Hyperthyroidism-Induced Upregulation of Neurodegeneration-Related Gene Expression in Metaplasticity-Induced Hippocampus.

INTRODUCTION: Thyroid hormones, which produce critical changes in our bodies even when their physiological levels alter slightly, are crucial hormones that influence gene transcription. Neuronal plasticity, on the other hand, requires both the activation of local proteins as well as protein translation and transcription in response to external signals. So far, no study has examined metaplastic long-term potentiation (LTP) and related gene expression levels in a hyperthyroid experimental model. METHODS: The Wistar male rats were administered 0.2 mg/kg/day of l-thyroxine for 21 days to induce hyperthyroidism. Perforant path was primed with 1-Hz low-frequency stimuli (LFS) for 900 s to investigate metaplasticity responses. The LFS was followed by high-frequency stimuli (HFS, 100 Hz) after 5 min. Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude were recorded from the granule cell layer of the dentate gyrus. The mRNA levels of genes related to neurodegeneration (Gsk-3ß, Cdk5, Akt1, Mapt, p35, Capn1, Bace1, and Psen2) were measured using the RT-PCR method for the stimulated hippocampus. RESULTS: Similar to euthyroid rats, hyperthyroid animals had a lower EPSP slope and PS after LFS. Depression of EPSP prevented subsequently induced EPSP-LTP, although HFS was able to elicit PS-LTP despite depression of PS amplitude in both groups. Despite similarities in metaplastic LTP responses, these electrophysiological findings were accompanied by increased Akt, Bace1, Cdk5, and p35-mRNA expressions and decreased Gsk-3ß mRNA expression in hyperthyroid rats' hippocampus. CONCLUSION: These data support the view that in thyroid hormone excess, the mechanism that keeps synaptic efficacy within a dynamic range occurs concurrently with increased mRNA expression of neurodegeneration-related genes. Our study encourages further examination of the increased risk of neurodegenerative disease in hyperthyroidism.

Pentoxifylline as Add-On Treatment to Donepezil in Copper Sulphate-Induced Alzheimer's Disease-Like Neurodegeneration in Rats.

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by behavioral, cognitive, and progressive memory impairments. Extensive neuronal loss, extracellular accumulation of insoluble senile amyloid-ß (Aß) plaques, and intracellular neurofibrillary tangles (NFTs) are the major pathological features. The present study aimed to investigate the therapeutic effect of donepezil (DON) and pentoxifylline (PTX) in combination to combat the neurodegenerative disorders (experimental AD) induced by CuSO4 intake in experimental rats. Thirty adult male Wistar rats (140-160 g) were used in this study. AD was first induced in rats by CuSO4 supplement to drinking water (10 mg/L) for 14 weeks. The AD group received no further treatment. Oral treatment with DON (10 mg/kg/day), PTX (100 mg/kg/day), or DON + PTX for the other three groups was started from the 10th week of CuSO4 intake for 4 weeks. Cortex markers like acetylcholine (ACh), acetylcholinesterase (AChE), total antioxidant capacity (TAC), and malondialdehyde (MDA) and hippocampus markers like ß-amyloid precursor protein cleaving enzyme 1 (BACE1), phosphorylated Tau (p-tau), Clusterin (CLU), tumor necrosis factor-α (TNF-α), caspase-9 (CAS-9), Bax, and Bcl-2 were measured. The histopathology studies were done by using hematoxylin and eosin and Congo red stains as well as immunohistochemistry for neurofilament. CuSO4 induced adverse histological and biochemical changes. The histological injury in the hippocampus was inhibited following the administration of the DON and PTX. The brain tissue levels of AChE, MDA, BACE1, p-tau, CLU, CAS-9, Bax, and TNF-α were significantly increased, while brain tissue levels of ACh, TAC, and Bcl-2 were significantly decreased in CuSO4-treated rats as compared with the untreated control group. The effects induced by either DON or PTX on most studied parameters were comparable. Combined treatment of DON and PTX induced remarkable results compared with their individual use. However, more clinical and preclinical studies are still required to further confirm and prove the long-term efficacy of such combination.

Dauricine alleviates cognitive impairment in Alzheimer's disease mice induced by D-galactose and AlCl3 via the Ca2+/CaM pathway.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. Dysregulation of intracellular Ca2+ homeostasis plays a critical role in the pathological development of AD. Dauricine (DAU) is a bisbenzylisoquinoline alkaloid isolated from Menispermum dauricum DC., which can prevent the influx of extracellular Ca2+ and inhibit the release of Ca2+ from the endoplasmic reticulum. DAU has a potential for anti-AD. However, it is unclear whether DAU can exert its anti-AD effect in vivo by regulating the Ca2+ related signaling pathways. Here, we investigated the effect and mechanism of DAU on D-galactose and AlCl3 combined-induced AD mice based on the Ca2+/CaM pathway. The results showed that DAU (1 mg/kg and 10 mg/kg for 30 days) treatment attenuated learning and memory deficits and improved the nesting ability of AD mice. The HE staining assay showed that DAU could inhibit the histopathological alterations and attenuate neuronal damage in the hippocampus and cortex of AD mice. Studies on the mechanism indicated that DAU decreased the phosphorylation of CaMKII and Tau and reduced the formation of NFTs in the hippocampus and cortex. DAU treatment also reduced the abnormally high expression of APP, BACE1, and Aß1-42, which inhibited the deposition of Aß plaques. Moreover, DAU could decrease Ca2+ levels and inhibit elevated CaM protein expression in the hippocampus and cortex of AD mice. The molecular docking results showed that DAU may have a high affinity with CaM or BACE1. DAU has a beneficial impact on pathological changes in AD mice induced by D-galactose and AlCl3 and may act by negative regulation of the Ca2+/CaM pathway and its downstream molecules such as CaMKII and BACE1.

Tannic acid inhibits lipopolysaccharide-induced cognitive impairment in adult mice by targeting multiple pathological features.

Tannic acid (TA) is a natural compound present abundantly in fruit such as grapes and green tea. In this study, we have evaluated the therapeutic efficacy of TA against Lipopolysaccharide (LPS)-induced oxidative stress-mediated memory impairment, neuroinflammation, insulin signaling impairment, and Amyloid Beta (Aß) deposition in adult male mice. The LPS was administered once per week and TA twice a week to adult male mice for three months consecutively. Behavioral studies were performed using different behavioral models such as balance beam, novel object recognition (NOR), Morris water maze (MWM), and Y-maze tests. The protein expression of different mediators such as TNF-α, p-JNK, pIRS636, BACE1, APP, and Aß was evaluated through western blot and immunofluorescence staining techniques. Biochemical assays were carried out to assess the antioxidant activities of TA. The computational study was conducted to predict the binding mode of TA with target sites of TNF-α. Behavioral studies showed that the TA-treated mice exhibited gradual memory improvement. TA significantly inhibited BACE1 activity and reduced production and accumulation of Aß in the hippocampus of mice brains. Moreover, the TA significantly inhibited LPS-induced ROS production and enhanced the glutathione levels. Furthermore, we have shown via the computational method for the first time that TA inhibits LPS-triggered TNF-á½° and its downstream signaling to reduce AD pathology including memory impairment, neuroinflammation, insulin signaling impairment, and Aß deposition in adult mice. Taken together our current study demonstrates that TA is a potential candidate for the abrogation of LPS-induced neurotoxicity and AD pathology in rodent's models.

Progress toward the discovery and development of efficacious BACE inhibitors.

BACE (beta-site amyloid precursor protein [APP] cleavage enzyme) is a transmembrane aspartyl protease responsible for the first cleavage event in the processing of APP to Abeta peptide. Amyloid plaques composed of Abeta peptides are hypothesized to be the root cause of neuronal cell death in Alzheimer's disease patients. Thus, BACE has become a target of significant interest for pharmaceutical and academic research. The recent literature relating to the discovery and development of efficacious BACE inhibitors is reviewed with particular emphasis on the patent literature.

Environmental allergens and asthma in urban elementary schools.

BACKGROUND: Asthma in school children is rising, and indoor allergens are very common triggers of asthma attacks; however, the risk of the school environment on asthma has not been well studied. OBJECTIVE: To determine the presence and the levels of common aeroallergens in schools, where asthma prevalence rates are high. METHODS: Settled dust samples were collected from 12 Baltimore City public elementary schools, and they were analyzed for the following allergens: cockroaches (Bla g 1/2), dust mites (Der f 1/p 1), dog (Can f 1), cat (Fel d 1), and mouse (Mus m 1). School asthma prevalence rates were correlated with allergen levels, and association between allergen levels and other risk factors present in the schools' environment was examined. RESULTS: The mean and range levels were 1.49 U/g (0 to 8) for Bla g 1/2; 0.38 microg/g (0 to 11.9) for the Der f 1/p 1; 1.44 microg/g (0.1 to 9.6) for Can f 1; 1.66 microg/g (0.2 to 12) for Fel d 1; and 6.24 microg/g (0.3 to 118.3) for Mus m 1. Dust mite, cat and dog allergens were significantly in rooms with carpet and/or area rugs, compared to rooms with bare floors (P < 0.05). Asthma prevalence rates varied from 11.8 to 20.8% between schools and positively correlation with the mean levels of Bla g 1/2 in the schools (P = 0.001). CONCLUSIONS: Common allergens that are known to trigger asthma were detected in all school environments, where asthma prevalence rates were high. However, the overall allergen levels were low, indicating that other factors, including exposures in the homes of asthmatic patients, may have more relevance to sensitization and symptoms than school exposures.

Indoor allergens and longitudinal FEV1 decline in older adults: the Normative Aging Study.

We investigated the relationship between home allergen exposure and decline in FEV1 in 10 asthmatic and 30 randomly selected, age-matched, nonasthmatic participants in the Normative Aging Study. We defined asthma as subject-reported wheezing apart from colds, with either a physician's diagnosis of asthma or a methacholine PD20 FEV1 of 8.6 micromol or less. We examined the relationship between the annual decline in FEV1 and the concentrations of the cockroach (Blattella germanica) allergens Bla g 1 and Bla g 2, the dust mite (Dermatophagoides pteronyssinus and Dermatophagoides farinae) allergens Der p 1 and Der f 1, and the cat (Felis domesticus) allergen Fel d 1 in house dust specimens. Bla g 1 (-79.8 ml/yr, p = 0.0006) and Bla g 2 (-40.81 ml/yr, p = 0.0004) were significant predictors of decline in FEV1 after adjustment for age, smoking, and baseline FEV1. These results were unchanged after elimination of the asthmatic subjects from the analysis. We conclude that cockroach allergen levels in homes is a risk factor for accelerated decline in FEV1 independent of airway responsiveness.

Exposure and sensitization to environmental allergen of predominantly Hispanic children with asthma in San Diego's inner city.

BACKGROUND: Environmental living conditions co-sorting with economic status may influence the disease morbidity rate of childhood asthma in ethnic minority urban poor populations. OBJECTIVES: This study was carried out to assess exposure and sensitization to environmental allergens in southeast San Diego children with current asthma-related symptoms and to determine the utility of environmental control measures. METHODS: Children, 9 to 12 years old, with current asthma-related symptoms were identified and enrolled at four school sites. Skin prick testing with aeroallergens was performed, and allergen in collected dust (from mattresses, pillows, and bedroom carpets) was quantified by enzyme immunoassay. Environmental control instruction and products were provided. RESULTS: Of 41 subjects who underwent skin testing, 51.2% were reactive to environmental allergens (39% to mite, 22% to cockroach, and 9.8% to cat). Mean allergen levels for sensitized subjects were: Der p 1 (11 subjects), 18,722 ng/gm dust; Der f 1 (8 subjects), 5345 ng/gm dust; Fel d 1 (3 subjects), 214 ng/gm dust; Bla 1 (8 subjects), 7.15 U/gm dust; and Bla 2 (8 subjects) 7.13 U/gm dust. Environmental allergen exposure levels were not significantly different between sensitized and nonsensitized subjects. Environmental control measures for mite exposure were completed in six homes of sensitized subjects. One month after treatment, allergen levels fell 91.2% for Der p 1, 98.9% for Der f 1, and 88.2% for Fel d 1. One year after treatment, mite and cat allergen levels remained low. Environmental control had no consistent impact on cockroach allergen levels. CONCLUSION: Environmental allergen sensitization and exposure may be cofactors contributing to increased disease severity in urban poor populations.

Atopic asthma caused by Candida albicans acid protease: case reports.

Two cases of atopic asthma caused by acid protease produced by Candida albicans are reported. Both patients had high levels of serum IgE antibodies against the acid protease and showed positive conjunctival and immediate bronchial responses when challenged with the protease. Significant histamine release was detected in both patients when their peripheral leukocytes were challenged with the protease antigen. These findings clearly showed that C. albicans acid protease is the causative allergen of atopic asthma.