Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42

A key event in Alzheimer's disease (AD) pathogenesis is the conversion of the peptide beta-amyloid (Abeta) from its soluble monomeric form into various aggregated morphologies in the brain. Preventing aggregation of Abeta is being actively pursued as a primary therapeutic strategy for treating AD. Trehalose, a simple disaccharide, has been shown to be effective in preventing the deactivation of numerous proteins and in protecting cells against stress. Here, we show that trehalose is also effective in inhibiting aggregation of Abeta and reducing its cytotoxicity, although it shows differential effects toward Abeta40 and Abeta42. When co-incubated with Abeta40, trehalose inhibits formation of both fibrillar and oligomeric morphologies as determined by fluorescence staining and atomic force microscopy (AFM). However, when co-incubated with Abeta42, trehalose inhibits formation only of the fibrillar morphology, with significant oligomeric formation still present. When aggregated mixtures were incubated with SH-SY5Y cells, trehalose was shown to reduce the toxicity of Abeta40 mixtures, but not Abeta42. These results provide additional evidence that aggregation of Abeta into soluble oligomeric forms is a pathological step in AD and that Abeta42 in particular is more susceptible to forming these toxic oligomers than Abeta40. These results also suggest that the use of trehalose, a highly soluble, low-priced sugar, as part of a potential therapeutic cocktail to control Abeta peptide aggregation and toxicity warrants further study.     

Low-dose lactulose produces a tonic contraction in the human colon

Lactulose (10-20 g day(-1)) is used to treat constipation. At this therapeutic dose, its effects on colonic motility remain unknown. Twenty-two healthy subjects swallowed a probe with an infusion catheter, six perfused catheters and a balloon connected to a barostat. Colonic phasic and tonic motor activity was recorded in fasting state. In group 1, four volunteers ingested 15 g lactulose and motility was recorded for 5 h after entry of lactulose into the caecum; in group 2, motility was recorded during (3 h) and 2 h after intracolonic infusion of isoosmotic and isovolumetric solutions containing sodium chloride alone (n = 9) or with 15 g lactulose (n = 9). In a last group of volunteers, isotopic colonic transit after ingestion of lactulose (10 g,n = 9) was assessed and compared with a control group (n = 17). Ingestion or intracolonic infusion of 15 g lactulose significantly decreased barostat bag volume (maximal decrease: 45 +/- 12% and 35 +/- 9% of basal value respectively). Phasic contractions remained unchanged. Tonic and phasic motility was unchanged by the isotonic and isovolumetric infusion of saline. Ingestion of lactulose significantly accelerated isotopic colonic transit time compared with the control group. We conclude that in healthy humans, 10-15 g ingestion or intracaecal infusion of lactulose produces a prolonged tonic contraction that may be involved in the laxative effect of lactulose.     

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABA_A receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions, such as the stress response, puberty, the ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurological diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability, which limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarises recent approaches that target the neuroactive steroid biosynthetic pathway at different levels aiming to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa and the pregnane xenobiotic receptor, as well as targeting of specific neurosteroidogenic enzymes such as 17β‐hydroxysteroid dehydrogenase type 10 or P450 side chain cleavage. Enhanced neurosteroidogenesis through these targets may be beneficial not only for neurodegenerative diseases, such as Alzheimer's disease and age‐related dementia, but also for neuropsychiatric diseases, including alcohol use disorders.     

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

Geoffrey Wingfield Harris' demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G(q) signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention.     

Brief report: Trait emotional intelligence,peer nominations,and scholastic achievement in adolescence

Current research on trait EI in adolescents suggests that the construct impacts on several important domains of youths' psychological functioning, including school adjustment and achievement. The purpose of this study is to explore the role of trait EI and of its subcomponents, on adolescent's academic achievement. Data were collected from 321 Italian adolescents (162 female; Mage = 15.5, SD = 1.86; aged 13–18 years) recruited from secondary schools. The effects of perceived and actual peer nominations, gender, personality dimensions, and non-verbal cognitive abilities were also controlled. Results highlight that trait EI as assessed by means of the TEIQue impacts Italian but not math's grades, while trait EI's factors predicted both academic subjects, with significant contributions of Self-Control and Sociability. Limitations and implications are discussed.     

Mitochondrial mechanisms of estrogen neuroprotection

Oxidative stress, bioenergetic failure and mitochondrial dysfunction are all implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD). The mitochondrial involvement in neurodegenerative diseases reflects the regulatory role mitochondrial failure plays in both necrotic cell death and apoptosis. The potent feminizing hormone, 17 β-estradiol (E2), is neuroprotective in a host of cell and animal models of stroke and neurodegenerative diseases. The discovery that 17-estradiol, an isomer of E2, is equally as neuroprotective as E2 yet is > 200-fold less active as a hormone, has permitted development of novel, more potent analogs where neuroprotection is independent of hormonal potency. Studies of structure–activity relationships and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca²⁺ loading otherwise sufficient to collapse membrane potential. The neuroprotective and mitoprotective potencies for a series of estrogen analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD.     

Effect of the MAO-B inhibitor,MDL72974, on superoxide dismutase activity and lipid peroxidation levels in the mouse brain

MDL72974 is a member of a series of MAO-B inhibitors to be used as potential therapeutic agents in the treatment of Parkinson's and Alzheimer's diseases. However, we have recently observed a reduction in the density of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra of mice treated with MDL72974. As oxidative stress is known to play a significant role in the nigrostriatal pathway, analysis of the relationship between TH⁺ cell losses induced by MDL72974 and by free radical production was investigated in the present study. Results demonstrate a significant increase in superoxide dismutase (SOD) activity, a key antioxidant, in the striatum and cerebellum of MDL72974-treated mice, presumably in response to free radical production. An increase in lipid peroxidation levels was also observed in the striatum of these animals in a manner which is consistent with oxidative stress-inducing agents. We therefore suggest that MDL72974 may be detrimental to dopaminergic neurons of the nigrostriatal pathway via free radical-mediated reactions. Synapse 28:208–211, 1998. © 1998 Wiley-Liss, Inc.     

Overcoming the blood-brain barrier to taxane delivery for neurodegenerative diseases and brain tumors

The blood-brain barrier (BBB) effectively prevents microtubule (MT)-stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for microtubule-stabilizing drug permeation across the BBB is the active efflux back into the circulation by the overexpression of the multidrug-resistant gene product 1 (MDR1) or P-glycoprotein (P-gp). This study has focused on strategies to overcome P-gp-mediated efflux of Taxol analogs, MT-stabilizing agents that could be used to treat brain tumors and, potentially, neurodegenerative diseases such as Alzheimer’s disease. However, taxol is a strong P-gp substrate that limits its distribution across the BBB and therapeutic potential in the CNS. We have found that addition of a succinate group to the C-10 position of paclitaxel (Taxol) results in an agent, Tx-67, with reduced interactions with P-gp and enhanced permeation across the BBB in both in vitro and in situ models. Our studies demonstrate the feasibility of making small chemical modifications to Taxol to generate analogs with reduced affinity for the P-gp but retention of MT-stabilizing properties, i.e., a taxane that may reach and treat therapeutic targets in the CNS.     

A Novel Neutrotrophic Property Of Glucagon-Like Peptide 1: A Promoter Of Nerve Growth Factor-Mediated Differentiation In PC12 Cells

The insulinotropic hormone glucagon-like peptide-1 (7-36)-amide (GLP-1) has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation and is presently in clinical trials as a therapy for type 2 diabetes mellitus. We report on the effects of GLP-1 and two of its long-acting analogs, exendin-4 and exendin-4 WOT, on neuronal proliferation and differentiation, and on the metabolism of two neuronal proteins in the rat pheochromocytoma (PC12) cell line, which has been shown to express the GLP-1 receptor. We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin (9-39). Furthermore, exendin-4 could promote NGF-initiated differentiation and may rescue degenerating cells after NGF-mediated withdrawal. These effects were induced in the absence of cellular dysfunction and toxicity as quantitatively measured by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays, respectively. Our findings suggest that such peptides may be used in reversing or halting the neurodegenerative process observed in neurodegenerative diseases, such as the peripheral neuropathy associated with type 2 diabetes mellitus and Alzheimer's and Parkinson's diseases. Due to its novel twin action, GLP-1 and exendin-4 have therapeutic potential for the treatment of diabetic peripheral neuropathy and these central nervous system disorders.     

The role of cannabinoids and leptin in neurological diseases

Cannabinoids exert a neuroprotective influence on some neurological diseases, including Alzheimer's, Parkinson's, Huntington's, multiple sclerosis and epilepsy. Synthetic cannabinoid receptor agonists/antagonists or compounds can provide symptom relief or control the progression of neurological diseases. However, the molecular mechanism and the effectiveness of these agents in controlling the progression of most of these diseases remain unclear. Cannabinoids may exert effects via a number of mechanisms and interactions with neurotransmitters, neurotropic factors and neuropeptides. Leptin is a peptide hormone involved in the regulation of food intake and energy balance via its actions on specific hypothalamic nuclei. Leptin receptors are widely expressed throughout the brain, especially in the hippocampus, basal ganglia, cortex and cerebellum. Leptin has also shown neuroprotective properties in a number of neurological disorders, such as Parkinson's and Alzheimer's. Therefore, cannabinoid and leptin hold therapeutic potential for neurological diseases. Further elucidation of the molecular mechanisms underlying the effects on these agents may lead to the development of new therapeutic strategies for the treatment of neurological disorders.     

Marcel Proust: genius and insomnia

Marcel Proust is considered one the greatest novelists of all times. His life was characterised by a long list of diseases. We analyse an important illness suffered by Proust: insomnia. It began in childhood and continued throughout his life, worsening progressively, and leading to a complete reversal of the sleep–wake cycle in the last years of the novelist's life. Several factors may be involved in the pathogenesis of Proust's insomnia. The beginning of insomnia since childhood, its characteristics, and the lack of precipitating factors suggest a form of idiopathic insomnia. Psychological traits of his personality (severe anxiety and depression) may have played a central role in the onset of insomnia. Further factors such as asthma and intake of stimulating substances may have had an important role in the maintenance and worsening of his insomnia. This sleep disorder affected both the lifestyle and literary genius of Marcel Proust. Insomnia is the prominent figure in the first novel (“Swann's way”) of Proust's masterpieces entitled “In search of lost time,” in which the novelist begins his journey through involuntary memory starting from his insomnia.     

The neuroprotective role of melatonin in neurological disorders

Melatonin is a neurohormone secreted from the pineal gland and has a wide‐ranging regulatory and neuroprotective role. It has been reported that melatonin level is disturbed in some neurological conditions such as stroke, Alzheimer's disease, and Parkinson's disease, which indicates its involvement in the pathophysiology of these diseases. Its properties qualify it to be a promising potential therapeutic neuroprotective agent, with no side effects, for some neurological disorders. This review discusses and localizes the effect of melatonin in the pathophysiology of some diseases.     

Deciphering the Roles of Trehalose and Hsp104 in the Inhibition of Aggregation of Mutant Huntingtin in a Yeast Model of Huntington’s Disease

Despite the significant amount of experimental data available on trehalose, the molecular mechanism responsible for its intracellular stabilising properties has not emerged yet. The repair of cellular homeostasis in many protein-misfolding diseases by trehalose is credited to the disaccharide being an inducer of autophagy, a mechanism by which aggregates of misfolded proteins are cleared by the cell. In this work, we expressed the pathogenic N-terminal fragment of huntingtin in Δnth1 mutant (unable to degrade trehalose) of Saccharomyces cerevisiae BY4742 strain. We show that the presence of trehalose resulted in the partitioning of the mutant huntingtin in the soluble fraction of the cell. This led to reduced oxidative stress and improved cell survival. The beneficial effect was independent of the expression of the major cellular antioxidant enzyme, superoxide dismutase. Additionally, trehalose led to the overexpression of the heat shock protein, Hsp104p, in mutant huntingtin-expressing cells, and resulted in rescue of the endocytotic defect in the yeast cell. We propose that at least in the initial stages of aggregation, trehalose functions as a stabiliser, increasing the level of monomeric mutant huntingtin protein, with its concomitant beneficial effects, in addition to its role as an inducer of autophagy.     

Membrane fluidity effects of estratrienes

Estrogens have demonstrable neuroprotective effects. This fact has lead to the proposed use of estrogens for the prevention and/or treatment of Alzheimer's disease. The exact protective mechanism estrogens provide is not fully understood. In this report, a potential non-genomic mechanism for estratrienes involving alterations in membrane fluidity was studied. Steroids, such as estrogen, are known to be membrane-active and can alter the lipid packing. In this study we used fluorescent methodologies to address the effect of naturally occurring steroids (17alpha and 17beta-estradiol, testosterone, and progesterone) and new estratriene analogs on membrane fluidity using liposomes and HT-22 hippocampal cells. The study's results indicate steroids, based on the estratriene nucleus, can modulate lipid packing as evidenced by (1) decreased membrane fusion events and (2) decreased membrane fluidity. The effects on the membrane were both time and concentration dependent. It was also demonstrated through rational design estratriene analogs can be synthesized with enhanced membrane effects. Finally, in a glutamate-induced toxicity HT-22 model, we also demonstrated cellular protection with the estratriene-based molecules and analogs. The data suggest the plethora of cellular actions of estrogens may relate to or be influenced by membrane effects of the steroid.     

Attachment,pain and detachment for the adults in divorce

Working from Beck's latest theoretical model (modes model, 1996), this study aimed to investigate cognitive and affective factors which may help to understand the processes involved in erectile dysfunction. Results suggest that sexually dysfunctional subjects differ from functional subjects in a range of cognitive and affective variables: sexual attitudes ('macho latino' attitude, demands for women's satisfaction and catastrophization of sexual failure consequences); automatic thoughts in sexual situations (performance demand and failure anticipation thoughts) and affect in the sexual context (essentially negative and directly connected to the above mentioned automatic thoughts). Results permit a re-examination of the main role performed by the cognitive-affective factors in sexual dysfunctional processes of this dysfunction and possibly suggest some future therapeutic approaches.     

Opioid system functional regulation in neurological disease management

There is increasing evidence to suggest a role for the opioid system in the control of pathophysiology of neurological disorders (Alzheimer's, Parkinson's, and Huntington's diseases, spinal cord injury, epilepsy, hypoxia, and autism). Resuscitation of the altered expression of the opioid system in various neurological disorders is of therapeutic importance. Such treatment may be beneficial in ameliorating the clinical symptoms of the disorder. This Mini‐Review provides a brief update on opioid system regulation in neurological disorders and focuses on the opioids' pharmacological importance. © 2010 Wiley‐Liss, Inc.     

Mini review – The role of Glucocerebrosidase and Progranulin as possible targets in the treatment of Parkinson's disease

As per recent reports, there is an association between glucocerebrosidase (Gcase) enzyme and Parkinson's disease (PD). In addition, certain mutations in the Gcase gene (GBA) and the progranulin (PGRN) gene are found to be linked with the imbalance in the levels of Gcase enzyme. This imbalance or decrease or impairment in Gcase activity can lead to Gaucher disease, frontotemporal lobar degeneration (FTLD), dementia, etc. Recent evidences suggest that the drugs used to treat these diseases can be used for PD. The present review has focused on the therapeutic approaches used for diseases linked with Gcase enzyme, which can be used for PD. The review also considered possible target specific novel strategies, which may help to meet the unmet needs in the treatment of PD.     

Frontotemporal degeneration,the next therapeutic frontier: Molecules and animal models for frontotemporal degeneration drug development

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled “FTD, the Next Therapeutic Frontier,” which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.