Preparation of Clinically Useful Sennoside-reduced Rhubarb.

OBJECTIVE: The aim of this study was to develop a method of removing sennoside to reduce the cathartic effect of rhubarb while conserving its other pharmacological activities. METHODS: Rhubarb powder was steam autoclaved at 121°C and 0.14 MPa for 20, 60, or 120 minutes, and HPLC analysis was conducted to determine levels of rhubarb components. Mice were fed non-autoclaved or 20-minute-autoclaved rhubarb extracts. Feces were collected and weighed over a 24-hour period. India ink was orally administered to determine the distance of fecal migration through the intestinal tract. RESULTS: Autoclaving 20, 60, and 120 minutes decreased sennoside A and B to trace levels but only autoclaving 20 minutes conserved most of the (+)-catechin, (-)-epicatechin, and (-)-epicatechin gallate contents (i.e., 69%, 90%, 88%, respectively). Therefore only rhubarb autoclaved for 20 minutes was used in subsequent experiments. Fecal output (in g) in mice treated with water (control), autoclaved rhubarb, and non-autoclaved rhubarb was 2.78 ± 0.07, 3.30 ± 0.13 (p = 0.348), and 3.81 ± 0.07 (p = 0.005). India ink migration was far less in mice treated with autoclaved rhubarb vs non-autoclaved rhubarb. CONCLUSION: Steam autoclaving the rhubarb for 20 minutes reduces sennoside levels and its cathartic activity while conserving its other pharmacological activities.

Thalamic contributions to Basal Ganglia-related behavioral switching and reinforcement.

Although the existence of prominent connections between the intralaminar thalamic nuclei and the basal ganglia has long been established, the limited knowledge of the functional relevance of this network has considerably hampered progress in our understanding of the neural mechanisms by which the thalamostriatal system integrates and regulates the basal ganglia circuitry. In this brief commentary, we will address this gap of knowledge through a discussion of the key points of a symposium entitled "Thalamic Contributions to Basal Ganglia-Related Behavioral Switching and Reinforcement" that will be presented at the 2011 Society for Neuroscience meeting. Recent anatomical and physiological data that support the role of the thalamostriatal system in action selection, attentional shifting, and reinforcement will be discussed. We will also address the possibility that degeneration of the thalamostriatal system could underlie some of the deficits in redirection of attention in response to salient stimuli seen in Parkinson's disease.

Roles of the thalamic CM-PF complex-Basal ganglia circuit in externally driven rebias of action.

The centromedian (CM)-parafascicular (PF) nuclear complex in the primate thalamus has reciprocal and specific connections with the basal ganglia. It has been argued that the thalamic CM-PF complex has a role in pain processing and attention. However, the functional relationship of this complex with the basal ganglia, which is considered to have a role in goal-directed movement, has not been well characterized. Here we present a hypothetical view that the thalamic CM-PF complex-basal ganglia circuit plays complementary roles in response bias. The basal ganglia are involved in creating 'reward-based pre-action bias', which facilitates the selection and execution of an action associated with a higher value. In contrast, when an action with a lower value is unexpectedly requested, the CM-PF induces an 'externally driven rebiasing' process in the striatum that aborts the pre-action bias and assists selecting and executing actions appropriate for unexpected situations. This model provides a framework for how the thalamic CM-PF complex and the basal ganglia function together in general for unexpected situations.

Peony root extract upregulates transthyretin and phosphoglycerate mutase in mouse cobalt focus seizure.

Cobalt focus is a seizure focus model in which cerebral neurons exhibit long-lasting severe spike discharges, followed by neuronal death. However, the neuronal death is prevented when peony root extract (PR) is administered prior to cobalt application. We tested the hypothesis that PR modulates the expression of neuroprotective proteins in the cerebrum of mouse cobalt focus by proteomic analysis using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry to screen for differentially expressed proteins. Analyses revealed that transthyretin, a carrier protein for thyroid hormones and retinoids, and the brain form of phosphoglycerate mutase, a glycolytic enzyme, were upregulated in the cobalt-treated mouse cerebrum and further increased by PR administration in association with upregulation of neurogranin/RC3, a target of the transcriptional activation by thyroid hormones and retinoids. These findings suggest that PR-induced protection of mouse cerebral neurons involves neurotrophic events caused by thyroid hormones and/or retinoids and enhanced glycolysis.

History- and current instruction-based coding of forthcoming behavioral outcomes in the striatum.

Animals optimize behaviors by predicting future critical events based on histories of actions and their outcomes. When behavioral outcomes like reward and aversion are signaled by current external cues, actions are directed to acquire the reward and avoid the aversion. The basal ganglia are thought to be the brain locus for reward-based adaptive action planning and learning. To understand the role of striatum in coding outcomes of forthcoming behavioral responses, we addressed two specific questions. First, how are the histories of reward and aversion used for encoding forthcoming outcomes in the striatum during a series of instructed behavioral responses? Second, how are the behavioral responses and their instructed outcomes represented in the striatum? We recorded discharges of 163 presumed projection neurons in the striatum while monkeys performed a visually instructed lever-release task for reward, aversion, and sound outcomes, whose occurrences could be estimated by their histories. Before outcome instruction, discharge rates of a subset of neurons activated in this epoch showed positive or negative regression slopes with reward history (24/44), that is, to the number of trials since the last reward trial, which changed in parallel with reward probability of current trials. The history effect was also observed for the aversion outcome but in far fewer neurons (3/44). Once outcomes were instructed in the same task, neurons selectively encoded the outcomes before and after behavioral responses (reward, 46/70; aversion, 6/70; sound, 6/70). The history- and current instruction-based coding of forthcoming behavioral outcomes in the striatum might underlie outcome-oriented behavioral modulation.

Molecular mechanism of preventive effect of peony root extract on neuron damage.

The molecular mechanism of the protective effects of peony root extract and its component substances on neuron damage induced by the cobalt focus epilepsy model and the EL mouse was investigated. Long-term administration of peony root extract for 30 days prior to metallic cobalt powder application to the cerebral cortex of mice resulted in increased expression of A20, an inhibitor gene of cell death. In the EL mouse, a hereditary epilepsy animal model with vulnerable neurons, increased expression of A20 was observed even without administration of peony root extract. Long-term administration of peony root extract to the EL mouse resulted in a marked increase of expression of A20. These results suggested that an increase in A20 expression is the main molecular mechanism of protective action of peony root extract on neuron damage.

Tonically active neurons in the primate caudate nucleus and putamen differentially encode instructed motivational outcomes of action.

To achieve a goal, animals procure immediately available rewards, escape from aversive events, or endure the absence of rewards. The neuronal substrates for these goal-directed actions include the limbic system and the basal ganglia. In the striatum, tonically active neurons (TANs), presumed cholinergic interneurons, were originally shown to respond to reward-associated stimuli and to evolve their activity through learning. Subsequent studies revealed that they also respond to aversive event-associated stimuli such as an airpuff on the face and that they are less selective to whether the stimuli instruct reward or no reward. To address this paradox, we designed a set of experiments in which macaque monkeys performed a set of visual reaction time tasks while expecting a reward, during escape from an aversive event, and in the absence of a reward. We found that TANs respond to instruction stimuli associated with motivational outcomes (312 of 390; 80%) but not to unassociated ones (51 of 390; 13%), and that they mostly differentiate associated instructions (217 of 312; 70%). We also found that a higher percentage of TANs in the caudate nucleus respond to stimuli associated with motivational outcomes (118 of 128; 92%) than in the putamen (194 of 262; 74%), whereas a higher percentage of TANs in the putamen respond to go signals for the lever release (112 of 262; 43%) than in the caudate nucleus (27 of 128; 21%), especially for an action expecting a reward. These findings suggest a distinct, pivotal role of TANs in the caudate nucleus and putamen in encoding instructed motivational contexts for goal-directed action planning and learning.