Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity

Adenosine is a neuromodulator in the nervous system and it has recently been observed that pharmacological blockade or gene disruption of adenosine A(2A) receptors confers neuroprotection under different neurotoxic situations in the brain. We now observed that coapplication of either caffeine (1-25 micro M) or the selective A(2A) receptor antagonist, 4-(2-[7-amino-2(2-furyl)(1,2,4)triazolo (2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol (ZM 241385, 50 nM), but not the A receptor antagonist, 8-cyclopentyltheophylline (200 nM), prevented the neuronal cell death caused by exposure of rat cultured cerebellar granule neurons to fragment 25-35 of beta-amyloid protein (25 micro M for 48 h), that by itself caused a near three-fold increase of propidium iodide-labeled cells. This constitutes the first in vitro evidence to suggest that adenosine A(2A) receptors may be the molecular target responsible for the observed beneficial effects of caffeine consumption in the development of Alzheimer's disease.     

GABAA receptor pharmacology of fluorinated derivatives of the novel sedative-hypnotic pyrazolopyrimidine indiplon

The function of gamma-aminobutyric acid type A receptors (GABA(A) receptors) is enhanced by various clinically important drugs including benzodiazepines that act on an allosteric site formed at the interface between the alpha and gamma subunits. In contrast to classical benzodiazepines, the novel pyrazolopyrimidine indiplon (N-methyl-N-{3-[7-(thiophene-2-carbonyl)-1,5,9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-2-yl]phenyl}acetamide; N-methyl-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide) demonstrates relative binding selectivity for the alpha1 subunit containing receptor subtypes, which are the most frequently expressed in the mammalian central nervous system. To investigate the pharmacological properties at GABA(A) receptors and to promote the development of alpha1 subunit selective radiotracers for positron emission tomography imaging, we have started with the evaluation of various fluorinated indiplon derivatives. Binding affinities were determined in homogenates from newborn and adult rats suggesting an alpha1 preference of the reference compounds indiplon, zaleplon as well as for all newly synthesized indiplon derivatives. In homogenated cerebellar tissue obtained from adult rat brain, known to primarily express alpha1 containing GABA(A) receptors, the high affinity of the basic indiplon structure was only slightly affected by an elongation of the alkyl substituent of the amide N from methyl (indiplon; K(i) 3.1 nM) via ethyl (2a, N-(2-fluoro-ethyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 5.4 nM) to propyl (2b, N-(3-fluoro-propyl)-N-{3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidine-7-yl]phenyl}-acetamide; K(i) 2.4 nM). Whole cell patch-clamp recordings at neuronal and recombinant GABA(A) receptors indicated that the fluorinated derivatives 2a and 2b have a high potency at alpha1beta3gamma2L isoforms comparable to indiplon (EC(50): 105, 158, and 81 nM, respectively), with 2b displaying the most pronounced efficacy at alpha3beta3gamma2L subtypes. In conclusion, the affinity profiles and functional properties of the newly synthesised fluorinated indiplon derivatives make compounds 2a and 2b suitable for the development of [(18)F]-labelled ligands at GABA(A) receptors containing the alpha1 subunit.     

Mechanisms involved in the relaxant action of the ethanolic extract of propolis in the guinea-pig trachea in-vitro

This study examines the mechanisms by which the standardised ethanolic extract of propolis induces relaxation of the guinea-pig trachea in-vitro. In guinea-pig trachea with or without epithelium and contracted by histamine, the propolis extract caused reproducible and graded relaxation, with a mean EC50 value of 3.8 or 10.5 microg mL(-1) and Emax of 100%, respectively. The propolis extract-induced relaxation was markedly reduced (26+/-9 and 96+/-3%) when guinea-pig tracheas were exposed to Krebs solution containing elevated K+ in the medium (40 or 80 mM). Pre-incubation of guinea-pig tracheas with tetraethylamonium (100 mM) or with 4-aminopyridine (10mM) reduced the propolis extract-induced relaxation by 31+/-10% and 28+/-2%. Likewise, apamin (0.1 microM), charybdotoxin (0.1 microM) or iberiotoxin (0.1 microM) caused marked inhibition of propolis extract-mediated relaxation in guinea-pig trachea (percentage of inhibition: 65+/-3%, 60+/-5% and 65+/-9%, respectively). Also, glibenclamide (1 microM) inhibited the relaxant response caused by the propolis extract by 57+/-4%. Omega-conotoxin GIVA (0.1 microM) or capsaicin (1 microM) produced small but significant inhibition (30+/-5% or 47+/-7%, respectively) of the propolis extract-induced relaxation. The vasoactive intestinal peptide (VIP) antagonist D-p-Cl-Phe6,Leu17[VIP] porcine (0.1 microM) inhibited relaxation by 55+/-5%, while propranolol (1 microM) induced a parallel rightward displacement (about 20 fold) of the propolis extract concentration-response curve. Finally, the propolis extract-induced relaxation was inhibited by the nitric oxide synthase inhibitor L-N(G)-nitroarginine (L-NOArg, 100 microM) (48+/-6%), and by the soluble guanylatecyclase inhibitormethylene blue (10 microM) (37+/-6%), whilethe moreselectivesoluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3-alquinoxalin-1-one (ODQ, 1 microM) produced only a parallel (about 3 fold) rightward displacement of the propolis extract concentration-response curve. Collectively, these results support the notion that the propolis extract-mediated relaxation in the guinea-pig trachea involves the release of nitric oxide, probably from sensory neurons, besides the activation of soluble guanylate cyclase and activation of Ca2+- and ATP-sensitive K+ channels. Furthermore, the stimulation of beta2-adrenergic and VIP receptors also seems to account for its relaxant action.     

Personality factors as predictors of alcohol consumption by university students

This study aimed to verify differences in personality factors between abstainers and drinkers and between individuals with higher versus lower levels of alcohol consumption in the previous three months, and to test the predictive power of factors for any lifetime alcohol consumption and for at least monthly alcohol consumption. A total of 169 university students participated, of whom 66.7% were women, with a mean age of 21.2 years. Lifetime alcohol consumption was 90.1%; 42.3% had consumed at least twice in the previous three months; and 57.7% consumed alcohol at least monthly. Participants with less frequent consumption in the previous three months showed higher mean scores for personality factors involving socialization and achievement, while those that consumed more frequently scored higher on extroversion. A predictive model showed that increments in extroversion contributed to increased odds of drinking alcohol, while increments in achievement decreased the odds of drinking. Personality characteristics were able to distinguish between different groups of drinkers and predict the frequency of alcohol consumption.     

Health and Health Care of Mothers and Children in a Suburban Area of Luanda,Angola

Population health data available in Angola are often insufficient to guide the planning of health interventions. To address this gap, the goal of the present study was to investigate the health of mothers and infants in a suburban municipality in Luanda (Cacuaco), in order to provide a baseline for future comparisons. This was a prevalence study investigating infants younger than 2 years of age and their mothers. Mothers were interviewed, and children’s height and weight were measured. Of 749 mothers interviewed, 98.5 % (95 % CI 98.2–99.1 %) had at least one prenatal visit and 51.7 % (95 % CI 47.4–56.3 %) had a health card. Most mothers with a health card had their first prenatal visit before the 20th week of pregnancy, and had at least four prenatal visits; 81.1 % (95 % CI 78.3–84.1 %) of mothers also had their child’s health card. Prevalence of exclusive breastfeeding at 6 months was 19 % (95 % CI 16.2–23.1 %). Prevalence of low height-for-age and low BMI-for-age were 32 and 6 %, respectively. Mothers with higher education levels were more likely to have had their first prenatal visit earlier, to have had more prenatal visits, to have given birth at a health facility, and to have her own and her child’s health cards. Results showed a high prevalence of prenatal care and a low frequency of acute malnutrition. Maternal education level, among factors studied, was the predominant correlate of more positive health behaviors. These findings suggest important progress of mother and child health in Cacuaco, and may serve as a baseline for the planning of health interventions.     

Deficits in a sustained attention task following nicotine withdrawal in rats

Objective Behavioural consequences of spontaneous and antagonist-precipitated withdrawal from nicotine upon performance of rats were compared alongside non-nicotinic antagonists in the 5-choice serial reaction time task (5-CSRTT).Methods Male hooded Lister rats were trained to detect and respond to brief flashes of light presented every 15 s in one of five holes until a stable level of performance was achieved.Results Surgical removal of osmotic minipumps from rats having received nicotine (3.16 mg/kg per day base SC) chronically for 7 days produced marked deficits in performance. Compared to saline-treated controls, deficits were apparent 10 h and 16 h following nicotine abstinence; the percentage of omission errors increased concomitantly with modest decreases in response accuracy. Tests conducted 34 h and 106 h post-withdrawal indicated a progressive and complete recovery in attention performance, respectively. In another experiment, following the exposure to the same nicotine regime, administration of the competitive nicotine receptor antagonist dihydro--erythroidine precipitated immediate deficits in performance that were greater than those observed in saline-treated subjects. Methyllycaconitine, an ₇ nicotinic receptor antagonist failed to precipitate attention deficits in nicotine-treated rats. Tests with SCH23390 and raclopride produced impairments that were similar in profile to nicotine withdrawal contrasting with non-specific effects of dizocilpine.Conclusions These results provide evidence of a cognitive impairment resulting from nicotine deprivation in rodents. Specifically, blockade of D₁ receptors by SCH23390 produced decrements in performance that were qualitatively similar but greater in magnitude to the alterations observed following nicotine withdrawal. Overall, assessing nicotine withdrawal in the 5-CSRTT presents an animal model that exhibits robust construct and face validity.     

Molecular imaging of σ receptors: synthesis and evaluation of the potent σ<Subscript>1</Subscript> selective radioligand [<Superscript>18</Superscript>F]fluspidine

Purpose  

Neuroimaging of σ₁ receptors in the human brain has been proposed for the investigation of the pathophysiology of neurodegenerative and psychiatric diseases. However, there is a lack of suitable ¹⁸F-labelled PET radioligands for that purpose.     

Blockade of adenosine A(1) receptors prevents methylphenidate-induced impairment of object recognition task in adult mice

Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A₁ receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A₁ receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5 mg/kg, i.p.), or an acute overdosage (50 mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5 mg/kg improved whereas 50 mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A₁ receptors immunocontent in the frontal cortex. The selective adenosine A₁ receptor antagonist, (DPCPX 1 mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A₁ receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.