence predicts the uptake of radiolabeled compound in tumor. Results: The structures of synthesized compounds were confirmed by mass spectroscopy. Radiochemical purity, Log P, and protein binding were ≥95%, -0.2%, and 23%, respectively. The radiolabeled compound was stable in saline and human plasma within 24 h with radiochemical purity ≥90%. There was no release of 99mTc within 4 h in competition with histidine. The affinity was 82 ± 26.38 nM, and the activity increased inside the cells over time. Biodistribution studies showed radioactivity accumulation in kidneys less than 99mTc-HYNIC-PSMA. There was a moderate accumulation of radioactivity in the liver and intestine. Conclusion: Based on the results, 99mTc(CO)3BPS-imidazole-EUK can potentially be used as an imaging agent for studies at prostate bed and distal areas. The chelate system can be potentially labeled with rhenium for imaging studies (fluorescent or scintigraphy) and therapy.

Microfluidic Synthesis of Ultrasmall Chitosan/Graphene Quantum Dots Particles for Intranasal Delivery in Alzheimer's Disease Treatment.

Nanoparticles (NPs) based therapies for Alzheimer's disease (AD) attract interest due to their ability to pass across or bypass the blood-brain barrier. Chitosan (CS) NPs or graphene quantum dots (GQDs) are promising drug carriers with excellent physicochemical and electrical properties. The current study proposes the combination of CS and GQDs in ultrasmall NP form not as drug carriers but as theranostic agents for AD. The microfluidic-based synthesis of the CS/GQD NPs with optimized characteristics makes them ideal for transcellular transfer and brain targeting after intranasal (IN) delivery. The NPs have the ability to enter the cytoplasm of C6 glioma cells in vitro and show dose and time-dependent effects on the viability of the cells. IN administration of the NPs to streptozotocin (STZ) induced AD-like models lead to a significant number of entrances of the treated rats to the target arm in the radial arm water maze (RAWM) test. It shows the positive effect of the NPs on the memory recovery of the treated rats. The NPs are detectable in the brain via in vivo bioimaging due to GQDs as diagnostic markers. The noncytotoxic NPs localize in the myelinated axons of hippocampal neurons. They do not affect the clearance of amyloid ß (Aß) plaques at intercellular space. Moreover, they showed no positive impact on the enhancement of MAP2 and NeuN expression as markers of neural regeneration. The memory improvement in treated AD rats may be due to neuroprotection via the anti-inflammation effect and regulation of the brain tissue microenvironment that needs to be studied.

Novel 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives, ligands of GABAA/benzodiazepine receptor complex: Design, synthesis, radioligand binding assay, and pharmacological evaluation.

Agonists of Benzodiazepine (BZD) receptor are exhaustively used in the control of muscle spasms, seizure, anxiety, and insomnia. BZDs have some unwanted effects; therefore, the development of new BZD receptor agonists with better efficacy and fewer unwanted effects is one of the subjects of interest. In this study, based on the pharmacophore/receptor model of the BZD binding site of GABAA receptors, a series of new 2-substituted-5-(4-chloro-2-phenoxy)phenyl-1,3,4-oxadiazole derivatives (6a-f) were designed. Energy minima conformers of the designed compounds and diazepam were well matched in conformational analysis and showed proper interaction with the BZD-binding site of the GABAA receptor model (α1ß2ϒ2) in docking studies. The designed compounds were synthesized in acceptable yield and evaluated for their in vitro affinity to the benzodiazepine receptor of rat brains by radioligand receptor binding assay. The results demonstrated that the affinities of most of the novel compounds were even higher than diazepam. The novel compound 6a with the best affinity in radioligand receptor binding assay (Ki=0.44 nM and IC50= 0.73±0.17 nM) had considerable hypnotic activity and weak anticonvulsant and anxiolytic effects with no negative effect on memory in animal models. Flumazenil as a selective benzodiazepine receptor antagonist was able to prevent hypnotic and anticonvulsant effects of 6a indicating the role of BZD receptors in these effects.

Novel Benzo[4,5]imidazo[1,2-a]pyrimidine derivatives as selective Cyclooxygenase-2 Inhibitors: Design, synthesis, docking studies, and biological evaluation.

The present study was aimed at the synthesis and evaluation of a new series of benzo[4,5]imidazo[1,2-a]pyrimidine having a methylsulfonyl group as COX-2 (cyclooxygenase-2) inhibitor pharmacophore. Molecular modeling studies were performed using the Autodock program, and the results demonstrated that methylsulfonyl pharmacophore was adequately placed into the COX-2 active site. The in vitro and in vivo COX-2 inhibitory effects were also evaluated. In the in vitro assay, all newly synthesized compounds showed moderate to good selectivity for the inhibition of the COX-2 enzyme. However, compound 2-(4-(methylsulfonyl) phenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine (5a) showed the highest COX-2 inhibitory effect (IC50: 0.05 µM) even more than celecoxib as the reference drug (IC50: 0.06 µM). For the in vivo study, the writing reflex test was used, and the results indicated that all synthesized compounds had well dose-dependent anti-nociceptive activity. The in vivo evaluation also showed that compound 2-(4-(methylsulfonyl)phenyl)-4-(p-tolyl)benzo[4,5]imidazo[1,2-a]pyrimidine (5d) had the highest activity in the writing reflex test (ED50: 5.75 mg/kg). In addition, the cytotoxicity effects of the synthesized compounds were tested on MCF-7 breast cancer cells, and all compounds showed considerable inhibitory results.

Antifatigue Effects of the Aqueous Extracts of Myrtle Berries, Apple and Clove: An Animal Study.

Background: Fatigue is one of the most prevalent symptoms, increasing worldwide with no specific medication for fatigue. Iranian traditional medicine (ITM), or Persian medicine, is a reliable source for discovering natural medicine for diseases and their symptoms. Myrtus communis L. (Myrtle), Malus domestica Borkh. (Apple), and Syzygium aromaticum (L.) Merr. & L. M. Perry (Clove) have been utilized as brain and heart tonics in ITM. Based on ITM, cardiac tonics decrease fatigue by enhancing heart function and increasing blood flow to tissues. These plants, particularly myrtle berries, have been utilized as potent enlivening agents that reduce mental fatigue. Objectives: This study aims to investigate the effects of aqueous extracts of these plants on weight-loaded forced swimming (WLFS) tests and three doses of aqueous myrtle extract in an animal model of chronic sleep deprivation-induced fatigue. Methods: Five groups of rats (n = 6) were evaluated: Sham, control, apple-treated, clove-treated, and myrtle-treated groups. After 28 days of treatment, the WLFS test was performed, and swimming time was recorded. Subsequently, central fatigue was induced in rats by chronic sleep deprivation for 21 days. Five groups of rats (n = 6) were evaluated: Sham, control (sleep-deprived, which received water), and three sleep-deprived + treatment groups, which received aqueous myrtle extract (350, 700, and 1000 mg/kg). An open field test on the 20th day and a WLFS test on the 21st day were performed. Results: The myrtle berries significantly increased glucose, reduced lactate dehydrogenase (LDH) levels, and enhanced swimming time. Fatigue caused by chronic sleep deprivation increased malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and LDH while decreased superoxide dismutase (SOD), glucose, and swimming time. In all treatment groups, SOD levels and swimming time were increased, whereas MDA, IL-1ß, and TNF-α levels were decreased significantly. Only the 1000 mg/kg dose significantly reduced LDH levels (P < 0.001). The treatment significantly improved the velocity and the total distance moved in the open-field test. Conclusions: According to the results, the myrtle berries reduced fatigue in two animal models, probably due to its phenolic compounds, flavonoids, and polysaccharides.

Hydroethanolic extract of Lavandula angustifolia ameliorates vincristine-induced peripheral neuropathy in rats.

Background and purpose: Peripheral neuropathy is one of the most common adverse effects of cancer chemotherapy. Vincristine is prescribed to treat a variety of carcinomas, including lymphoma and leukemia, and may cause progressive peripheral neuropathy due to the damage of microtubules and mitochondria of neurons and affects inflammatory processes. This study was designed to evaluate the effects of Lavandula angustifolia hydroalcoholic extract (LHE) of aerial part on vincristine-induced peripheral neuropathy in a rat model. Experimental approach: Neuropathy was induced in rats by daily intraperitoneal administration of vincristine (0.1 mg/kg for 2 weeks). Following the induction of neuropathy, animals were treated with the LHE (100, 200, and 400 mg/kg, p.o.) or pregabalin (20 mg/kg, IP) for 2 weeks, and their responses to vincristine-induced hyperalgesia and locomotor impairment were measured. Findings/Results: LHE, at the dose of 400 mg/kg, showed analgesic effects in response to thermal hyperalgesia, tactile allodynia, and gait impairment. Also, pregabalin (20 mg/kg, IP) improved the symptoms of vincristine-induced peripheral neuropathy. Conclusions and implications: According to the results, we can conclude that LHE alleviates neuropathic symptoms of vincristine and the effect is probably related to the presence of phenols and flavonoids in the extract.

Effects of Ziziphus Jujuba Extract Alone and Combined with Boswellia Serrata Extract on Monosodium Iodoacetate Model of Osteoarthritis in Mice.

Background: As a chronic joint condition, osteoarthritis (OA) is a common problem among older people. Pain, aching, stiffness, swelling, decreased flexibility, reduced function, and disability are the symptoms of arthritis. Objectives: In this study, we tested the extracts of Ziziphus jujuba (ZJE) and Boswellia serrata (BSE) to reduce OA symptoms as an alternative treatment. Methods: NMRI mice were administered an intra-articular injection of monosodium iodoacetate (MIA; 1 mg/10 mL) in the left knee joint cavity for the induction of OA. Hydroalcoholic extracts of ZJE (250 and 500 mg/kg), BSE (100 and 200 mg/kg), and combined ZJE and BSE were orally administered daily for 21 days. Following behavioral tests, plasma samples were collected to detect inflammatory factors. To screen for general toxicity, acute oral toxicity was evaluated. Results: Oral administration of all the hydroalcoholic extracts significantly increased the locomotor activity, pixel values of the foot-print area, paw withdrawal threshold, the latency of the withdrawal response to heat stimulation, and decreased the difference between pixel values of hind limbs compared to the vehicle group. Also, the elevated levels of IL-1ß, IL-6, and TNF-α were reduced. As tested in this study, ZJE and BSE were practically nontoxic and had a high degree of safety. Conclusions: This study demonstrated that the oral administration of ZJE and BSE slows the progression of OA through anti-nociceptive and anti-inflammatory properties. Oral co-administration of ZJE and BSE extracts can be used as herbal medicine to inhibit OA progression.

Brain Homogenate of a Rat Model of Alzheimer's Disease Modifies the Secretome of 3D Cultured Periodontal Ligament Stem Cells: A Potential Neuroregenerative Therapy.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to neuronal cell death and manifested by cognitive disorders and behavioral impairment. Mesenchymal stem cells (MSCs) are one of the most promising candidates to stimulate neuroregeneration and prevent disease progression. Optimization of MSC culturing protocols is a key strategy to increase the therapeutic potential of the secretome. Objectives: Here, we investigated the effect of brain homogenate of a rat model of AD (BH-AD) on the enhancement of protein secretion in the secretome of periodontal ligament stem cells (PDLSCs) when cultured in a 3D environment. Moreover, the effect of this modified secretome was examined on neural cells to study the impact of the conditioned medium (CM) on stimulation of regeneration or immunomodulation in AD. Methods: PDLSCs were isolated and characterized. Then, the spheroids of PDLSCs were generated in a modified 3D culture plate. PDLSCs-derived CM was prepared in the presence of BH-AD (PDLSCs-HCM) and the absence of it (PDLSCs-CM). The viability of C6 glioma cells was assessed after exposure to different concentrations of both CMs. Then, a proteomic analysis was performed on the CMs. Results: Differentiation into adipocytes and high expression of MSCs markers verified the precise isolation of PDLSCs. The PDLSC spheroids were formed after 7 days of 3D culturing, and their viability was confirmed. The effect of CMs on C6 glioma cell viability showed that both CMs at low concentrations (> 20 mg/mL) had no cytotoxic effect on C6 neural cells. The results showed that PDLSCs-HCM contains higher concentrations of proteins compared to PDLSCs-CM, including Src-homology 2 domain (SH2)-containing PTPs (SHP-1) and muscle glycogen phosphorylase (PYGM) proteins. SHP-1 has a role in nerve regeneration, and PYGM is involved in glycogen metabolism. Conclusions: The modified secretome derived from 3D cultured spheroids of PDLSCs treated by BH-AD as a reservoir of regenerating neural factors can serve as a potential source for AD treatment.

Optimization binding studies of opioid receptors, saturation and competition, using [3H]-DAMGO.

BACKGROUND: Opioid analgesics are prescribed for the moderate to severe pain in the clinic. New analogs of µ-opioid receptors are introduced because they may have less adverse effects and better efficacy. However, these new analogs have to be screened for their receptor affinity before entering clinical trial phases. A common method to do such screening is using radioligand-binding-assay, which is a fast and precise screening technique if the assays are done at an optimum condition. One of the main challenges in this type of screening is to separate free/unbound radioligands from bound radioligands. In this study, we applied a centrifugation method instead of a filtration method to separate free radioligands from bound radioligands, and also optimized the conditions for radioligand receptor binding studies of µ-opioid receptors, saturation, and the competition. METHODS: We used the midbrain and brainstem of naltrexone-treated rats as a source of µ-opioid receptors, and [3H]-DAMGO as the radioligand. Naloxone was also used to determine non-specific binding. A given amount of membrane protein was incubated with an increasing amount of radioligand at 37 °C to saturate the receptors at equilibrium and the amount of radioligand saturated in the receptors were used in competition studies. RESULTS: 160 µg membrane protein saturated with 20 nM [3H]-DAMGO at 37 °C for 35 min with Kd (15.06 nM, 95% CI 8.117-22.00) and Bmax (0.4750 pmol/mg, 95% CI 0.3839-0.5660). CONCLUSION: Applying the centrifugation method instead of the filtration to separate free from bound radioligand produced repeatable and reliable results. The optimum conditions for radioligand binding were used in competition studies which resulted in the expected outcomes.

Synthesis of 4,6-diphenylpyrimidin-2-ol derivatives as new benzodiazepine receptor ligands.

Benzodiazepines (BZDs) have been widely used in neurological disorders such as insomnia, anxiety, and epilepsy. The use of classical BZDs, e.g., diazepam, has been limited due to adverse effects such as interaction with alcohol, ataxia, amnesia, psychological and physical dependence, and tolerance. In the quest for new benzodiazepine agonists with more selectivity and low adverse effects, novel derivatives of 4,6-diphenylpyrimidin-2-ol were designed, synthesized, and evaluated. In this series, compound 2, 4-(2-(benzyloxy)phenyl)-6-(4-fluorophenyl)pyrimidin-2-ol, was the most potent analogue in radioligand binding assay with an IC50 value of 19 nM compared to zolpidem (IC50 = 48 nM), a nonbenzodiazepine central BZD receptor (CBR) agonist. Some compounds with a variety of affinities in radioligand receptor binding assay were selected for in vivo evaluations. Compound 3 (IC50 = 25 nM), which possessed chlorine instead of fluorine in position 4 of the phenyl ring, exhibited an excellent ED50 value in most in vivo tests. Proper sedative-hypnotic effects, potent anticonvulsant activity, appropriate antianxiety effect, and no memory impairment probably served compound 3, a desirable candidate as a benzodiazepine agonist. The pharmacological effects of compound 3 were antagonized by flumazenil, a selective BZD receptor antagonist, confirming the BZD receptors' involvement in the biological effects of the novel ligand.

Novel Derivatives of diphenyl-1,3,4-oxadiazol as Ligands of Benzodiazepine Receptors; Synthesize, Binding Assay and Pharmacological Evaluation.

Benzodiazepines (BZD) are among the main classes of tranquilizing drugs, bearing much less toxicity compared to other drugs acting on the CNS. Considering the pharmacophore model of BZD binding to GABA-A receptor, novel diphenyl 1,3,4-oxadiazole compounds as BZD ligands were designed. The compounds were synthesized and structurally confirmed using LCMS, IR and NMR techniques. We investigated the affinity of the compounds to BZD receptors using radioligand [3H]-flumazenil by in-vitro studies. In addition, sedative-hypnotic, anxiety, anticonvulsant, muscle relaxant, memory impairment, and motor coordination activities of the synthesized compounds were evaluated using in-vivo studies. Based on in-vitro studies, compounds 7i and 7j were the most potent with IC50 values of 1.54 and 1.66 nM respectively. In-vivo studies showed that compound 7i has the highest impact on increased sedation, muscle relaxation, and decreased anxiety and these observations were antagonized by flumazenil. Compounds 7e and 7i were the most potent anticonvulsant agents among synthesized compounds in both MES and PTZ induced seizure tests. All synthesized compounds significantly decreased latency to fall in the Rotarod test but none of them had a significant impact on the memory impairment test.

An Intensified Acrolein Exposure Can Affect Memory and Cognition in Rat.

Acrolein is a clear, colorless liquid and a highly reactive α, ß-unsaturated aldehyde. Acrolein, a byproduct and initiator of oxidative stress, has a major role in the pathogenesis of disorders including pulmonary, cardiovascular, atherosclerosis, and neurodegenerative diseases. Environmental or dietary exposure and endogenous production are common sources of acrolein. Widespread exposure to acrolein is a major risk for human health; therefore, we decided to investigate the neurological effects of acrolein. In this study, we used male Sprague-Dawley rats and exposed them orally to acrolein (0.5, 1, 3, and 5 mg/kg/day) for 90 days and investigated the neurobehavioral and electrophysiological disturbances. We also assessed the correlation between neurotoxicity and CSF concentration of acrolein in the rats. The results showed that chronic oral administration of acrolein at 5 mg/kg/day impaired learning and memory in the neurobehavioral tests. In addition, acrolein decreased the release of excitatory neurotransmitters such as glutamate in electrophysiological studies. Our data demonstrated that chronic oral exposure of acrolein at a dose of 5 mg/kg leads to a direct correlation between neurotoxicity and its CSF concentration. In conclusion, exposure to acrolein as a major pollutant in the environment may cause cognitive problems and may have serious neurocognitive effects on humans.

Synthesis and radioligand-binding assay of 2,5-disubstituted thiadiazoles and evaluation of their anticonvulsant activities.

In this study, a number of 2,5-disubstituted 1,3,4-thiadiazoles were synthesized using an appropriate synthetic route, and their anticonvulsant activity was determined by the maximal electroshock seizure (MES) test and their neurotoxicity was evaluated by the rotarod test. Additionally, their hypnotic activity was tested using the pentobarbital-induced sleep test. Compounds 7 (ED50 = 1.14 and 2.72 µmol/kg in the MES and sleep tests, respectively) and 11 (ED50 = 0.65 and 2.70 µmol/kg in the MES and sleep tests, respectively) were the most potent ones in the sleep test and anticonvulsant test, showing a comparable activity with diazepam as the reference drug. The results of in vivo studies, especially the antagonistic effects of flumazenil, and also the radioligand-binding assay confirmed the involvement of benzodiazepine (BZD) receptors in the anticonvulsant and hypnotic activity of compounds 7 and 11. Finally, the docking study of compound 11 in the BZD-binding site of the GABAA (gamma-aminobutyric acid) receptor confirmed the possible binding of the compound to the BZD receptors. We concluded that the novel 1,3,4-thiadiazole derivatives with appropriate substitution at positions 2 and 5 of the heterocyclic ring had a good affinity to BZD receptors and showed significant efficacy in the pharmacological tests.

Neuro-Behavioral Profile and Toxicity of the Essential Oil of Dorema ammoniacum Gum as an Anti-seizure, Anti-nociceptive, and Hypnotic Agent with Memory-enhancing Properties in D-Galactose Induced Aging Mice.

In this study, we focused on the neuro-behavioral profile, toxicity, and possible mechanisms of action of Dorema ammoniacum gum essential oil (DAG-EO). For this purpose, passive avoidance and Y-maze tests were performed to evaluate the potential effect of DAG-EO in the attenuation of memory impairment induced by 49 days administration of D-galactose and acute injection of scopolamine. Anticonvulsant and anti-nociceptive activities of DAG-EO were evaluated in the pentylenetetrazole and maximal electroshock-induced models of seizure and acetic acid-induced writhing tests, respectively. To find the possible mechanism of action, flumazenil and naloxone were used. Furthermore, the possible side effects were determined in the open field, grip strength, and rotarod tests. Our findings supported that 7-day administration of DAG-EO (50 and 100 mg/kg) improves memory impairment induced following administration of D-galactose and scopolamine. It was also revealed that DAG-EO possesses a dose-dependent sedative-hypnotic (100 mg/kg), anticonvulsant (ED50 ≈ 170 mg/kg), and anti-nociceptive (ED50 ≈ 175 mg/kg) activities possibly mediated via directly and/or indirectly modulation of GABAA and opioid receptors. No side effect was observed except muscle relaxation which was less than that of diazepam. The output of this study confirms anti-seizure, anti-nociceptive, sedative-hypnotic, and memory-enhancing properties of DAG-EO by modulation of GABAA receptors.

Cardioprotective Effects of Atorvastatin Are Mediated Through PPARγ in Paraquat-Exposed Rats.

BACKGROUND: Paraquat poisoning is one of leading intoxication worldwide without an effective antidote and treatment protocol. Among the other organs, cardiotoxicity of paraquat has been frequently reported. AIM: The protective effects of atorvastatin (STN) on paraquat-induced cardiotoxicity and the role of peroxisome proliferator-activated receptors γ in the mediation of STN effects were investigated. METHODS: Forty-two male Wistar rats were aliquoted into control or test groups. The animals in test groups in addition of paraquat received saline normal (PQ), pioglitazone (PGT), atorvastatin (STN), PGT + STN, PGT + GW9662, and/or STN + GW9662 for 14 days. RESULTS: PGT and STN lowered lipid peroxidation rate, nitric oxide concentration, and activity of myeloperoxidase and CK/MB in the heart. PGT and STN protected from thiol molecules reduction and PQ-induced histopathological injuries. STN regulated the PQ-induced upregulation of COX-II expression in the heart. All STN-related protective effects were reversed by GW9662 as PPARγ antagonist. CONCLUSIONS: These data suggest a cardioprotective effect for STN against the PQ-induced inflammation and oxidative stress. The pharmacologic approach of these findings indicates that STN through PPARγ pathway lowered the PQ-induced cardiotoxicity.

Evaluation of Anticonvulsant Effect of Aqueous and Methanolic Extracts of Seven Inula Species.

In Iranian traditional medicine, Inula species have been used for the treatment of seizure. In this study we decided to investigate the anticonvulsant activity of seven species from this genus to find an effective remedy for seizure with less adverse effects compared to the available medicines. Aqueous and methanolic extracts of Inula britannica, Inula helenium, Inula viscidula, Inula oculus-christi, Inula aucheriana, Inula thapsoides, and Inula salicina were prepared and their antiepileptic activity was investigated by maximal electroshock (MES) and pentylentetrazole (PTZ) tests on Male NMRI Albino mice. Diazepam was used as positive control in both tests. In addition, two extracts with the best anticonvulsant activities were selected and their sedative and hypnotic effects were evaluated using open field and righting reflex tests, respectively. The effects of the both extracts on memory and motor coordination were also assessed by step-through passive avoidance and rotarod tests, respectively. Aqueous extract of Inula britannica and Inula viscidula showed the best activity in MES model and their ED50 (with 95% confidence interval) was 19.5 (7.9~48.5) mg/kg and 12.7(10.0~16.3) mg/kg, respectively. None of the extracts showed noticeable anticonvulsant effects in the PTZ model. The active extracts also showed sedative-hypnotic effects in righting reflex and open field tests. Furthermore, both extracts did not affect the memory and motor coordination in the experimental models. The anticonvulsant and sedative activities of the extracts were antagonized by flumazenil, indicating that benzodiazepine receptors are probably involved in the effects. This study indicates that Inula britannica and Inula viscidula are good candidates for further phytochemical and mechanistic studies in order to find anticonvulsant and sedative-hypnotic compounds with less adverse effect on memory and motor coordination.

Evaluation and comparison of the antidepressant-like activity of Artemisia dracunculus and Stachys lavandulifolia ethanolic extracts: an in vivo study.

Several studies have supported the preventive and therapeutic values of phenolic compounds including chlorogenic acid, syringic acid, vanillic acid, ferulic acid, caffeic acid, luteolin, rutin, catechin, kaempferol, and quercetin in mental disorders. Since these secondary metabolites are reported as the phenolic compounds of Artemisia dracunculus (A. dracunculus) and Stachys lavandulifolia (S. lavandulifolia), the main aim of this study was the evaluation and comparison of the phenolic contents, flavonoids, and antidepressant-like activity of Artemisia dracunculus with Stachys lavandulifolia. Antidepressant-like activity of the extracts was evaluated in the forced swimming test (FST) and the tail suspension test (TST). Moreover, the open field test was conducted to evaluate the general locomotor activity of mice following treatment with the extracts. Since phenolic compounds and flavonoids play main roles in pharmacological effects, the phenolic and flavonoid contents of the extracts were measured. Though significant difference between the phenolic contents of the extracts was not observed, but S. lavandulifolia exhibited higher flavonoid contents. Animal treatment with extracts decreased the immobility times in both FST and TST compared to the vehicle group without any significant effect on the locomotor activity of animals. Also, S. lavandulifolia at 400 mg/kg showed higher potency in both tests compared to A. dracunculus. Our results provided promising evidence on the antidepressant-like activity of both extracts which could be related to flavonoids as the main components of the extracts, but more studies need to be conducted to specify the main compounds and the mechanisms involved in the observed effects.