Beneficial effect of lupeol and metformin in mouse model of intracerebroventricular streptozotocin induced dementia.

This study examines the effectiveness of lupeol and metformin in a mouse model of dementia generated by intracerebroventricular streptozotocin (i.c.v., STZ). Dementia was induced in Swiss mice with the i.c.v. administration of STZ at a dosage of 3 mg/kg on the first and third day. The assessment of dementia involved an examination of the Morris Water Maze (MWM) performance, as well as a number of biochemical and histological studies. STZ treatment resulted in significant decrease in MWM performance; various biochemical alterations (increase in brain acetyl cholinesterase (AChE) activity, thiobarbituric acid reactive species (TBARS), nitrite/nitrate, and reduction in nuclear factor erythroid 2 related factor-2 (Nrf-2), reduced glutathione (GSH) levels) and neuroinflammation [increased myeloperoxidase (MPO) activity & neutrophil infiltration]. The administration of Lupeol (50 mg/kg & 100 mg/kg; p.o.) and Metformin (150 mg/kg & 300 mg/kg; p.o.) demonstrated a considerable reduction in the behavioral, biochemical, and histological alterations produced by STZ. Low dose combination of lupeol (50 mg/kg; p.o.) and Metformin (150 mg/kg; p.o.) produced more pronounced effect than that of high doses of either agent alone. It is concluded that Lupeol and Metformin has shown efficacy in dementia with possible synergism between the two and can be explored as potential therapeutic agents for managing dementia of Alzheimer's disease (AD) type.

Quetiapine Moderates Doxorubicin-Induced Cognitive Deficits: Influence of Oxidative Stress, Neuroinflammation, and Cellular Apoptosis.

Chemotherapy is considered a major choice in cancer treatment. Unfortunately, several cognitive deficiencies and psychiatric complications have been reported in patients with cancer during treatment and for the rest of their lives. Doxorubicin (DOX) plays an important role in chemotherapy regimens but affects both the central and peripheral nervous systems. Antipsychotic drugs alleviate the behavioral symptoms of aging-related dementia, and the atypical class, quetiapine (QUET), has been shown to have beneficial effects on various cognitive impairments. The present investigation aimed to determine the possible mechanism underlying the effect of thirty-day administrations of QUET (10 or 20 mg/kg, p.o.) on DOX-induced cognitive deficits (DICDs). DICDs were achieved through four doses of DOX (2 mg/kg, i.p.) at an interval of seven days during drug treatment. Elevated plus maze (EPM), novel object recognition (NOR), and Y-maze tasks were performed to confirm the DICDs and find the impact of QUET on them. The ELISA tests were executed with oxidative [malondialdehyde (MDA), catalase, and reduced glutathione (GSH)], inflammatory [cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and tumor necrosis factor-alpha (TNF-α)], and apoptosis [B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein (Bax), and Caspase-3] markers were assessed in the brain homogenate to explore the related mechanisms. DICD lengthened the transfer latency time in EPM, shortened the exploration time of the novel object, reduced the discrimination ability of the objects in NOR, and lowered the number of arm entries and time spent in the novel arm. QUET alleviated DICD-related symptoms. In addition, QUET reduced neuronal oxidative stress by reducing MDA and elevating GSH levels in the rat brain. Moreover, it reduced neuronal inflammation by controlling the levels of COX-2, NF-κB, and TNF-α. By improving the Bcl-2 level and reducing both Bax and Caspase-3 levels, it protected against neuronal apoptosis. Collectively, our results supported that QUET may protect against DICD, which could be explained by the inhibition of neuronal inflammation and the attenuation of cellular apoptosis protecting against oxidative stress.

Aripiprazole Attenuates Cognitive Impairments Induced by Lipopolysaccharide in Rats through the Regulation of Neuronal Inflammation, Oxidative Stress, and Apoptosis.

Background and Objectives: Aripiprazole (APZ), an atypical antipsychotic, is mainly prescribed for conditions such as schizophrenia and bipolar disorder, while ongoing research indicates promising neuroprotective qualities. APZ's mechanism of action, involving the regulation of neurotransmitter levels, appears to contribute to its potential to shield neural tissues from specific forms of harm and degeneration. Materials and Methods: To investigate its neuroprotective mechanisms, groups of rats were orally administered APZ at 1 or 2 mg/kg once daily for a 30-day period. In addition, neuronal toxicity was induced through intraperitoneal injection of four doses of lipopolysaccharide (LPS) at a concentration of 1 mg/kg. To evaluate cognitive function, particularly, short-term recognition memory, the procedure implemented the novel object recognition (NOR) task. Subsequently, brain tissues were gathered to examine markers linked with neuroinflammation, oxidative stress, and apoptosis. Results: The administration of LPS led to a decline in memory performance during the NOR tasks. Simultaneously, this LPS treatment raised inflammatory markers like cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and nuclear factor kappa B (NF-κB), increased oxidative markers such as malondialdehyde (MDA), and triggered apoptosis markers like Caspase-3 and Bcl2 associated X protein (Bax) within the brain. Furthermore, it decreased levels of antioxidants like reduced glutathione (GSH) and catalase, as well as the anti-apoptotic marker B-cell lymphoma (Bcl)-2 in brain tissue. The use of APZ resulted in enhanced recognition memory performance, as indicated by improved exploration and discrimination abilities of the objects in the NOR task. Moreover, APZ lowered the markers associated with neuronal vulnerability, such as COX-2, NF-κB, MDA, Caspase-3, and Bax. Additionally, it increased the levels of protective markers, including GSH, catalase, and Bcl-2 in LPS-challenged brains. Conclusions: In summary, the findings suggest that APZ exhibits protective properties against neuronal inflammation, oxidative stress, and apoptosis markers in the context of inflammatory-related neurodegeneration. Additional in-depth investigations are needed to further explore potential applications.

Impact of levetiracetam on cognitive impairment, neuroinflammation, oxidative stress, and neuronal apoptosis caused by lipopolysaccharides in rats.

Introduction: Neuroinflammation is associated with the elevation of toxic proinflammatory mediators that promote neurodegeneration and subsequently affect cognition. Causes of inflammation in the neuronal cells are believed to initiate various neurodegenerative disorders, mainly Alzheimer's disease. Levetiracetam is a second-generation antiepileptic drug. There is evidence supporting the memory-enhancing effect of levetiracetam from numerous experimental and clinical studies. Therefore, this research focused on finding its protective effects against lipopolysaccharides prompted cognitive impairment and exploring possible mechanisms underlining their neuroprotection. Methodology: Two doses (100 or 200 mg/kg) of levetiracetam were administrated orally for 30 days. Additionally, four doses (250 µg/kg) of lipopolysaccharide were injected peripherally to induce neurotoxicity. Behavioral tests were carried out using various maze models. At the end of the tests, brain tissues were collected for biochemical evaluations. Cholinergic, neuroinflammatory, apoptosis, and oxidative-related parameters were analyzed in the brain homogenate to explore the possible mechanisms of action of levetiracetam. Results: In lipopolysaccharide-induced rats, levetiracetam indicated a reduction (p < 0.01) in transfer latency using the elevated plus-maze. An improvement (p < 0.01) in novel and familiar objects exploration time using novel object recognition test. A rise (p < 0.05) in novel arm entries and extended time spent in the novel arm using the Y-maze test. In extension, the levels of acetylcholine (p < 0.001), anti-inflammatory factors (transforming growth factor-ß1; p < 0.01 and interleukin-10; p < 0.05), and an antioxidant (catalase; p < 0.01) were elevated in lipopolysaccharide-induced rats after the administration of levetiracetam. In contrast, inflammatory factors (cyclooxygenase-2; p < 0.05, nuclear factor kappa B; p < 0.05, tumor necrosis factor-α; p < 0.01, and interleukin-6 (p < 0.01), apoptosis inducers (BCL2-associated X protein; p < 0.05 and Caspase-3 (p < 0.001), and oxidative stress (malondialdehyde; p < 0.05) were considerably reduced with levetiracetam in lipopolysaccharide-induced rats. Conclusion: The collective results suggested that levetiracetam may be able to treat neuroinflammatory-related memory loss by enhancing cholinergic activity while reducing neuroinflammation, cellular apoptosis, and oxidative stress.

Levetiracetam Ameliorates Doxorubicin-Induced Chemobrain by Enhancing Cholinergic Transmission and Reducing Neuroinflammation Using an Experimental Rat Model and Molecular Docking Study.

Cancer chemotherapy-induced cognitive impairment (chemobrain) is a major complication that affects the prognosis of therapy. Our study evaluates the nootropic-like activity of levetiracetam (LEVE) against doxorubicin (DOX)-induced memory defects using in vivo and molecular modelling. Rats were treated with LEVE (100 and 200 mg/kg, 30 days) and chemobrain was induced by four doses of DOX (2 mg/kg, i.p.). Spatial memory parameters were evaluated using an elevated plus maze (EPM) and Y-maze. Additionally, acetylcholinesterase (AChE) and the neuroinflammatory biomarkers cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nuclear factor-κB (NF-κB), and tumor necrosis factor-alpha (TNF-α) were analyzed using brain homogenate. PharmMapper was used for inverse docking and AutoDock Vina was used for molecular docking. LEVE treatment significantly diminished the DOX-induced memory impairment parameters in both the EPM and Y-maze. In addition, the drug treatment significantly reduced AChE, COX-2, PGE2, NF-κB, and TNF-α levels compared to DOX-treated animals. The inverse docking procedures resulted in the identification of AChE as the potential target. Further molecular modelling studies displayed interactions with residues Gly118, Gly119, and Ser200, critical for the hydrolysis of ACh. Analysis of the results suggested that administration of LEVE improved memory-related parameters in DOX-induced animals. The 'nootropic-like' activity could be related to diminished AChE and neuroinflammatory mediator levels.

Biotechnological Innovations from Ocean: Transpiring Role of Marine Drugs in Management of Chronic Disorders.

Marine drugs are abundant in number, comprise of a diverse range of structures with corresponding mechanisms of action, and hold promise for the discovery of new and better treatment approaches for the management of several chronic diseases. There are huge reserves of natural marine biological compounds, as 70 percent of the Earth is covered with oceans, indicating a diversity of chemical entities on the planet. The marine ecosystems are a rich source of bioactive products and have been explored for lead drug molecules that have proven to be novel therapeutic targets. Over the last 70 years, many structurally diverse drug products and their secondary metabolites have been isolated from marine sources. The drugs obtained from marine sources have displayed an exceptional potential in the management of a wide array of diseases, ranging from acute to chronic conditions. A beneficial role of marine drugs in human health has been recently proposed. The current review highlights various marine drugs and their compounds and role in the management of chronic diseases such as cancer, diabetes, neurodegenerative diseases, and cardiovascular disorders, which has led to the development of new drug treatment approaches.

Natural and Synthetic Agents Targeting Reactive Carbonyl Species against Metabolic Syndrome.

Reactive carbonyl species (RCS) may originate from the oxidation of unsaturated fatty acids and sugar in conditions of pathology. They are known to have high reactivity towards DNA as well as nucleophilic sites of proteins, resulting in cellular dysfunction. It has been considered that various pathological conditions are associated with an increased level of RCS and their reaction products. Thus, regulating the levels of RCS may be associated with the mitigation of various metabolic and neurodegenerative disorders. In order to perform a comprehensive review, various literature databases, including MEDLINE, EMBASE, along with Google Scholar, were utilized to obtain relevant articles. The voluminous review concluded that various synthetic and natural agents are available or in pipeline research that hold tremendous potential to be used as a drug of choice in the therapeutic management of metabolic syndrome, including obesity, dyslipidemia, diabetes, and diabetes-associated complications of atherosclerosis, neuropathy, and nephropathy. From the available data, it may be emphasized that various synthetic agents, such as carnosine and simvastatin, and natural agents, such as polyphenols and terpenoids, can become a drug of choice in the therapeutic management for combating metabolic syndromes that involve RCS in their pathophysiology. Since the RCS are known to regulate the biological processes, future research warrants detailed investigations to decipher the precise mechanism.

Sukkari dates seed improves type-2 diabetes mellitus-induced memory impairment by reducing blood glucose levels and enhancing brain cholinergic transmission: In vivo and molecular modeling studies.

Cognitive decline is one of the serious complications associated with diabetes mellitus (T2DM) of type-2. In this reported work, the effect of aqueous sukkari dates seed extract (ASSE) was evaluated in T2DM-induced rats. T2DM was induced using intraperitoneal injection of nicotinamide and streptozocin (STZ) administration. The diabetic rats were then treated orally with 200 mg/kg and 400 mg/kg of dates seed extract for 30 days and results were compared with metformin-treated groups. The memory functions were assessed using three maze models. Glucose and insulin levels in the blood and acetylcholine, acetylcholinesterase brain homogenates were estimated. The results showed a significant reduction in transfer latency (TL) (p < 0.001) during the elevated plus maze (EPM) test. The novel object recognition (NOR) test revealed a longer exploration time (p > 0.05) with novel objects and a higher discrimination index (p > 0.05). The Y-maze test also showed a significant increase in the number of entries to the novel arm (p > 0.05) and the total number of entries in the trial (p > 0.01) as well as in test (p > 0.05) sessions. Reduction in blood glucose (p > 0.05) and improvement in blood insulin (p > 0.05) levels were also noted. Improvement in ACh levels (p > 0.001) with 400 mg/kg of ASSE and reduction in AChE (p > 0.001) with both doses of ASSE were also observed in the brain homogenates. The results of ASSE were found comparable with the metformin-treated rats. The estimation of phytochemical constituents displayed a significant presence of phenolic content. Further, molecular modeling studies showed ellagic acid, catechin, and epicatechin as the potential molecule interacting with GSK-3ß, α-amylase, and AChE and may be responsible for observed bioactivity. In conclusion, ASSE has the ability to alleviate T2DM-related cognitive impairments.

Exploring the therapeutic promise of targeting Rho kinase in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease caused by dysregulated inflammatory reactions, T lymphocyte invasion into the joints, and articular thickening. Immune cells, primarily tumor necrosis factor-alpha (TNF-α) and chemokines (interleukin or IL-1), which are predominantly generated by activated macrophages cells, have also been involved with the pathogenesis of rheumatoid arthritis. Rho GTPases are integral factors of biochemical cascades utilized by antigens, and also by cellular receptors, cytokines, and chemokines, to modulate inflammatory reactions, according to growing data. The Rho family is a group of G proteins that govern a variety of biological and physiological activities such as mobility, actin stress fiber production, growth, and polarity. Research suggests that the Rho A and Rho-associated coiled-coil kinase (ROCK) regulatory cascade could be essential in several autoimmune conditions, including RA. ROCK is activated in the synovial of rheumatoid arthritis patients, while the blocking of ROCK with fasudil could also decrease IL-6, TNF-α, and IL-1. This review covers current developments in understanding the overactivation of Rho enzyme activity in RA suppressed by ROCK inhibitors which can be utilized for the treatment of autoimmune disease. We offer an outline of the function of ROCK inhibitors in immune cells and discuss findings which emphasize the rising participation of this category of kinases within the pathological process of autoimmune disorders. Assuming the potential ability of ROCK as a therapeutic, we define approaches that might be used to inhibit Rho kinase activity in rheumatoid disorders.

Polyphenols Targeting MAPK Mediated Oxidative Stress and Inflammation in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disorder, predominantly symmetric, which causes joint inflammation, cartilage degeneration and bone erosion, resulting in deformity and the loss of physical function. Although the management of RA has steadily improved, the pathophysiological mechanism is incompletely elucidated, and therapeutic options are still limited. Due to shortcomings in the efficacy or safety profiles of conventional RA therapies, therapeutic alternatives have been considered. Therefore, natural extracts containing polyphenolic compounds can become promising adjuvant agents for RA global management, due to their antioxidant, anti-inflammatory and apoptotic properties. Polyphenols can regulate intracellular signaling pathways in RA and can generate different immune responses through some key factors (i.e., MAPK, interleukins (ILs 1 and 6), tumor necrosis factor (TNF), nuclear factor light k chain promoter of activated receptor (NF-κB), and c-Jun N-terminal kinases (JNK)). The critical function of the Toll like-receptor (TLR)-dependent mitogen-activating protein kinase (MAPK) signaling pathway in mediating the pathogenic characteristics of RA has been briefly discussed. Oxidative stress can trigger a change in transcription factors, which leads to the different expression of some genes involved in the inflammatory process. This review aims to provide a comprehensive perspective on the efficacy of polyphenols in mitigating RA by inhibiting signaling pathways, suggesting future research perspectives in order to validate their use.

Neuroimmunomodulatory properties of DPSCs in an in vitro model of Parkinson's disease.

In neurodegenerative diseases, such as Alzheimer's and Parkinson's, microglial cell activation is thought to contribute to their degeneration by producing neurotoxic compounds. While dental pulp stem cells (DPSCs) have been regarded as the next possible cell source for cell replacement therapy (CRT), their actual role when exposed in such harsh environment remains elusive. In this study, the immunomodulatory behavior of DPSCs from human subjects was investigated in a coculture system consisting of neuron and microglia which were treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, which mimics the inflammatory conditions and contribute to degeneration of dopaminergic (DA-ergic) neurons. Assessments were performed on their proliferation, extent of DNA damage, productions of reactive oxygen species (ROS) and nitric oxide (NO), as well as secretion of inflammatory mediators. Notably, DPSCs were shown to attenuate their proliferation, production of ROS, and NO significantly (P < 0.05). Additionally, their immunomodulatory properties were distinct although insignificant changes were observed in DNA damage. Despite DPSCs were exposed to such harsh environment, they were still able to express neuronal markers such as Nestin, Pax 6, and Nurr1, at least by twofold thereby indicating their applicability for CRT especially in PD conditions. To conclude, DPSCs were shown to have immunomodulatory capacities which could probably serve as secondary effects upon transplantation in a CRT regime. © 2017 IUBMB Life, 69(9):689-699, 2017.

Effect of dental pulp stem cells in MPTP-induced old-aged mice model.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic (DA-ergic) neurons in the substantia nigra (SN) and represented as a huge threat to the geriatric population. Cell replacement therapies (CRTs) have been proposed as a promising strategy to slow down or replace neuronal loss. Among the widely available cell sources, dental pulp stem cells (DPSCs) portray as an attractive source primarily due to their neural crest origin, ease of tissue procurement and less ethical hurdles. MATERIALS AND METHODS: We first demonstrated the in vitro differentiation ability of DPSCs towards DA-ergic-like cells before evaluating their neuro-protection/neuro-restoration capacities in MPTP-induced mice. Transplantation via intrathecal was performed with behavioural assessments being evaluated every fortnight. Subsequent analysis investigating their immuno-modulatory behaviour was conducted using neuronal and microglial cell lines. RESULTS: It was apparent that the behavioural parameters began to improve corresponding to tyrosine hydroxylase (TH), dopamine transporter (DAT) and dopamine decarboxylase (AADC) immunostaining in SN and striatum as early as 8-week post-transplantation (P < 0·05). About 60% restoration of DA-ergic neurons was observed at SN in MPTP-treated mice after 12-week post-transplantation. Similarly, their ability to reduce toxic effects of MPTP (DNA damages, reactive oxygen species and nitric oxide release) and regulate cytokine levels was distinctly noted (P < 0·05) upon exposure in in vitro model. CONCLUSIONS: Our results suggest that DPSCs may provide a therapeutic benefit in the old-aged PD mice model and may be explored in stem cell-based CRTs especially in geriatric population as an attempt towards 'personalized medicine'.

Lactobacilli-fermented cow's milk attenuated lipopolysaccharide-induced neuroinflammation and memory impairment in vitro and in vivo.

Nutritional interventions are now recommended as strategies to delay Alzheimer's disease (AD) progression. The present study evaluated the neuroprotective effect (anti-inflammation) of lactic acid bacteria (either Lactobacillus fermentum LAB9 or L. casei LABPC) fermented cow's milk (CM) against lipopolysaccharide (LPS)-activated microglial BV2 cells in vitro. The ability of CM-LAB in attenuating memory deficit in LPS-induced mice was also investigated. ICR mice were orally administered with CM-LAB for 28 d before induction of neuroinflammation by LPS. Learning and memory behaviour were assessed using the Morris Water Maze Test. Brain tissues were homogenised for measurement of acetylcholinesterase (AChE), antioxidative, lipid peroxidation (malondialdehyde (MDA)) and nitrosative stress (NO) parameters. Serum was collected for cytokine analysis. CM-LAB9 and CM-LABPC significantly (P < 0·05) decreased NO level but did not affect CD40 expression in vitro. CM-LAB attenuated LPS-induced memory deficit in mice. This was accompanied by significant (P < 0·05) increment of antioxidants (SOD, GSH, GPx) and reduction of MDA, AChE and also pro-inflammatory cytokines. Unfermented cow's milk (UCM) yielded greater cytokine lowering effect than CM-LAB. The present findings suggest that attenuation of LPS-induced neuroinflamation and memory deficit by CM-LAB could be mediated via anti-inflammation through inhibition of AChE and antioxidative activities.

Enhanced memory in Wistar rats by virgin coconut oil is associated with increased antioxidative, cholinergic activities and reduced oxidative stress.

CONTEXT: Virgin coconut oil (VCO) has been reported to possess antioxidative, anti-inflammatory and anti-stress properties. OBJECTIVE: Capitalizing on these therapeutic effects, this study investigated for the first time the potential of VCO on memory improvement in vivo. MATERIALS AND METHODS: Thirty male Wistar rats (7-8 weeks old) were randomly assigned to five groups (n = six per group). Treatment groups were administered with 1, 5 and 10 g/kg VCO for 31 days by oral gavages. The cognitive function of treated-rats were assessed using the Morris Water Maze Test. Brains were removed, homogenized and subjected to biochemical analyses of acetylcholine (ACh) and acetylcholinesterase (AChE), antioxidants [superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx) and glutathione reductase (GRx)], lipid peroxidase [malondialdehyde (MDA)] as well as nitric oxide (NO). α-Tocopherol (αT; 150 mg/kg) was also included for comparison purposes. RESULTS: VCO-fed Wistar rats exhibited significant (p < 0.05) improvement of cognitive functions [reduced escape latency (≥ 1.8 s), reduced escape distance (≥ 0.3 m) and increased total time spent on platform (≥ 1 s)]. The findings were accompanied by elevation of ACh (15%), SOD (8%), CAT (≥ 54%), GSH (≥ 20%) and GPx (≥ 12%) and reduction of AChE (≥17%), MDA (> 33%) and NO (≥ 34%). Overall, memory improvement by VCO was comparable to αT. DISCUSSION AND CONCLUSION: VCO has the potential to be used as a memory enhancer, the effect of which was mediated, at least in part, through enhanced cholinergic activity, increased antioxidants level and reduced oxidative stress.

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies.

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC50: 0.68±0.13µM) with strong DPPH and ABTS radical scavenging activity (IC50: 13.77±0.25µM and IC50: 12.59±0.21µM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC50: 0.74±0.09µM) and with DPPH and ABTS radical scavenging activity (IC50: 13.52±0.62µM and IC50: 13.13±0.85µM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.

The role of multifunctional drug therapy as an antidote to combat experimental subacute neurotoxicity induced by organophosphate pesticides.

Organophosphate pesticides are used in agriculture where they are associated with numerous cases of intentional and accidental misuse. These toxicants are potent inhibitors of cholinesterases leading to a massive build-up of acetylcholine which induces an array of deleterious effects, including convulsions, oxidative damage and neurobehavioral deficits. Antidotal therapies with atropine and oxime yield a remarkable survival rate, but fail to prevent neuronal damage and behavioral problems. It has been indicated that multifunction drug therapy with potassium channel openers, calcium channel antagonists and antioxidants (either single-agent therapy or combination therapy) may have the potential to prevent cell death and/or slow down the processes of secondary neuronal damage. The aim of the present study, therefore, was to make a relative assessment of the potential effects of nicorandil (2 mg/kg), clinidipine (10 mg/kg), and grape seed proanthocyanidin (GSPE) extract (200 mg/kg) individually against subacute chlorpyrifos induced toxicity. The test drugs were administered to Wistar rats 2 h after exposure to Chlorpyrifos (CPF). Different behavioral studies and biochemical estimation has been carried in the study. The results showed that chronic administration of CPF significantly impaired learning and memory, along with motor coordination, and produced a marked increase in oxidative stress along with significantly reduced acetylcholine esterase (AChE) activity. Treatment with nicorandil, clinidipine and GSPE was shown to significantly improve memory performance, attenuate oxidative damage and enhance AChE activity in rats. The present study also suggests that a combination of nicorandil, clinidipine, and GSPE has a better neuroprotective effect against subacute CPF induced neurotoxicity than if applied individually. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1017-1026, 2016.

2-AZETIDINONE DERIVATIVES: SYNTHESIS, ANTIMICROBIAL, ANTICANCER EVALUATION AND QSAR STUDIES.

A series of 2-azetidinone derivatives was synthesized from hippuric acid and evaluated for its in vitro antimicrobial and anticancer activities. Antimicrobial properties of the title compounds were investigated against Gram positive and Gram negative bacterial as well as fungal strains. Anticancer activity was performed against breast cancer (MCF7) cell lines. Antimicrobial activity results revealed that N-{2-[3-chloro-2-(2- chlorophenyl)-4-oxoazetidin-1-ylamino]-2-oxoethyl}benzamide (4) was found to be the most potent antimicrobial agent. Results of anticancer study indicated that the synthesized compounds exhibited average anticancer potential and N-[2-(3-chloro-2-oxo-4-styrylazetidin-1-ylamino)-2-oxoethyl]benzamide (17) was found to be most potent anticancer agent against breast cancer (MCF7) cell lines. QSAR models indicated that the antibacterial, antifungal and the overall antimicrobial activities of the synthesized compounds were governed by topological parameters, Balaban index (J) and valence zero and first order molecular connectivity indices (°χv and ¹χv).

SYNTHESIS, ANTIMICROBIAL, ANTICANCER EVALUATION AND QSAR STUDIES OF THIAZOLIDIN-4-ONE DERIVATIVES.

In this study, a novel series of 4-thiazolidinone derivatives (1-17) was synthesized and evaluated for its in vitro antimicrobial and anticancer potentials. N-(2-(5-(4-nitrobenzylidene)-2-(4-chlorophenyl)-4-oxothia- zolidin-3-ylamino)-2-oxoethyl) benzamide (7, pMICam = 1.86 µM/mL) was found to be the most active antimi- crobial agent. The anticancer study results demonstrated that N-(2-(5-(4-hydroxybenzylidene)-2-(4- methoxyphenyl)-4-oxothiazolidin-3-ylamino)-2-oxoethyl) benzamide (10, IC50 = 18.59 µM) was the most active anticancer agent. QSAR studies indicated the importance of topological parameter, Kier's α third order shape index (κα3) as well as electronic parameters, cosmic total energy (cos E) and energy of highest occupied molecular orbital (HOMO) in describing the antimicrobial activity of synthesized compounds.

Enhancement of ß-secretase inhibition and antioxidant activities of tempeh, a fermented soybean cake through enrichment of bioactive aglycones.

CONTEXT: Soybean and its fermented products are the most common source of isoflavones in human food. OBJECTIVE: The present study quantifies the major glycosides and aglycones in soybean and its fermented product tempeh isoflavone extracts. The comparision of antioxidant effects and BACE1 inhibitory activity between the isoflavones of soybean and tempeh were also established. MATERIALS AND METHODS: The major isoflavones such as daidzein and genistein (aglycones), and their sugar conjugates (glycosides) daidzin and genistin in soybean and tempeh isoflavones were quantified using HPLC analysis. Comparative studies on BACE 1 (ß-site amyloid precursor protein cleaving enzyme 1 or ß-secretase 1) inhibition and free-radical scavenging activities (diphenyl-1-picrylhydrazyl (DPPH) and ferrous ion chelating ability) were conducted. RESULTS: The amount of actives (mg/100 g) in soybean isoflavone compared with tempeh isoflavone is as follows: daidzein 16.72 mg/100 g versus 38.91 mg/100 g, genistein 11.10 mg/100 g versus 24.03 mg/100 g, daidzin 6.16 mg/100 g versus 0.69 mg/100 g, and genistin 24.61 mg/100 g versus 6.57 mg/100 g. The IC50 values of soybean and tempeh isoflavones against BACE1 were 10.87 and 5.47 mg/ml, respectively. The tempeh isoflavone had a more potent DPPH free-radical scavenging activity (IC50 = 2.67 mg/ml) than the soybean isoflavone (IC50 = 10 mg/ml). The ferrous ion chelating ability of the isoflavones was practically similar (IC50 = 10.40 mg/ml, soybean and 11.13 mg/ml, tempeh). DISCUSSION AND CONCLUSION: The present study indicates that tempeh is a healthy supplement to alleviate oxidative stress through the enrichment of aglycones.

Assessing the Influence of Intermittent Alcohol Access on Acrylamide-Induced Neuronal Toxicity in an Experimental Rat Model.

Tobacco and alcohol have been identified as health risk behaviors associated with significant unfavorable health consequences, ranking within the list of the top ten causes of mortality and disability-adjusted life years (DALY). The combustion of tobacco leads to the formation of acrylamide (ACR), which is well known for its neurotoxic effects. Similarly, alcohol consumption has also been widely recognized for its neurotoxic effects. Both substances can affect neurons and neuroglia cells through various pathways. This study sought to examine the impacts of co-administration of ACR and intermittent-access ethanol (IAE) consumption over a period of one month. The experimental group received 20 mg/kg of ACR, administered orally, along with IAE of 20% ethanol sessions lasting 24 h, three times per week. The cognitive outcomes were assessed utilizing the elevated plus maze (EPM), which was employed as a means of assessing the capability to learn and remember, the novel object recognition (NOR) test, which was employed to assess recognition memory, and the Y-maze, which was used to explore a new environment and navigate. Additionally, ELISA assays were performed to examine underlying mechanisms, including markers associated with inflammation (NF-κB, PGE2, and TNF-α), apoptosis (Bcl2, Bax, and Caspase-3), and oxidative stress (MDA, catalase, and GSH). These markers were assessed in the brain homogenate as part of the investigation. Furthermore, a histopathological study was conducted. The findings indicated that NF-κB levels increased significantly in the combination of ACR and IAE groups (ACR + IAE) compared to either the ACR-alone or IAE-alone groups. However, parallel changes were observed in TNF-α, PGE2, Bax, Bcl-2, Caspase-3, GSH, and CAT levels when comparing the ACR + IAE group to the ACR-alone group. Comparable alterations were noted between the ACR + IAE treatment and IAE-alone groups in TNF-α, Bcl-2, MDA, GSH, and CAT levels. Moreover, the histopathological analysis revealed significant changes between the ACR + IAE and the ACR- or IAE-alone groups. Regarding memory parameters assessed using tests including EPM, NOR, and Y-maze, considerable changes were observed across all treatment groups as opposed to the control. Surprisingly, there were no notable differences in the NOR and Y-maze tasks between the alone and combination treatment. Further study is necessary to explore the long-term alteration of co-administering ACR and IAE on behavior, memory, and neurotoxicity-related mechanisms, in order to elucidate their combined effects more clearly.