What do we know about the mechanism of action of the placebo?

The placebo is a substance or a procedure capable to induce a subjective or objective healing effect, but which efficacy or mechanism of action could not be demonstrated by the conventional scientific procedures. The main objective of this review is to synthesize the theories about the way the placebo acts. Conditioning, expectancy and desire theories, as well as the possible symbolic level in which placebo acts are reviewed. Some recent investigations showed that nerobiological responses elicited by placebo administration mimic those induced by it corresponding active drug. Finally, following evidences from development research, we suggest, that early expierences provide individuals with a "correction program of physiological functions" which could be eventually activated by contextual clues, as placebo.     

Is Phosphodiesterase inhibition a new mechanism of antidepressant action?

Summary Unlike conventional antidepressants, rolipram (a new approach in the treatment of depression) stimulates both the presynaptic and the postsynaptic component of monoaminergic transmission. Several double blind trials are under way to assess the clinical efficacy and safety of this compound. The present study was a randomized, 4-week interindividual double blind double-dummy comparison with desipramine in inpatients with major (DSM-III) and/or endogenous (ICD-9) depressions. After a minimum washout period of three days the patients received either 0.50 mg rolipram or 25 mg desipramine orally t.i.d. for the first three days, then 0.75 mg rolipram or 50 mg desipramine t.i.d. until day 28. Rating tests were based principally on the AMDP-system and the HAMD scale. The study showed no differences between the two drugs as regards the efficacy, but a definite trend in favour of rolipram as regards the side effects and, in particular, anticholinergic effects.     

Antiepileptic drug discovery: does mechanism of action matter?

This commentary discusses briefly the role of the mechanism of antiepileptic action in discovery of drugs for the treatment of epilepsy. More specifically, two questions are addressed. (1) Has mechanism-driven antiepileptic drug discovery brought us better epilepsy treatment? Although this question is difficult to answer, the short answer is "not yet." Modern antiepileptic drugs with new or modified mechanisms of action do not seem to have substantially improved the efficacy or the safety of epilepsy treatment. In fact, some modern antiepileptic drugs such as progabide, tiagabine, and vigabatrin have been associated with a number of safety issues. (2) Why do drugs with new mechanisms seem to have failed to deliver better treatment? Although it is always difficult to know why something did not occur, one putative explanation may be worthwhile to consider. The past development of new antiepileptic drugs targeted putative mechanisms of seizure generation. As seizures are only symptoms of the underlying epilepsy, blocking seizure generation can provide at best only symptomatic treatment. It may be that the failure in treating drug-resistant seizures is related, at least in part, to the failure of current drugs in targeting the mechanisms underlying epilepsy. In conclusion, continuing to develop new antiepileptic drugs for drug-resistant epilepsy by targeting seizure generation may be futile and one possible explanation of why we do not seem to make substantial progress in the treatment of drug-resistant epilepsy. Developing antiepileptic drugs with antiepileptogenic activity may be a clue to better treatment of presently drug-resistant epilepsy.     

Psychopharmacology of anticonvulsants: do all anticonvulsants have the same mechanism of action?

ISSUE: Anticonvulsants are not a single therapeutic class, but are composed of multiple distinct subclasses with different mechanisms of action, efficacies, and side effects.     

Thought–action fusion as a mediator of religiosity and obsessive-compulsive symptoms

Background and ObjectivesThought-action fusion (TAF), or maladaptive cognitions regarding the relationship between mental events and behaviours, has been implicated in the development and maintenance of obsessive-compulsive disorder (OCD). As some religions promote TAF-like appraisals, it has been proposed that religiosity may play a role in the transformation of normally occurring intrusive thoughts into clinically distressing obsessions. No research, however, has experimentally investigated the mediating role of TAF on the relationship between religiosity and OC symptoms.Methods85 Christian, Jewish, and Atheist/Agnostic participants were exposed to an experimental thought-induction protocol and reported on their associated levels of distress, guilt, feelings of responsibility, and urge to suppress target intrusions experienced during a 5-min monitoring period. Participants also completed measures of obsessive-compulsive symptomatology, TAF beliefs, and general psychopathology.ResultsUsing PROCESS and bootstrapping analyses, a test of the conditional indirect effects of religiosity on obsessive-compulsive symptoms revealed that Christianity moderated the effects of religiosity on moral TAF beliefs, which in turn mediated the relationship between religiosity and obsessive-compulsive symptoms. Furthermore, in the Christian group, moral TAF beliefs mediated the relationship between religiosity and ratings of guilt and responsibility following the experimental protocol.LimitationsThe use of university students with moderate levels of religiosity.ConclusionsCollectively the results suggest that obsessional thinking is not attributable to religion per se, but that teachings underlying certain religious doctrines may fuel TAF beliefs that are implicated in the maintenance of OCD.     

The mechanism of action of angiostatin: can you teach an old dog new tricks?

What is angiostatin? In 1994, Folkman and colleagues published a landmark paper describing anti-tumor effects in mice with a purified fragment of plasminogen they named angiostatin (1). Although many papers have been published describing activities of cryptic polypeptides derived from plasminogen fragments, this was the first report which associated plasminogen kringles 1-4 as a suppressor of metastasis development. This review will describe what is known about the mechanism of action of angiostatin from the current literature.     

Is the organisation of goal-directed action modality specific? A common temporal structure

With the help of kinematic analysis, the temporal organization of the complex daily activity 'drinking from a bottle with a glass' was described in detail. The analysis focused on the sequential action structure, the prehensile acts, and the bimanual coordination as well as on the effect of different instruction modalities on these parameters to explore the underlying representation for this complex action. Movements of the two arms were recorded in three-dimensional space with the help of an optoelectronic device in 12 normal subjects under four conditions: (1) action pantomime after verbal instruction; (2) action imitation after observation of the action performed by the experimenter without the objects; (3) action pantomime while seeing, but not touching the objects; and finally (4) action execution with objects.Despite high execution variability, the temporal structure of the action could be precisely described by the relative duration and peak velocity of action segments, by the MGA-object size-correlation, and by linear regression analysis between the onsets of functionally related action segments. A similar structure of the action as characterized by these kinematic parameters was retained across different instruction modalities. Only when the action was executed with the objects, the interval between the movement onsets of either hand and the peak velocity of the manipulative acts were reduced, while no change was observed across the other three instruction modalities. This stability of the temporal structure suggests the existence of a level in the representation of an action where all the modalities converge.     

Identification of novel small molecule activators of nuclear factor-κB with neuroprotective action via high-throughput screening

Neuronal noncytokine-dependent p50/p65 nuclear factor-κB (the primary NF-κB complex in the brain) activation has been shown to exert neuroprotective actions. Thus neuronal activation of NF-κB could represent a viable neuroprotective target. We have developed a cell-based assay able to detect NF-κB expression enhancement, and through its use we have identified small molecules able to up-regulate NF-κB expression and hence trigger its activation in neurons. We have successfully screened approximately 300,000 compounds and identified 1,647 active compounds. Cluster analysis of the structures within the hit population yielded 14 enriched chemical scaffolds. One high-potency and chemically attractive representative of each of these 14 scaffolds and four singleton structures were selected for follow-up. The experiments described here highlighted that seven compounds caused noncanonical long-lasting NF-κB activation in primary astrocytes. Molecular NF-κB docking experiments indicate that compounds could be modulating NF-κB-induced NF-κB expression via enhancement of NF-κB binding to its own promoter. Prototype compounds increased p65 expression in neurons and caused its nuclear translocation without affecting the inhibitor of NF-κB (I-κB). One of the prototypical compounds caused a large reduction of glutamate-induced neuronal death. In conclusion, we have provided evidence that we can use small molecules to activate p65 NF-κB expression in neurons in a cytokine receptor-independent manner, which results in both long-lasting p65 NF-κB translocation/activation and decreased glutamate neurotoxicity.     

Facilitative effects of VNS on the motor threshold: implications for its antidepressive mode of action?

In the present study, the effects of vagus nerve stimulation (VNS) on the resting motor threshold (rMT) of patients treated with repetitive transcranial magnetic stimulation were evaluated. Patients showed a significant decrease in the rMT during VNS-on stimulation. VNS was the only significant factor affecting rMT changes and did not appear to be a static variable. Further studies should focus on the effect of VNS on neural neurogenesis in depressive disorders, and the effects of other treatment options for major depressive disorder on the rMT should also be determined.     

Neuroprotective action of proline-rich polypeptide-1 in β-amyloid induced neurodegeneration in rats

It is recognized that the main trigger of Alzheimer disease related neurodegeneration is β-amyloid peptide, which subsequently generates different metabolic disorders in neuron and finally leads to neuronal death. Several biologically active products were tested as neuroprotectors, but only few of them demonstrated any efficiency. Proline-rich polypeptide-1 was tested as a neuroprotective agent on Aβ25-35 animal model of Alzheimer disease. Biochemical analysis (determination of spectrum of neuroactive amino acids, such as glutamate, gamma-aminobutyric acid, glycine, aspartate and taurine), as well as behavioral, electrophysiological and morphological studies were performed to reveal the neuroprotective potential of proline-rich polypeptide in rats. Based on the results of our study it can be concluded that proline-rich polypeptide-1 has a potential to be one of the effective preventive or therapeutic agents against neurodegenerative disorders, such as Alzheimer disease.     

Functional significance of the rapid regulation of brain estrogen action: where do the estrogens come from?

Estrogens exert a wide variety of actions on reproductive and non-reproductive functions. These effects are mediated by slow and long lasting genomic as well as rapid and transient non-genomic mechanisms. Besides the host of studies demonstrating the role of genomic actions at the physiological and behavioral level, mounting evidence highlights the functional significance of non-genomic effects. However, the source of the rapid changes in estrogen availability that are necessary to sustain their fast actions is rarely questioned. For example, the rise of plasma estrogens at pro-estrus that represents one of the fastest documented changes in plasma estrogen concentration appears too slow to explain these actions. Alternatively, estrogen can be synthesized in the brain by the enzyme aromatase providing a source of locally high concentrations of the steroid. Furthermore, recent studies demonstrate that brain aromatase can be rapidly modulated by afferent inputs, including glutamatergic afferents. A role for rapid changes in estrogen production in the central nervous system is supported by experiments showing that acute aromatase inhibition affects nociception as well as male sexual behavior and that preoptic aromatase activity is rapidly (within min) modulated following mating. Such mechanisms thus fulfill the gap existing between the fast actions of estrogen and their mode of production and open new avenues for the understanding of estrogenic effects on the brain.     

Amplitude of sensory nerve action potential in early stage diabetic peripheral neuropathy： an analysis of 500 cases

Early diagnosis of diabetic peripheral neuropathy is important for the successful treatment of diabetes mellitus. In the present study, we recruited 500 diabetic patients from the Fourth Affiliated Hospital of Kunming Medical University in China from June 2008 to September 2013：221 cases showed symptoms of peripheral neuropathy （symptomatic group） and 279 cases had no symptoms of peripheral impairment （asymptomatic group）. One hundred healthy control subjects were also recruited. Nerve conduction studies revealed that distal motor latency was longer, sensory nerve conduction velocity was slower, and sensory nerve action potential and amplitude of compound muscle action potential were significantly lower in the median, ulnar, posterior tibial and common peroneal nerve in the diabetic groups compared with control subjects. Moreover, the alterations were more obvious in patients with symptoms of peripheral neuropathy. Of the 500 diabetic patients, neural conduction abnormalities were detected in 358 cases （71.6%）, among which impairment of the common peroneal nerve was most prominent. Sensory nerve abnormality was more obvious than motor nerve abnormality in the diabetic groups. The amplitude of sensory nerve action potential was the most sensitive measure of peripheral neuropathy. Our results reveal that varying degrees of nerve conduction changes are present in the early, asymptomatic stage of diabetic peripheral neuropathy.