Potential Central Nervous System Research Articles

The Blood-Brain Barrier Permeability of Lignans and Malabaricones from the Seeds of Myristica fragrans in the MDCK-pHaMDR Cell Monolayer Model.

The blood-brain barrier (BBB) permeability of twelve lignans and three phenolic malabaricones from the seeds of Myristica fragrans (nutmeg) were studied with the MDCK-pHaMDR cell monolayer model. The samples were measured by high-performance liquid chromatography and the apparent permeability coefficients (Papp) were calculated. Among the fifteen test compounds, benzonfuran-type, dibenzylbutane-type and arylnaphthalene-type lignans showed poor to moderate permeabilities with Papp values at 10−8–10−6 cm/s; those of 8-O-4′-neolignan and tetrahydrofuran-lignan were at 10−6–10−5 cm/s, meaning that their permeabilities are moderate to high; the permeabilities of malabaricones were poor as their Papp values were at 10−8–10−7 cm/s. To 5-methoxy-dehydrodiisoeugenol (2), erythro-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4-dimethoxyphenyl)-propan-1-ol acetate (6), verrucosin (8), and nectandrin B (9), an efflux way was involved and the main transporter for 6, 8 and 9 was demonstrated to be P-glycoprotein. The time and concentration dependency experiments indicated the main transport mechanism for neolignans dehydrodiisoeugenol (1), myrislignan (7) and 8 was passive diffusion. This study summarized the relationship between the BBB permeability and structure parameters of the test compounds, which could be used to preliminarily predict the transport of a compound through BBB. The results provide a significant molecular basis for better understanding the potential central nervous system effects of nutmeg.

In vivo Study on Depressant Effects and Muscle Coordination Activity of Galphimia glauca Stem Methanol Extract.

Background:Galphimia glauca is an evergreen shrub found across peninsular India, belonging to family Malpighiaceae.Objective:The objective of this study was to assess the in vivo depressant effects and muscle coordination activity of G. glauca stem methanol extract (GGSME).Materials and Methods:The stem methanol extract was administered in Swiss albino mice in 1 day to study the central nervous system (CNS) depressant and muscle coordination activity employing animal models such as sodium pentobarbital-induced sleep test, hole-board test, open field test, pentylenetetrazole (PTZ)-induced convulsions, picrotoxin-induced convulsions, grip strengthening test in mice, and Rota-rod test.Results:The LD50 of GGSME was found to be >2000 mg/kg body weight (b.w.). Mice treated with stem methanol extract at 100, 200, and 400 mg/kg, b.w. doses extended the sleeping time induced by sodium pentobarbital (40 mg/kg. b.w., i.p.). The stem methanol extract at 400 mg/kg dose showed a significant (P ≤ 0.001) dose-dependent decrease in the number of rears and head dipping number in the hole-board test. The extract exhibited a significant (P ≤ 0.001) effect on the ambulatory behavior of mice in the open field test and also extended the onset of seizures induced by PTZ (90 mg/kg b.w., i.p.) and picrotoxin (10 mg/kg, b.w., i.p.). The extract also exhibited significant (P ≤ 0.001) effects on muscle coordination in rota-rod and grip strengthening test in mice.Conclusion:The study results conclude that the GGSME has a potential CNS depressant and muscle relaxant effects compared to the standard drugs.SUMMARY Anxiety is implicated in the number of psychiatric disordersIn vivo depressant activity is studied employing animal models like Sodium pentobarbital-.induced sleep test, Hole-board test, Open field test, Pentylenetetrazole induced convulsions and Picrotoxin-induced convulsions tests.Muscle coordination activity is studied employing animal models like Grip strengthening test in mice and Rota-.rod test.The GABAergic system plays a significant role in CNS depressant and muscle relaxant effects.The study proves the traditional claims of the plant used in the treatment of phobia, panic, stress, anxiety and it is as well used in producing a calming effect on the nerves. Abbreviations Used: WHO: World Health Organization; CNS: Central nervous system; GGSME: Galphimia glauca stem methanol extract; IAEC: Institutional Animal Ethics Committee; OECD: The Organization for Economic Co-operation and Development; PTZ: Pentylenetetrazole; REM: Rapid eye movement; GABA: γ-aminobutyric acid; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; b.w: Body weight; i.p: Intraperitoneal; p.o: per oral

Koponyacsont-laesiók komputertomográfiás vizsgálata és paleoradiológiai aspektusai

[Background and purpose - Introducing the multidisciplinary paleoradiology research at the Institute of Diagnostic Imaging and Radiation Oncology of the Kaposvár University, highlighting the cases with potential central nervous system involvement - from the scanning methods to the 3D printing - in order to draw attention to the historical background and clinical aspects of certain pathological conditions. Methods - The authors developed the examination protocols for three different CT scanners. Among the examined archaeological remains cranial lesions were identified in 26 cases, from which 4 cases with potential central nervous system involvement are demonstrated. The scanning parameters and the advantages of secondary image reconstructions (multiplanar reconstruction, maximum intensity projection, three-dimensional volume rendering technique) are presented with the cases. Results - The authors demonstrate a case with destructive skull lesions due to syphilis from the 15th century AD, a condition rarely seen or even unknown nowadays in the modern world. With the CT images of the skull base fracture from the Iron Age, signs of healing could be verified. Using the CT images a non-invasive approach is presented in the case of the craniofacial osteosarcoma in order to visualize the local status and the direct intracranial propagation. Advantages of the 3D VRT reconstructions are shown in the case of unilateral coronal suture synostosis. Conclusion - Paleoradiological CT examinations serve as a non-invasive, non-destructive tool for studying archaeological remains and artifacts. The special applications provided by the imaging modality contribute to the conventional paleopathological investigations. Keywords: paleoradiology, computed tomography, 3D reconstruction, skull lesions, paleopathology]

Retinal and Optic Disc Alterations in Alzheimer ’s Disease: the Eye as a Potential Central Nervous System Window

Pathologic changes in the retina and optic nerve are observed in patients with Alzheimer´s disease (AD), even in early stages of the dementia. In our clinical ophthalmology practice, we use optical coherence tomography (OCT), a noninvasive, rapid, objective, and reliable technology that enables for quantification of the retinal nerve fiber layer (RNFL), namely the retinal ganglion cell axons that eventually form the optic nerve. The opportunity to analyze a part of the central nervous system by such a simple exploration led to several studies demonstrating thinning of the RNFL and central retina in AD patients compared with healthy subjects. Here we present some of our investigations in AD patients using Spectral Domain-OCT. Our results suggest that axonal loss secondary to pathologic alterations in the brains of AD patients can be observed by OCT. We also analyzed the association between retinal and RNFL thicknesses and neurologic characteristics, disease duration and severity, and found that mean RNFL thickness was significantly correlated with disease duration, indicating that the progression of AD is associated with a progressive loss of ganglion cells.

Neurobehavioral hazard identification and characterization for caffeine

This report evaluates the scientific literature on caffeine with respect to potential central nervous system (CNS) effects, specifically effects on sleep, anxiety, and aggression/risk-taking. Caffeine has been the subject of more scientific safety studies than any other food ingredient. It is important, therefore, to evaluate new studies in the context of this large existing body of knowledge. The safety of caffeine can best be described in a narrative form, and is not usefully expressed in terms of a “bright line” numerical value like an “acceptable daily intake” (ADI). Caffeine intake has been associated with a range of reversible physiological effects, in a few studies at levels of less than 100 mg in sensitive individuals. It is also clear that many people can tolerate much greater levels – perhaps up to 600–800 mg/day or more – without experiencing such effects. The reasons for this type of variability in response are described in this report. Based on all the available evidence, there is no reason to believe that experiencing such effects from caffeine intake has any significant or lasting effect on health. The point at which caffeine intake may cause harm to the CNS is not readily identifiable, in part because data on the effects of daily intakes greater than 600 mg is limited. Effects of caffeine on risk-taking and aggressive behavior in young people have received considerable publicity, yet are the most difficult to study because of ethical concerns and limitations in the ability to design appropriate studies. At present, the weight of available evidence does not support these concerns, yet this should not preclude ongoing careful monitoring of the scientific literature.

A novel radioligand for the ATP-gated ion channel P2X7: [3H] JNJ-54232334

The ATP-gated ion channel P2X7 has emerged as a potential central nervous system (CNS) drug target based on the hypotheses that pro-inflammatory cytokines such as IL-1β that are released by microglia, may contribute to the etiology of various disorders of the CNS including depression. In this study, we identified two closely related P2X7 antagonists, JNJ-54232334 and JNJ-54140515, and then tritium labeled the former to produce a new radioligand for P2X7. JNJ-54232334 is a high affinity ligand for the rat P2X7 with a pKi of 9.3±0.1. In rat cortical membranes, [3H] JNJ-54232334 reached saturable binding with equilibrium dissociation (Kd) constant of 4.9±1.3nM. The compound displayed monophasic association and dissociation kinetics with fast on and off rates. In rat brain sections, specific binding of [3H] JNJ-54232334 was markedly improved compared to the previously described P2X7 radioligand, [3H] A-804598. In P2X7 knockout mouse brain sections, [3H] A-804598 bound to non-P2X7 binding sites in contrast to [3H] JNJ-54232334. In rat or wild type mouse brain sections [3H] JNJ-54232334 bound in a more homogenous and region independent manner. The ubiquitous expression of P2X7 receptors was confirmed with immunohistochemistry in rat brain sections. The partial displacement of [3H] A-804598 binding resulted in the underestimation of the level of ex vivo P2X7 occupancy for JNJ-54140515. Higher levels of P2X7 ex vivo occupancy were measured using [3H] JNJ-54232334 due to less non-specific binding. In summary, we describe [3H] JNJ-54232334 as a novel P2X7 radioligand, with improved properties over [3H] A-804598.

Potential Central Nervous System Involvement in Sudden Unexpected Infant Deaths and the Sudden Infant Death Syndrome.

Sudden unexpected infant death (SUID) in infancy which includes Sudden Infant Death Syndrome (SIDS) is the commonest diagnosed cause of death in the United States for infants 1 month to 1 year of age. Central nervous system mechanisms likely contribute to many of these deaths. We discuss some of these including seizure disorders, prolonged breath holding, arousal from sleep and its habituation, laryngeal reflex apnea potentiated by upper airway infection, and failure of brainstem-mediated autoresuscitation. In the conclusions section, we speculate how lives saved through back sleeping might result in later developmental problems in certain infants who otherwise might have died while sleeping prone.

374. Therapeutic Effect of Platelet Transfusions for Acute Neuronopathic Gaucher Disease

Enzyme replacement therapy has led to resolution of most visceral manifestations in Gaucher disease (GD), but it is also limited by the instability of acid beta -glucosidase enzyme (GCase) in circulation, liver 1st bypass, and high cost. In addition, intravenous enzyme administration has not been effective for ameliorating central nervous system (CNS) deficits. Platelets are blood elements that contain cytoplasmic secretory vesicles. The involvement of platelet containing proteins in inflammation and angiogenesis has recently been indicated. We have recently shown that platelets/megakaryocytes could serve as efficient and protective depots for lysosomal enzyme generation and distribution. In this study the potential therapeutic benefits of platelet transfusion in treating neuronopathic GD (nGD) was evaluated using a murine model of acute nGD (4L;C). This model resembles the CNS phenotype and biochemistry of types 2 and 3 Gaucher disease, and premature death results from progressive CNS disease. Platelets containing significant amounts of wild type GCase (19 U/109 plt) were isolated from GFP mice and transfused weekly for four times into 4L;C mice beginning at 21 days of age. The average percentages of donor-derived platelets were at mean of 10% to 12.9% (ranging from 7.2 to 16.1%) as measured one hour after each transfusion by flow cytometry analysis with anti-CD41 staining for GFP-positive donor platelets. Clearance curves of transfused platelets were similar in 4L;C and wild-type recipients with comparable half-life of GFP+ platelets (t1/2=50 h), suggesting the lack of an immune-response against platelet-derived normal GCase in nGD mice. Importantly, the life-span of treated 4L;C mice was significantly extended from 46 days [untreated 4L;C (n=22)] to 54 days [treated, (n=7)]. Potential CNS benefits were assessed using hindlimb gait analysis that evaluated motor function. In comparison to normal controls, the untreated 4L;C mice exhibited abnormal splaying of their hindlimbs and progressive paresis. The platelet-treated 4L;C mice improved significantly toward normal behavior and had delays in the age of onset for CNS signs. Immunohistochemistry analysis showed that numbers of CD68+ cells were decreased in the cerebellum, brainstem and cortex of treated 4L;C mice, indicating the reduction of pro-inflammation by platelet transfusion. The clearance of GFP+ platelets by liver and spleen was shown by GFP signals detected in those organs of treated 4L;C mice. Quantification of the pathogenic lipids, glucosylceramide and glucosylsphingosine, is in progress to assess potential metabolic correction in various regions of brain and visceral organs in platelet-treated nGD mice. More studies are underway to further investigate possible mechanism(s) involved. In summary, our results demonstrate that repeated, moderate levels of platelet transfusion could extend the life span of nGD mice and improve CNS deficits. abbbb

BDNF Influences the Excitability of Subfornical Organ Neurons

Brain‐derived neurotrophic factor (BDNF) is a peptide known to be involved in several mammalian physiological processes. Expression of BDNF transcripts has been identified in the subfornical organ (SFO), a circumventricular organ involved in fluid balance and energy homeostasis. Microarray analysis has demonstrated that levels of transcript expression in the SFO are differentially regulated by fluid and food deprivation, with levels of BDNF expression increasing significantly in response to dehydration, and decreasing in response to starvation (Hindmarch et al 2008). The current study was therefore undertaken in order to determine the effects of BDNF on the excitability of SFO neurons. We used the whole‐cell patch clamp technique to determine the influence of BDNF on the membrane potential of dissociated SFO neurons as well as that of SFO neurons in slice preparation. We found that 86% of dissociated neurons responded when treated with BDNF (2 nM), all of which depolarized (mean 14 mV). Additionally, 75% of neurons tested in the slice preparation responded when treated with BDNF (2 nM). Of these, 67% showed a depolarization (mean 12 mV) and 33% hyperpolarized (mean ‐18 mV). This study suggests the SFO as a potential central nervous system site at which BDNF may act directly to influence homeostatic regulation.Supported by the Canadian Institutes for Health Research

Characterization of binding and inhibitory properties of TAK-063, a novel phosphodiesterase 10A inhibitor.

Phosphodiesterase 10A (PDE10A) inhibition is a novel and promising approach for the treatment of central nervous system disorders such as schizophrenia and Huntington’s disease. A novel PDE10A inhibitor, TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one] has shown high inhibitory activity and selectivity for human recombinant PDE10A2 in vitro; the half-maximal inhibitory concentration was 0.30 nM, and selectivity over other phosphodiesterases (PDEs) was more than 15000-fold. TAK-063 at 10 µM did not show more than 50% inhibition or stimulation of 91 enzymes or receptors except for PDEs. In vitro autoradiography (ARG) studies using rat brain sections revealed that [3H]TAK-063 selectively accumulated in the caudate putamen (CPu), nucleus accumbens (NAc), globus pallidus, substantia nigra, and striatonigral projection, where PDE10A is highly expressed. This [3H]TAK-063 accumulation was almost entirely blocked by an excess amount of MP-10, a PDE10A selective inhibitor, and the accumulation was not observed in brain slices of Pde10a-knockout mice. In rat brain sections, [3H]TAK-063 bound to a single high-affinity site with mean ± SEM dissociation constants of 7.2 ± 1.2 and 2.6 ± 0.5 nM for the CPu and NAc shell, respectively. Orally administered [14C]TAK-063 selectively accumulated in PDE10A expressing brain regions in an in vivo ARG study in rats. Striatal PDE10A occupancy by TAK-063 in vivo was measured using T-773 as a tracer and a dose of 0.88 mg/kg (p.o.) was calculated to produce 50% occupancy in rats. Translational studies with TAK-063 and other PDE10A inhibitors such as those presented here will help us better understand the pharmacological profile of this class of potential central nervous system drugs.

Pharmacokinetic Study and Optimal Formulation of New Anti-Parkinson Natural Compound Schisantherin A.

Our recent studies showed that schisantherin A (StA) is a promising candidate for PD treatment, but the pharmacokinetic profile of StA is largely unknown. The effects of different formulations on the pharmacokinetics and bioavailability of StA were investigated by HPLC equipped with a vacuum degasser, a quaternary pump, a manual sampler, and an ultraviolet detector. The absolute bioavailability of StA in nanoemulsion formulation was significantly increased from 4.3% to 47.3%. To the best of our knowledge, this is the first report of absolute bioavailability for StA in rats and successful increase of bioavailability of StA by nanoemulsion formulation. The pharmacokinetic profiles of StA could be significantly improved by a safe nanoemulsion formulation. This study provides a successful example of advanced delivery system for improving the bioavailability of potential central nervous system (CNS) drug candidate with poor solubility. This novel approach could be an effective alternative solution to overcome the shortcomings of conventional poor drug delivery of CNS drugs. The results of present study not only indicate that StA has potential to be developed as a promising oral therapeutic agent for the management of PD but also shed light on novel way to improve bioavailability of PD drugs.

Association between myasthenia gravis and cognitive function: A systematic review and meta-analysis.

The course of myasthenia gravis (MG) is complicated by increased reports of cognitive defects in both human and animal models, which suggests potential central nervous system (CNS) damage. We conducted a systematic review of the relationships between MG and cognitive function. This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Major databases were searched to examine the neuropsychological studies of adults with MG. Weighted effect sizes were pooled by cognitive domain. Eight studies representing 300 subjects were included. Eight cognitive domain categories were identified: (i) Mini-Mental State Examination (MMSE), (ii) language, (iii) processing speed, (iv) verbal learning and memory, (v) visual learning and memory, (vi) attention span, (vii) response fluency, and (viii) motor performance. Nine (cognitive domain categories, MMSE, language, processing speed, verbal learning and memory (except for delayed recall memory), and motor performance) of 16 cognitive tasks revealed significant moderate effect sizes. Verbal logical-delayed memory, finger tapping with the preferred hand, and the Symbol Digit Modalities Test showed a greater magnitude relationship to cognitive function than did other specific cognitive domains. Verbal learning and memory seems to be the most significant affected according to cognitive domain categories. For MG, the ability of attention, response fluency, visual learning, and memory seems to be reserved. The MG patients seem to perform significantly worse than the non-MG controls in a range of cognitive domains. Our findings should be interpreted with caution because of the clinical and methodological heterogeneity of included studies.

Quantitative Evaluation of Noncontrast Computed Tomography of the Head for Assessment of Anemia.

Anemia is an underdiagnosed clinical entity with significant mortality and morbidity. We aimed to assess whether attenuation of dural venous sinuses correlates with hemoglobin/hematocrit and to determine if the degree of anemia can be predicted by quantitative analysis of unenhanced computed tomography (CT) of the head. This is an institutional review board-approved retrospective study including 500 patients who underwent emergency department investigation for potential central nervous system etiology of their symptoms with unenhanced CT head at a tertiary care center. Computed tomographic attenuation values were obtained by 2 independent readers, whereas 2 separate investigators collected clinical data. Regression analyses were performed to evaluate the strength of correlation and the predictability of anemia and its severity on unenhanced CT. Receiver operating characteristic curve analyses were performed to evaluate sensitivity, specificity, as well as positive and negative predictive values. A total of 243 met the inclusion criteria, and attenuation values for all the dural venous sinuses were averaged and categorized according to hemoglobin values of less than 8, 8 to 10, 10 to 14, and greater than 14. Mean CT attenuation values for both readers were 36.30, 42.35, 47.99, and 53.25 Hounsfield units. Regression analysis revealed the highest positive correlation of hemoglobin/hematocrit with attenuation at the confluence of sinuses with R value of 0.63 and 0.60. The sensitivity, specificity, and negative predictive value of detecting hemoglobin of less than 10 at confluence of sinuses were 91.2%, 88.5%, and 98.6%, respectively. Interobserver agreement was found to be good (0.64) using the κ statistic. Our study substantiates direct positive correlation between CT attenuation of dural venous sinuses and hemoglobin/hematocrit, with strongest correlation at the confluence of sinuses with good sensitivity, specificity, and negative predictive value.

In vitro porcine blood–brain barrier model for permeability studies: pCEL-X software pKaFLUX method for aqueous boundary layer correction and detailed data analysis

In vitro blood–brain barrier (BBB) models from primary brain endothelial cells can closely resemble the in vivo BBB, offering valuable models to assay BBB functions and to screen potential central nervous system drugs. We have recently developed an in vitro BBB model using primary porcine brain endothelial cells. The model shows expression of tight junction proteins and high transendothelial electrical resistance, evidence for a restrictive paracellular pathway. Validation studies using small drug-like compounds demonstrated functional uptake and efflux transporters, showing the suitability of the model to assay drug permeability. However, one limitation of in vitro model permeability measurement is the presence of the aqueous boundary layer (ABL) resulting from inefficient stirring during the permeability assay. The ABL can be a rate-limiting step in permeation, particularly for lipophilic compounds, causing underestimation of the permeability. If the ABL effect is ignored, the permeability measured in vitro will not reflect the permeability in vivo. To address the issue, we explored the combination of in vitro permeability measurement using our porcine model with the pKaFLUX method in pCEL-X software to correct for the ABL effect and allow a detailed analysis of in vitro (transendothelial) permeability data, Papp. Published Papp using porcine models generated by our group and other groups are also analyzed. From the Papp, intrinsic transcellular permeability (P0) is derived by simultaneous refinement using a weighted nonlinear regression, taking into account permeability through the ABL, paracellular permeability and filter restrictions on permeation. The in vitro P0 derived for 22 compounds (35 measurements) showed good correlation with P0 derived from in situ brain perfusion data (r2=0.61). The analysis also gave evidence for carrier-mediated uptake of naloxone, propranolol and vinblastine. The combination of the in vitro porcine model and the software analysis provides a useful tool to better predict BBB permeability in vivo and gain better mechanistic information about BBB permeation.

Excitability of the motor cortex in de novo patients with celiac disease.

IntroductionCeliac disease (CD) may initially present as a neurological disorder or may be complicated by neurological changes. To date, neurophysiological studies aiming to an objective evaluation of the potential central nervous system involvement in CD are lacking.ObjectiveTo assess the profile of cortical excitability to Transcranial Magnetic Stimulation (TMS) in a group of de novo CD patients.Materials and methodsTwenty CD patients underwent a screening for cognitive and neuropsychiatric symptoms by means of the Mini Mental State Examination and the Structured Clinical Interview for DSM-IV Axis I Disorders, respectively. Instrumental exams, including electroencephalography and brain computed tomography, were also performed. Cortico-spinal excitability was assessed by means of single and paired-pulse TMS using the first dorsal interosseus muscle of the dominant hand. TMS measures consisted of resting motor threshold, motor evoked potentials, cortical silent period (CSP), intracortical inhibition (ICI) and facilitation (ICF). None of the CD was on gluten-free diet. A group of 20 age-matched healthy controls was used for comparisons.ResultsCD showed a significantly shorter CSP (78.0 vs 125.0 ms, p<0.025), a reduced ICI (0.3 vs 0.2, p<0.045) and an enhanced ICF (1.1 vs 0.7, p<0.042) compared to controls. A dysthymic disorder was identified in five patients. The effect size between dysthymic and non-dysthymic CD patients indicated a low probability of interference with the CSP (Cohen's d -0.414), ICI (-0.278) and ICF (-0.292) measurements.ConclusionA pattern of cortical excitability characterized by “disinhibition” and “hyperfacilitation” was found in CD patients. Immune system dysregulation might play a central role in triggering changes of the motor cortex excitability.

Traitement anticholinergique de l’hyperactivité vésicale de la personne âgée et ses impacts sur la cognition. Revue de la littérature

Describe the central nervous system (CNS) adverse effects of anticholinergic drugs used for the treatment of overactive bladder (OAB) in the elderly. Relevant data from the literature were identified primarily through a Medline search of articles published through December 2013. The search terms included overactive bladder, central nervous system, elderly, anticholinergic, and antimuscarinic. Articles were chosen for inclusion based on their pertinence to the focus on treatment of OAB in the elderly. Several anticholinergic drugs are available for the treatment of OAB, including oxybutinin, tolterodine, trospium chloride, solifenacine, fesoterodine. Among the agents reviewed, penetration of the blood-brain barrier (as predicted by lipophilicity, polarity, and molecular size and structure) is highest for oxybutinin, lower for tolterodine, solifenacine, and darifenacine, and lowest for fesoterodine and trospium chloride. Unwanted CNS adverse effects depend in part on patient specific variability in pharmacokinetic parameters, blood-brain barrier permeability, degree of cholinergic neuronal degeneration, total anticholinergic drug burden and patient's baseline cognitive status. The spectrum of anticholinergic CNS adverse effects ranges from drowsiness to hallucinations, severe cognitive impairment, and coma. Among the different anticholinergic agents, oxybutinin has been associated with cognitive impairment and trospium chloride and fesoterodine have shown favorable CNS tolerability. Anticholinergic drugs improve significatively overactive bladder symptoms in older adults. However, potential CNS adverse effects of anticholinergic agents used in OAB must lead to a full evaluation before and during the treatment in order to evaluate benefice, risks and central side effects in this frail population.

Central Nervous System HIV Infection in “Less-Drug Regimen” Antiretroviral Therapy Simplification Strategies

Less-drug regimens (LDR) refer to combinations of either two antiretroviral drugs or ritonavir-boosted protease inhibitor (PI) monotherapy. They may represent a simplification strategy in patients with persistently suppressed human immunodeficiency virus (HIV) viremia, with the main benefits of reducing drug-related toxicities and costs. Systemic virological efficacy of LDR is slightly lower as compared with combined antiretroviral therapy (cART), but patients with failure do not usually develop drug resistance and resuppress HIV replication after reintensification. A major concern of LDR is the lower efficacy in the virus reservoirs, especially in the central nervous system (CNS), where viral compartmentalization and independent evolution of infection may lead to CNS viral escape, often associated with neurologic symptoms. The authors reviewed studies of virological and functional CNS efficacy of LDR, particularly of boosted PI monotherapy regimens, for which more information is available. Symptomatic viral CSF escape was observed mainly in PI/r monotherapy patients with plasma failure and low nadir CD4+ cell counts, and resolved upon reintroduction of triple drug cART, whereas asymptomatic viral failure in CSF was not significantly more frequent in patients on PI/r monotherapy compared with patients on standard cART. In addition, there was no difference in functional outcomes between PI monotherapy and cART patients, irrespective of CSF viral escape. More data are needed on the CNS effect of dual ART regimens and, in general, on long-term efficacy of LDR. Simplification with LDR may be an attractive option in patients with suppressed viral load, if they are well selected and monitored for potential CNS complications.

Analgesic, antibacterial and central nervous system depressant activities of Albizia procera leaves

To ascertain analgesic, antibacterial and central nervous system (CNS) depressant activities of ethyl acetate, dichloromethane and carbon tetrachloride fractions of methanol extract of Albizia procera (A. procera) leaves. Leaves extracts of A. procera were tested for analgesic activity by acetic acid induced and formalin test method in mice. The in vitro antibacterial activity was performed by agar well diffusion method. CNS depressant activity was evaluated by hole cross and open field tests. All the extracts at 200 mg/kg exhibited significant (P<0.01) analgesic activity in acetic acid induced and formalin tests method in mice. Analgesic activity of the ethyl acetate fraction was almost same like as standard drug indomethacin in acetic acid induced method. The CNS depressant activity of the extracts at 500 mg/kg was comparable to the positive control diazepam as determined by hole cross and open field test method. The extracts exhibited moderate antimicrobial activity against all the tested microorganisms (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, Esherichia coli, Shigella soneii, Shigella boydii) at concentration of 0.8 mg/disc. The measured diameter of zone of inhibition for the extracts was within the range of 7 to 12 mm which was less than the standard kanamycin (16-24 mm). It is concluded that all the extracts possess potential analgesic and CNS depressants activity. This study also showed that different fractions of methanol extract could be potential sources of new antimicrobial agents.

Prolactin influences the excitability of subfornical organ neurons (1129.3)

Prolactin is a hormone that is involved in multiple physiological functions in vertebrates. Prolactin receptor mRNA has been identified in the subfornical organ (SFO) through microarray analysis (Hindmarch et al 2008). The current study was therefore carried out in order to determine the effects of prolactin on the excitability of SFO neurons. We used the whole‐cell patch clamp technique to determine the influence of prolactin on the membrane potential of dissociated SFO neurons. We found that 55% (11 of 20) of neurons responded when treated with prolactin (1 uM and 100nM). Of the cells that responded, 54% (n=6) depolarized with a mean depolarization of 7.7 ± 3.3 mV and 46% (n=5) hyperpolarized with a mean hyperpolarization of ‐8.0 ± 3.6 mV. This study suggests the SFO as a potential central nervous system site at which prolactin may act to influence central autonomic integration.Grant Funding Source: Canadian Institutes for Health Research

Hiv-Associated Neurocognitive Disease: Case Studies and Suggestions for Diagnosis and Management in Different Patient Subgroups

The incidence of HIV-associated dementia has decreased significantly with the introduction of combination antiretroviral therapy; however, milder or more subtle forms of neurocognitive disorders associated with HIV appear to remain common. There is a lack of consensus on when to screen and on which methods are most appropriate for identifying patients at risk of neurocognitive impairment. Multiple factors (demographic, social, genetic, psychological and medical) can play a role in its aetiology and progression, including potential central nervous system toxicity of antiviral therapy. It is important to identify these factors in order to apply relevant management strategies. In this review, we discuss a series of case studies that address some of the challenges presented by the diagnosis and management of HIV-associated neurocognitive impairment in different patient types.