Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations.

Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature.

Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations.

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method.

Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans.

The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration-dependent hyperthermia.

Regional distribution of sodium-dependent excitatory amino acid transporters in rat spinal cord.

Background/objective: The excitatory amino acid transporters (EAATs), or sodium-dependent glutamate transporters, provide the primary mechanism for glutamate removal from the synaptic cleft. EAAT distribution has been determined in the rat brain, but it is only partially characterized in the spinal cord.

Methods: The regional anatomic distribution of EAATs in spinal cord was assessed by radioligand autoradiography throughout cervical, thoracic, and lumbar cord levels in female Sprague-Dawley rats.

Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus.

Exercise is an important facet of behavior that enhances brain health and function. Increased expression of the plasticity molecule brain-derived neurotrophic factor (BDNF) as a response to exercise may be a central factor in exercise-derived benefits to brain function. In rodents, daily wheel-running exercise increases BDNF gene and protein levels in the hippocampus.

Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome.

Amyloid-beta (Abeta) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimer's disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of Abeta clearance on the development of tau pathology. Here we show that Abeta immunotherapy reduces not only extracellular Abeta plaques but also intracellular Abeta accumulation and most notably leads to the clearance of early tau pathology.

Assessment of behavior in animal models of spinal cord injury.

There has been a significant increase in the amount of research directed at understanding pathologic and behavioral consequences of spinal cord injury (SCI), and attempts to promote recovery of function. Several different approaches can be used to induce SCI; each has particular strengths and weaknesses. Ultimately, behavior is an extremely relevant outcome measure for determining the functional consequences of the initial injury, spontaneous recovery of function, and the efficacy of therapeutic interventions that are developed.

Spatial learning is delayed and brain-derived neurotrophic factor mRNA expression inhibited by administration of MK-801 in rats.

Brain-derived neurotrophic factor (BDNF) is involved in activity-dependent plasticity and interacts with the neurotransmitter glutamate. Glutamate N-methl-D-aspartate (NMDA) receptor activation increases BDNF expression, while BDNF facilitates NMDA activity, with both involved in spatial learning. Administration of the NMDA receptor antagonist MK-801 can impair this leaning.

Can estrogen play a significant role in the prevention of Alzheimer's disease?

In women the abrupt decline estrogen levels at menopause may be associated with cognitive deficits and increased risk for Alzheimer's disease (AD); estrogen replacement therapy may reduce this risk. Animal studies indicate that estrogen modulates neurotransmitter systems, regulates synaptogenesis, and is neuroprotective. These beneficial effects occur in brain areas critical to cognitive function and involved in AD.

Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum.

Brain-derived neurotrophic factor (BDNF) enhances synaptic plasticity and neuron function. We have reported that voluntary exercise increases BDNF mRNA levels in the hippocampus; however, mechanisms underlying this regulation have not been defined. We hypothesized that medial septal cholinergic and/or gamma amino butyric acid (GABA)ergic neurons, which provide a major input to the hippocampus, may regulate the baseline gene expression and exercise-dependent gene upregulation of this neurotrophin.

Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer's disease and Down's syndrome brain.

Granulovacuolar degeneration (GVD) is a diagnostic neuropathological feature of Alzheimer's disease (AD). In some neurons, apoptosis has been hypothesized to be a primary mechanism causing neuronal cell death in AD. In this study we investigated CA1 neurons with GVD in AD and Down's syndrome (DS) brain.

Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus.

We investigated the possibility that estrogen and exercise interact in the hippocampus and regulate brain-derived neurotrophic factor (BDNF), a molecule increasingly recognized for its role in plasticity and neuron function. An important aspect of this study is to examine the effect of different time intervals between estrogen loss and estrogen replacement intervention. We demonstrate that in the intact female rat, physical activity increases hippocampal BDNF mRNA and protein levels.

Spatial learning induces neurotrophin receptor and synapsin I in the hippocampus.

We report that rats learning a spatial memory task in the Morris water maze show elevated expression of the signal transduction receptor for BDNF and the synaptic associated protein synapsin I in the hippocampus. Nuclease protection assays showed maximal levels of TrkB and synapsin I mRNAs in the hippocampus by the time that asymptotic learning performance had been reached (Day 6). Increases in synapsin I mRNA were matched by changes in synapsin I protein as revealed by western blot analysis.

Culture and regeneration of human neurons after brain surgery.

Cortical human brain tissue was obtained from 11 craniotomies for intractable epilepsy or tumor resection. Neuregen transport medium preserved viability at 4 degrees C during transfer to the culture laboratory. Cells were isolated and cultured by methods previously developed for adult rat neurons (Brewer GJ.

Physical activity-antidepressant treatment combination: impact on brain-derived neurotrophic factor and behavior in an animal model.

The mechanism of antidepressant action, at the cellular level, is not clearly understood. It has been reported that chronic antidepressant treatment leads to an up-regulation of brain-derived neurotrophic factor (BDNF) mRNA levels in the hippocampus, and that physical activity (voluntary running) enhances this effect. We wished to investigate whether BDNF expression brought about by these interventions may overcome deficits caused by acute stress, and might impact behavior in an animal model.

Expression of metabotropic glutamate receptor 5 is increased in astrocytes after kainate-induced epileptic seizures.

In the CNS there is a differential distribution of the metabotropic glutamate receptor 5 (mGluR5) in neurons and glia. Hippocampal nerve cells contain large amounts of the receptor transcript and protein that are expressed at very low levels in astrocytes. This is unexpected, as mGluR-induced phosphoinositide hydrolysis is substantial in cultured astrocytes and is mediated only by mGluR5 in these cells.

Learning upregulates brain-derived neurotrophic factor messenger ribonucleic acid: a mechanism to facilitate encoding and circuit maintenance?

Brain-derived neurotrophic factor (BDNF) promotes neuron survival, enhances sprouting, protects neurons against insult, and may be involved in several aspects of learning and memory. In this study, rats trained to locate a submerged platform in a water maze had elevated levels of BDNF messenger ribonucleic acid (mRNA) in the hippocampus (p < .05), a structure associated with spatial memory.

Spatial learning and physical activity contribute to the induction of fibroblast growth factor: neural substrates for increased cognition associated with exercise.

New evidence indicates that neural activity regulates the expression of trophic factors in the brain but regulation of these molecules by select aspects of behaviour remains solely a fascinating possibility. We report that following training in the Morris water maze, a spatial memory task, the hippocampus and cerebellum of learning rats exhibited an increase in basic fibroblast growth factor messenger RNA. Basic fibroblast growth factor messenger RNA levels were higher during the learning of the task and decreased once asymptotic performance was reached, suggesting an involvement of basic fibroblast growth factor in learning/memory.

Life-long dietary restriction attenuates age-related increases in hippocampal glial fibrillary acidic protein mRNA.

The expression of astrocyte-specific glial fibrillary acidic protein increases after experimental lesions and is elevated throughout the brain in aged rodents and primates. Clusterin (ApoJ) expression increases in astrocytes and microglia after lesions, but changes during aging have not been reported. Dietary restriction (DR) delays the onset and progression of many age-related physiological deficits in rodents.

Memory training for individuals with Alzheimer's disease improves name recall.

Alzheimer's disease is clinically characterized by a variety of progressive cognitive deficits, most notably an impaired ability to acquire new information, such as name recall. Eleven demented patients and 11 controls participated in a 4 week memory program that included training in name-face recall. Individuals were taught strategies for name-face rehearsal, and administered task specific and standardized tests to assess the intervention efficacy.

Roles of metabotropic glutamate receptors in brain plasticity and pathology.

In summary, the mGluRs are a large family of receptor subtypes with diverse properties in terms of transduction coupling, pharmacology, and anatomical distribution. Many divergent studies have demonstrated that activation of these receptors can result in either neuroprotection or neuropathology. We hypothesized that the mGluRs of astrocytes may have a role in determining the response following administration of mGluR agonists in vivo, and we have defined a suitable in vitro model for the study of these receptors.

Vulnerability of the hippocampus to kainate excitotoxicity in the aged, mature and young adult rat.

Sensitivity to excitotoxic damage was assessed in young adult, mature and aged male Sprague-Dawley rats. Kainic acid was injected into the hippocampus and the size of the hippocampal lesion rated. Intrahippocampal injection of kainic acid produced lesions in aged animals that were significantly smaller than lesions in the young rats (P < 0.

Magnetic resonance imaging of the aging brain in Down syndrome.

MRI studies to date have confirmed and expanded upon findings of morphologic differences between the brains of subjects with DS and those of the general population found by CT and post-mortem examination. [table; see text] Hippocam pal and neocortical structures are smaller in DS while unexpectedly the parahippocampal gyrus was found to be larger. MRI has demonstrated that subjects with DS develop signs associated with [table; see text] brain aging at an earlier age.

Decreased levels of C1q in cerebrospinal fluid of living Alzheimer patients correlate with disease state.

Recent reports that complement proteins comprising the classical pathway are associated with senile plaques suggest that activation of the classical complement cascade in Alzheimer's disease tissue results in bystander cell lysis and may contribute to AD neuropathology. Analysis of cerebrospinal fluid may prove to be a useful means of detecting changes in immunological activity in the brain. We use an enzyme-linked immunosorbent assay to measure levels of C1q, a subunit of the classical complement cascade, in the CSF of patients clinically diagnosed with possible or probable AD.