Decrease In Acetylcholinesterase Activity Research Articles

Brain cholinergic alterations in rats subjected to repeated immobilization or forced swim stress on lambda-cyhalothrin exposure

Role of immobilization stress (IMS), a psychological stressor and forced swim stress (FSS), a physical stressor was investigated on the neurobehavioral toxicity of lambda-cyhalothrin (LCT), a new generation type-II synthetic pyrethroid. Pre-exposure of rats to IMS (15 min/day) or FSS (3 min/day) for 28 days on LCT (3.0 mg/kg body weight, p.o.) treatment for 3 days resulted to decrease spatial learning and memory and muscle strength associated with cholinergic-muscarinic receptors in frontal cortex and hippocampus as compared to those exposed to IMS or FSS or LCT alone. Decrease in acetylcholinesterase activity, protein expression of ChAT and PKC-β1 associated with decreased mRNA expression of CHRM2, AChE and ChAT in frontal cortex and hippocampus was also evident in rats pre-exposed to IMS or FSS on LCT treatment, compared to rats exposed to IMS or FSS or LCT alone. Interestingly, changes both in behavioral and neurochemical endpoints were marginal in rats subjected to IMS or FSS for 28 days or those exposed to LCT for 3 days alone, compared to controls. The results suggest that stress is an important contributor in LCT induced cholinergic deficits.

Propensity of Withania somnifera to Attenuate Behavioural, Biochemical, and Histological Alterations in Experimental Model of Stroke.

The present study was designed to evaluate the beneficial effects of Withania somnifera (WS) pre-supplementation on middle cerebral artery occlusion (MCAO) model of ischemic stroke. Ischemic stroke was induced in the rats by inserting intraluminal suture for 90min, followed by reperfusion injury for 24h. The animals were assessed for locomotor functions (by neurological deficit scores, narrow beam walk and rotarod test), cognitive and anxiety-like behavioural functions (by morris water maze and elevated plus maze test). MCAO animals showed significant impairment in locomotor and cognitive functions. Neurobehavioural changes were accompanied by decreased acetylcholinesterase activity, increased oxidative stress in terms of enhanced lipid peroxidation and lowered thiol levels in the MCAO animals. In addition, MCAO animals had cerebral infarcts and the presence of pycnotic nuclei. Single-photon emission computerized tomography (SPECT) of MCAO animals revealed a cerebral infarct as a hypoactive area. On the other hand, pre-supplementation with WS (300mg/kg body weight) for 30days to MCAO animals was effective in restoring the acetylcholinesterase activity, lipid peroxidation, thiols and attenuated MCAO induced behavioural deficits. WS significantly reduced the cerebral infarct volume and ameliorated histopathological alterations. Improved blood flow was observed in the SPECT images from the brain regions of ischemic rats pre-treated with WS. The results of the study showed a protective effect of WS supplementation in ischemic stroke and are suggestive of its potential application in stroke management.

Neurobehavioral and biochemical changes in Nauphoeta cinerea following dietary exposure to chlorpyrifos

The present study aimed to increase our understanding about the mode of toxic action of organophosphate pesticides in insects by evaluating the biochemical and neurobehavioral characteristics in Nauphoeta cinerea exposed to chlorpyrifos (CPF)-contaminated diet. The insects were exposed for 35 consecutive days to CPF at 0.078, 0.15625, 0.3125 and 0.625μg/g feed. Locomotor behavior was assessed for a 10-min trial in a novel arena and subsequently, biochemical analyses were carried out using the cockroaches’ heads. In comparison to control, CPF-exposed cockroaches showed significant decreases in the total distance traveled, body rotation, turn angle and meandering, along with significant increase in the number of falls, time and episodes of immobility. The marked decrease in the exploratory profiles of CPF-exposed cockroaches was confirmed by track plots, whereas occupancy plot analyses showed a progressive dispersion at 0.15625μg/g feed group. Moreover, the heads of CPF-exposed cockroaches showed marked decrease in acetylcholinesterase activity and antioxidant status with concomitant significant elevation in dichlorofluorescein oxidation and lipid peroxidation levels in CPF-treated cockroaches. Gas Chromatography–Mass Spectrometry analyses revealed bioaccumulation of CPF in cockroaches exposed to concentrations above 0.078μg/g feed. The findings from this investigation showed N. cinerea as a value model organism for the risk assessment of environmental organophosphate contamination in insects.

In Vitro Biomarker Responses of Earthworm Lumbricus terrestris Exposed to Herbicide Sekator and Phosphate Fertilizer

Earthworms are important soil macroinvertebrates and are often used in assessing soil pollution. The present study was conducted in order to investigate the effect of two compounds, triple superphosphate (TSP; fertilizer), sekator (herbicide), and their mixture at two agricultural doses on a Lumbricus terrestris population. Neurotoxicity (acetylcholinesterase (AChE)), metabolization (glutathione-S-transferase (GST)), glutathione (GSH), and protein content were evaluated as biomarkers. Treated earthworms with sekator showed a non-significant increase of protein content (p > 0.05). In contrast, protein content increased significantly (p < 0.0001) up to (104.75 ± 4.75 and 109.09 ± 5.4 μg/worm) after 72 h of exposure with TSP and the mixture, respectively. As compared with TSP exposure, sekator in mixture substantially decreased AChE activity. In control series, the GST activities and GSH concentrations remain stable after 72 h while sekator and TSP induced the biomarker responses, which was proportional to exposure time and administered dose. Non-significant correlations were recorded between AChE and GSH, GST and the protein contents in most interactions. The obtained results indicate that application of sekator in mixture with triple superphosphate could have harmful effects on earthworms since it caused significant changes in measured biomarkers.

Effects of realistic concentrations of TiO₂ and ZnO nanoparticles in Prochilodus lineatus juvenile fish.

The impact of nanoparticles on fish health is still a matter of debate, since nanotechnology is quite recent. In this study, freshwater benthonic juvenile fish Prochilodus lineatus were exposed through water to three concentrations of TiO2 (0.1, 1, and 10 μg l(-1)) and ZnO (7, 70, and 700 μg l(-1)) nanoparticles, as well as to a mixture of both (TiO2 1 μg l(-1) + ZnO 70 μg l(-1)) for 5 and 30 days. Nanoparticle characterization revealed an increase of aggregate size in the function of concentration, but suspensions were generally stable. Fish mortality was high at subchronic exposure to 70 and 700 μg l(-1) of ZnO. Nanoparticle exposure led to decreased acetylcholinesterase activity either in the muscle or in the brain, depending on particle composition (muscle-TiO2 10 μg l(-1); brain-ZnO 7 and 700 μg l(-1)), and protein oxidative damage increased in the brain (ZnO 70 μg l(-1)) and gills (ZnO 70 μg l(-1) and mixture) but not in the liver. Exposed fish had more frequent alterations in the liver (necrosis, vascular congestion, leukocyte infiltration, and basophilic foci) and gills (hyperplasia and epithelial damages, e.g., epithelial disorganization and epithelial loss) than the control fish. Thus, predicted concentrations of TiO2 and ZnO nanoparticles caused detectable effects on P. lineatus that may have important consequences to fish health. But, these effects are much more subtle than those usually reported in the scientific literature for high concentrations or doses of metal nanoparticles.

Activity of cholinesterases, pyruvate kinase and adenosine deaminase in rats experimentally infected by Fasciola hepatica: Influences of these enzymes on inflammatory response and pathological findings

The aim of this study was to investigate acetylcholinesterase (AChE) in total blood and liver tissue; butyrylcholinesterase (BChE) in serum and liver tissue; adenosine deaminase (ADA) in serum and liver tissue; and pyruvate kinase (PK) in liver tissue of rats experimentally infected by Fasciola hepatica. Animals were divided into two groups with 12 animals each, as follows: group A (uninfected) and group B (infected). Samples were collected at 20 (A1 and B1;n=6 each) and 150 (A2 and B2; n=6 each) days post-infection (PI). Infected animals showed an increase in AChE activity in whole blood and a decrease in AChE activity in liver homogenates (P<0.05) at 20 and 150 days PI. BChE and PK activities were decreased (P<0.05) in serum and liver homogenates of infected animals at 150 days PI. ADA activity was decreased in serum at 20 and 150 days PI, while in liver homogenates it was only decreased at 150 days PI (P<0.05). Aspartate aminotransferase and alanine aminotransferase activities in serum were increased (P<0.05), while concentrations of total protein and albumin were decreased (P<0.05) when compared to control. The histological analysis revealed fibrous perihepatitis and necrosis. Therefore, we conclude that the liver fluke is associated with cholinergic and purinergic dysfunctions, which in turn may influence the pathogenesis of the disease.

Polysaccharides from Flammulina velutipes improve scopolamine-induced impairment of learning and memory of rats

Flammulina velutipes has been reported to be beneficial in learning and memory capabilities, but the mechanisms underlying this remain unclear. In this study, Morris water maze and biochemical analyses of rat brain were used to evaluate the effects of F. velutipes polysaccharides (FVP) on scopolamine-induced learning and memory impairments. Results suggested that FVP significantly decreased the escape latency and total swimming distance of rats in the hidden platform test and increased the numbers of platform crossing and swimming distance of rats in the probe test. Biochemical examinations revealed that FVP significantly elevates SOD and GSH-Px activities, as well as neurotransmitter levels. The increased acetylcholine content owed to the increased acetylcholine acetyltransferase activity and decreased acetylcholinesterase activity. Moreover, learning and memory associated signalling pathways were activated by FVP elevating the expression of connexin 36 and p-CaMK II. These results conclusively proved that FVP is a potent agent against the progression of cognitive impairment.

Biomarkers of environmental stress in gills of Pinna nobilis (Linnaeus 1758) from Balearic Island

In aquatic environments, bivalve molluscs are used as sentinel species for environmental biomonitoring. In this study Pinna nobilis specimens, the biggest Mediterranean bivalve, were collected in the Magaluf bay (Mallorca), a touristic location and in a pristine area of the Cabrera National Park as the control location. Histological and histochemical analysis in gills of specimens sampled from Magaluf exhibited evident tissue alterations with high presence of haemocytes. Lower acetylcholinesterase (AChE) activity and protein expression were also found in the gills of specimens collected from Magaluf compared with the control area. The determination of antioxidant enzyme activities, such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, showed a higher activities of these antioxidant enzymes and total glutathione content in samples from Magaluf bay than in Cabrera. In conclusion, the present study demonstrated that human activities result in morphological tissue alterations and a reduced AChE activity in gills of P. nobilis. Moreover, these stressful environmental conditions induced an adaptive response in P. nobilis as evidenced by increased antioxidant defences and a decreased AChE activity. CapsuleThe human activities induce oxidative stress in P. nobilis as evidenced by increased antioxidant defences and a decreased acetylcholinesterase activity.

Transcriptomic, Biochemical, and Histopathological Responses of the Clam Ruditapes decussatus from a Metal-Contaminated Tunis Lagoon.

This study was designed to investigate the molecular (transcriptional expression), biochemical (oxidative stress and neurotoxicity), and histopathological effects of metal contamination in the gill of clams (Ruditapes decussatus) sampled from the Tunis lagoon. The concentrations of five heavy metals (Cd, Pb, Hg, Cu, and Zn) in surface sediments and their accumulation in soft tissues of R. decussatus were evaluated in three sites (Z1, Z2, and Z3). A metal contamination state of Tunis lagoon sediments was noted with spatial variations with relatively high levels at Z2. Biomarker analyses showed an increase in glutathione S-transferase and catalase activities and lipid peroxidation levels and a decrease in acetylcholinesterase activity in the studied sites. Molecular investigation showed a significant overexpression of: cytochrome c oxidase subunit I, ribosomal RNA 16S, Cu/Zn superoxide dismutase, heat shock protein 70, and metallothioneins in the three sampling sites. Moreover, our data were correlated to severe and diverse histopathological alterations in the clam gills. The principal component analysis showed that the Z2 region is more affected by metal contamination than Z1 and Z3 regions. Current field results suggest the use of several combined biomarkers at different cell levels instead of individual ones in monitoring programs.

Assessment of water pollution in the Brazilian Pampa biome by means of stress biomarkers in tadpoles of the leaf frog Phyllomedusa iheringii (Anura: Hylidae).

The Brazilian Pampa biome is currently under constant threat due to increase of agriculture and improper management of urban effluents. Studies with a focus on the assessment of impacts caused by human activities in this biome are scarce. In the present study, we measured stress-related biomarkers in tadpoles of the leaf frog Phyllomedusa iheringii, an endemic species to the Pampa biome, and tested its suitability as a bioindicator for the assessment of potential aquatic contamination in selected ponds (S1 and S2) nearby agricultural areas in comparison to a reference site. A significant decrease in acetylcholinesterase activity was observed in S2 when compared to S1 and reference. The levels of total-hydroperoxides were increased in S2 site. In parallel, increased activity of the antioxidant enzymes catalase, superoxide dismutase and glutathione S-transferase were observed in S2 when compared to S1 and reference. Further studies are necessary in order to correlate the changes observed here with different chemical stressors in water, as well as to elucidate mechanisms of toxicity induced by pesticides in amphibian species endemic to the Pampa biome. Nevertheless, our study validates Phyllomedusa iheringii as a valuable bioindicator in environmental studies.

The role of multifunctional drug therapy against carbamate induced neuronal toxicity during acute and chronic phase in rats

The current study has been designed to examine the effect of multifunctional drug therapy on carbofuran induced acute (2.187mg/kg, s.c.) and sub-acute (0.2187mg/kg, s.c.) neurotoxicity in male wistar rats. Drug treatment which includes nimodipine (Ca2+ channel blocker), diazepam, ropinirole (dopamine agonist) and GSPE (antioxidant) was started 2h after carbofuran administration. Morris water maze was employed for aiming spatial memory. Narrow beam walk and rotarod were employed for testing motor functions. Brain acetylcholinesterase activity, thiobarbituric acid reactive species, nitrite, reduced glutathione, catalase levels, and mitochondrial complexes were also estimated. Carbofuran treatment resulted in significant development of cognitive and motor functions manifested as impairment in learning and memory along with increased thiobarbituric acid reactive species, nitrite levels and decreased acetylcholinesterase activity, reduced glutathione, catalase levels, and mitochondrial complexes. The standard antidote therapy (atropine) was not able to provide neuroprotection but was able to provide symptomatic relief. The multifunctional drug therapy attenuated carbofuran induced cognitive and motor dysfunction, acetylcholinesterase activity and other biochemical parameters. The triple combination in sub-acute study may be avoided in future as two drug combinations provide adequate neuroprotection. Thus it can be concluded that standard antidotal therapy may not provide neuroprotection while the multifunctional drug therapy offers neuroprotection against carbofuran and may dramatically increase survival and life quality.

Acetylcholinesterase is associated with a decrease in cell proliferation of hepatocellular carcinoma cells

Acetylcholinesterase (AChE), the enzyme that rapidly splits acetylcholine into acetate and choline, presents non-cholinergic functions through which may participate in the control of cell proliferation and apoptosis. These two features are relevant in cancer, particularly in hepatocellular carcinoma (HCC), a very aggressive liver tumor with high incidence and poor prognosis in advanced stages. Here we explored the relation between acetylcholinesterase and HCC growth by testing the influence of AChE on proliferation of Huh-7 and HepG2 cell lines, addressed in monolayer cultures, spheroid formation and human liver tumor samples. Results showed a clear relation in AChE expression and cell cycle progression, an effect which depended on cell confluence. Inhibition of AChE activity led to an increase in cell proliferation, which was associated with downregulation of p27 and cyclins. The fact that Huh-7 and HepG2 cell lines provided similar results lent weight to the relationship of AChE expression with cell cycle progression in hepatoma cell lines at least. Human liver tumor samples exhibited a decrease in AChE activity as compared with normal tissue. The evidence presented herein provides additional support for the proposed tumor suppressor role of AChE, which makes it a potential therapeutic target in therapies against hepatocellular carcinoma.

Olfactory Dysfunction and Neurotransmitter Disturbance in Olfactory Bulb of Transgenic Mice Expressing Human A53T Mutant α-Synuclein

Parkinson disease is a multi-system neurodegenerative disease characterized by both motor and non-motor symptoms. Hyposmia is one of the early non-motor symptoms occurring in more than 90% of Parkinson disease cases, which can precede motor symptoms even several years. Up to now, the relationship between hyposmia and Parkinson disease remains elusive. Lack of proper animal models of hyposmia restricts the investigation. In this study we assessed olfactory function in Prp-A53T-α-synuclein transgenic (αSynA53T) mice which had been reported to show age-dependent motor impairments and intracytoplasmic inclusions. We also examined cholinergic and dopaminergic systems in olfactory bulb of αSynA53T mice by immunofluorescent staining, enzyme linked immunosorbent assay and western blot. We found that compared to wild type littermates, αSynA53T mice at 6 months or older displayed a deficit of odor discrimination and odor detection. No significant changes were found in olfactory memory and odor habituation. Furthermore compared to wildtype littermates, in olfactory bulb of αSynA53T mice at 10 months old we detected a marked decrease of cholinergic neurons in mitral cell layer and a decrease of acetylcholinesterase activity, while dopaminergic neurons were found increased in glomerular layer, accompanied with an increase of tyrosine hydroxylase protein. Our studies indicate that αSynA53T mice have olfactory dysfunction before motor deficits occur, and the cholinergic and dopaminergic disturbance might be responsible for the Parkinson disease-related olfactory dysfunction.

Inhibitory effects of sodium arsenite and acacia honey on acetylcholinesterase in rats.

This study was conducted to investigate the effect of sodium arsenite and Acacia honey on acetylcholinesterase (AChE) activity and electrolytes in the brain and serum of Wistar rats. Male Wistar albino rats in four groups of five rats each were treated with distilled water, sodium arsenite (5 mg/kg body weight), Acacia honey (20% v/v), and sodium arsenite and Acacia honey, daily for one week. The sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the brain with the combined treatment being more potent. Furthermore, sodium arsenite and Acacia honey significantly (P < 0.05) decreased AChE activity in the serum. Strong correlation was observed between the sodium and calcium ion levels with acetylcholinesterase activity in the brain and serum. The gas chromatography mass spectrometry analysis of Acacia honey revealed the presence of a number of bioactive compounds such as phenolics, sugar derivatives, and fatty acids. These findings suggest that sodium arsenite and/or Acacia honey modulates acetylcholinesterase activities which may be explored in the management of Alzheimer's diseases but this might be counteracted by the hepatotoxicity induced by arsenics.

A three generation study with effect of imidacloprid in rats: Biochemical and histopathological investigation

Objectives:This study was designed to evaluate the dose-dependent toxic effects of imidacloprid on the female ratsthat were treated through three generations (F0, F1, and F2). F2 female rats were sacrificed at the end of the experiment to see the long-term effect of imidacloprid.Materials and Methods:Rats were divided into three groups of 6 each. Group I served as control. Group II served as treated I and given 1/45th LD50 (10 mg/kg/day) of imidacloprid. Group III served as treated II and given 1/22th LD50 (20 mg/kg/day) of imidacloprid. After 60 days, oral administration of imidacloprid females were mated with normal males to get F1 and F2 generation. F2 generation female rats were sacrificed at the end of the experiment. Biochemical and a histopathological investigation was done for three groups of F2 generation and statistically analyzed by ANOVA.Results:Average feed intake of F2 female rats was significantly reduced (P < 0.01) at 20 mg/kg/day dose of imidacloprid. There was a significant increase in the activity of alanine aminotransferase, AKP, and glucose 6-phosphate dehydrogenase in Group III rats of F2 generation. There was a significant decrease in acetylcholine esterase activity in plasma and brain of both the imidacloprid treated groups. Tissue samples of liver, kidney, and brain of females of F2 generation showed histopathological condition.Conclusion:The results indicated that imidacloprid at a dose of 20 mg/kg bw/day exerts significant toxicological effects on biochemical and histological studies of F2 generation females as compare to 10 mg/kg bw/day.

Bacopa monniera (CDRI-08) Upregulates the Expression of Neuronal and Glial Plasticity Markers in the Brain of Scopolamine Induced Amnesic Mice.

Preclinical studies on animal models have discerned the antiamnesic and memory-enhancing potential of Bacopa monniera (Brahmi) crude extract and standardized extracts. These studies primarily focus on behavioral consequences. However, lack of information on molecular underpinnings has limited the clinical trials of the potent herb in human subjects. In recent years, researchers highlight plasticity markers as molecular correlates of amnesia and being crucial to design therapeutic targets. In the present report, we have investigated the effect of a special extract of B. monniera (CDRI-08) on the expression of key neuronal (BDNF and Arc) and glial (GFAP) plasticity markers in the cerebrum of scopolamine induced amnesic mice. Pre- and postadministration of CDRI-08 ameliorated amnesic effect of scopolamine by decreasing acetyl cholinesterase activity and drastically upregulating the mRNA and protein expression of BDNF, Arc, and GFAP in mouse cerebrum. Interestingly, the plant extract per se elevated BDNF and Arc expression as compared to control but GFAP was unaltered. In conclusion, our findings provide the first molecular evidence for antiamnesic potential of CDRI-08 via enhancement of both neuronal and glial plasticity markers. Further investigations on detailed molecular pathways would encourage therapeutic application of the extract in memory disorders.

Calotropis procera: A potential cognition enhancer in scopolamine and electroconvulsive shock-induced amnesia in rats.

Objectives:Present study evaluates the effect of Calotropis procera (Apocynaceae) dry latex on cognitive function in rats using scopolamine and electroconvulsive shock (ECS) induced amnesia model.Materials and Methods:Male Wistar rats were pretreated with 200, 400 and 800 mg/kg of C. procera dry latex in scopolamine-induced amnesia model. Dose showing maximum effect in cognitive performance was selected and further evaluated using scopolamine and ECS-induced amnesia model for its effect on neurochemical enzymes and cognitive performance. Acetylcholinesterase (AChE) activity, β amyloid1-42, and dopamine level were analyzed, while the cognitive performance was assessed by elevated plus maze, step-through passive avoidance test, and Morris water maze. Simultaneously, C. procera dry latex (25, 50, 100, 250, 500, and 1000 μg/mL) was screened for in vitro AChE inhibition assay.Results:Pretreatment with (200, 400 and 800 mg/kg) C. procera dry latex shows dose dependent increase in cognitive performance in scopolamine-induced amnesia. Further, pretreatment with the selected dose (800 mg/kg) showed significant improvement in transfer latency (P < 0.001, P < 0.01), escape latency (P < 0.05), time spent in target quadrant (P < 0.001) also significant decrease in AChE activity (P < 0.05), β amyloid1-42 level (P < 0.001), and increase in dopamine level (P < 0.01) in rat brain homogenate when compared with scopolamine and ECS disease control groups. IC50 for C. procera dry latex was found to be <1000 μg/mL.Conclusions:Pretreatment with C. procera dry latex (800 mg/kg) produced significant cognition enhancement by improving cognitive performance and decreasing the marker neurochemical enzyme activity in scopolamine and ECS-induced amnesia model.

Biochemical and molecular evidences on the protection by magnesium oxide nanoparticles of chlorpyrifos-induced apoptosis in human lymphocytes.

Background:Chlorpyrifos (CP) is one of the most widely used organophosphate (OP) insecticides in agricultural and residential pest control with its attendant adverse health effect. In the present study, it is proposed to investigate the possible modulatory role of magnesium oxide nanoparticles (MgO NPs) against CP-induced toxicity in human lymphocytes and determine the mechanisms lying behind this protection by viability and biochemical assays.Materials and Methods:Isolated lymphocytes were exposed to 12 μg/mL CP either alone or in combination with different concentrations of MgO NPs (0.1 μg/mL, 1 μg/mL, 10 μg/mL, and 100 μg/mL). After a 3-day incubation, the viability and oxidative stress markers including cellular mitochondrial activity, caspase-3 and -9 activities, total antioxidant power, lipid peroxidation, and myeloperoxidase (MPO) activity were measured. Also, the levels of tumor necrosis factor-α (TNF-α) as inflammatory index, along with acetylcholinesterase (AChE) activity were measured. Statistical differences were determined using one-way analysis of variance (ANOVA) and Dunnett's multiple comparison tests.Results:It is indicated that CP-exposed lymphocytes treated with MgO NPs resulted in a substantial reduction in the pace of mortality as well as the stages of oxidative stress in a dose-dependent manner. Also, MgO NPs (100 μg/mL) meaningfully restored CP-induced increase of TNF-α (P < 0.001) and decrease of AChE activity (P < 0.001) and were capable of preventing CP-treated human lymphocytes from apoptosis (P < 0.001).Conclusion:Our results demonstrate that MgO NPs in approximate 100 nm diameter not only make cells resistant to the toxic properties of CP but also attenuate toxic effects of CP, which is demonstrating the potential of MgO NPs to be applied in future immune deficiency therapeutic strategies.

Changes in immunity parameters and blood cytokine concentrations after chronic nitrile acrylate intoxication.

Experiments on outbred albino rats showed that chronic nitrile acrylate intoxication (60 days, 0.05 LD50 per day subcutaneously) led to reduction of T-dependent humoral immune response (T-independent humoral immune response was less affected); parameters cell immunity were suppressed to a greater extent than parameters of humoral immune reactions. Equal attenuation of the functions of Th1 and Th2 lymphocytes, decrease of the blood levels of immunoregulatory, pro- and anti-inflammatory cytokines (IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-13), and decrease of acetyl cholinesterase activity in thymic and splenic T lymphocytes were observed.

Inhibiting β-amyloid-associated Alzheimer's pathogenesis in vitro and in vivo by a multifunctional dimeric bis(12)-hupyridone derived from its natural analogue.

Fibrillar aggregates of β-amyloid protein (Aβ) is the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit the formation of Aβ fibrils and block Aβ fibrils-associated toxicity may have therapeutic potential to combat AD. Bis(12)-hupyridone (B12H) is a multifunctional homodimer derived from huperzine A, which is an anti-AD drug in China. In the current study, the inhibitory effect of B12H on the formation of Aβ fibrils and their associated toxicity was investigated both in vitro and in vivo. By using Thioflavin T fluorescence assay, we found that B12H (0.3-3μM) directly inhibited Aβ fibrils formation following co-incubation of B12H and Aβ1-40 at 37°C for 6days in vitro. However, huperzine A, at the same concentrations, did not show significant inhibitory effect on Aβ1-40 fibrils formation. Moreover, B12H markedly reduced Aβ1-40-induced cytotoxicity in cultured SH-SY5Y cells, as evidenced by the increase in cell viability, the decrease in lactate dehydrogenase release, and the reduction of apoptotic nuclei. Most importantly, B12H (0.2 and 0.4mg/kg) reduced intracerebroventricular Aβ1-40 infusion-induced cognitive and memory impairments in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with increasing choline acetyltransferase activity and decreasing acetylcholinesterase activity. Collectively, our study provided novel sights into the potential application of B12H in AD treatment.