Just of interest....

MHP-133, a Drug with Multiple CNS Targets: Potential for Neuroprotection and Enhanced Cognition.

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MHP-133, a Drug with Multiple CNS Targets: Potential for Neuroprotection and Enhanced Cognition.

Neurochem Res. 2007 Apr 3;

Authors: Buccafusco JJ, Powers JC, Hernandez MA, Prendergast MA, Terry AV, Jonnala RR

MHP-133 is one of a novel series of compounds designed to target multiple brain substrates expected to have synergistic actions in the treatment of cognitive and neurodegenerative disorders such as Alzheimer's disease. The strategy was to develop compounds with multiple targets relevant for enhancing cognition and memory, but avoiding the serious side effects attributed to high potency cholinergic agonists. MHP-133 was shown to interact with subtypes of cholinergic, serotonergic, and imidazoline receptors and to weakly inhibit acetylcholinesterase activity. In vitro, the drug enhanced nerve growth factor (TrkA) receptor expression; it prevented excitotoxicity in a hippocampal slice preparation; and increased the secretion of soluble (non-toxic) amyloid precursor protein. MHP-133 also enhanced cognitive performance by rats and by non-human primate in tasks designed to assess working memory. The results of this study are consistent with the potential use of MHP-133 in the treatment of neurodegenerative disorders such as Alzheimer's disease.

PMID: 17404838 [PubMed - as supplied by publisher]

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Endocannab review

Endocannabinoids and synaptic function in the CNS.

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Endocannabinoids and synaptic function in the CNS.

Neuroscientist. 2007 Apr;13(2):127-37

Authors: Hashimotodani Y, Ohno-Shosaku T, Kano M

Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance. NEUROSCIENTIST 13(2):127-137, 2007.

PMID: 17404373 [PubMed - in process]

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WM and cellular correlates

From cognitive to neural models of working memory.

From cognitive to neural models of working memory.

Philos Trans R Soc Lond B Biol Sci. 2007 Mar 30;

Authors: D'Esposito M

Working memory refers to the temporary retention of information that was just experienced or just retrieved from long-term memory but no longer exists in the external environment. These internal representations are short-lived, but can be stored for longer periods of time through active maintenance or rehearsal strategies, and can be subjected to various operations that manipulate the information in such a way that makes it useful for goal-directed behaviour. Empirical studies of working memory using neuroscientific techniques, such as neuronal recordings in monkeys or functional neuroimaging in humans, have advanced our knowledge of the underlying neural mechanisms of working memory. This rich dataset can be reconciled with behavioural findings derived from investigating the cognitive mechanisms underlying working memory. In this paper, I review the progress that has been made towards this effort by illustrating how investigations of the neural mechanisms underlying working memory can be influenced by cognitive models and, in turn, how cognitive models can be shaped and modified by neuroscientific data. One conclusion that arises from this research is that working memory can be viewed as neither a unitary nor a dedicated system. A network of brain regions, including the prefrontal cortex (PFC), is critical for the active maintenance of internal representations that are necessary for goal-directed behaviour. Thus, working memory is not localized to a single brain region but probably is an emergent property of the functional interactions between the PFC and the rest of the brain.

PMID: 17400538 [PubMed - as supplied by publisher]

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PC and epilepsy

Olfactory abnormalities in Huntington's disease: Decreased plasticity in the primary olfactory cortex of R6/1 transgenic mice and reduced olfactory discrimination in patients.

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Olfactory abnormalities in Huntington's disease: Decreased plasticity in the primary olfactory cortex of R6/1 transgenic mice and reduced olfactory discrimination in patients.

Brain Res. 2007 Mar 12;

Authors: Lazic SE, Goodman AO, Grote HE, Blakemore C, Morton AJ, Hannan AJ, van Dellen A, Barker RA

Reduced neuronal plasticity in the striatum, hippocampus, and neocortex is a common feature of transgenic mouse models of Huntington's disease (HD). Doublecortin (DCX) and polysialylated neural cell adhesion molecule (PSA-NCAM) are associated with structural plasticity in the adult mammalian brain, are markers of newly formed neurons in the dentate gyrus of the adult hippocampus, and are highly expressed in primary olfactory (piriform) cortex. Animal studies have demonstrated that a reduction in plasticity in the piriform cortex is associated with a selective impairment in odour discrimination. Therefore, the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex were quantified as measures of plasticity in early stage (fifteen week old) R6/1 transgenic HD mice. The transgenic mice had a large reduction in the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex, similar to that previously reported in the R6/2 mice. We also tested whether odour discrimination, as well as identification and detection, were impaired in HD patients and found that patients (at a similar disease stage as the mice) had an impairment in odour discrimination and identification, but not odour detection. These results suggest that olfactory impairments observed in HD patients may be the result of reduced plasticity in the primary olfactory cortex.

PMID: 17400200 [PubMed - as supplied by publisher]

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Cannabinoid and metabolic disorder

Cannabinoid receptors as therapeutic targets for obesity and metabolic diseases.

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Cannabinoid receptors as therapeutic targets for obesity and metabolic diseases.

Curr Opin Pharmacol. 2006 Dec;6(6):586-91

Authors: Bellocchio L, Mancini G, Vicennati V, Pasquali R, Pagotto U

One of the most interesting pharmacological targets proposed in the past ten years for fighting obesity and related metabolic disorders is the endocannabinoid system. The role of the endocannabinoid system is crucial in regulating the rewarding properties of food, in controlling energy balance by acting at the hypothalamic circuitries involved in food intake, and in peripheral metabolism by influencing adipocytes, hepatocytes, myocytes and pancreatic endocrine cells. Obesity seems to be a condition associated with a pathological overactivation of the endocannabinoid system; therefore, restoring a normal endocannabinoid tone by antagonizing the cannabinoid receptor type 1 (CB(1)) could help arrest both the development and the maintenance of obesity.

PMID: 17027338 [PubMed - indexed for MEDLINE]

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Untitled

Correction: searching for plasticity in dissociated cortical cultures on multi-electrode arrays.

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Correction: searching for plasticity in dissociated cortical cultures on multi-electrode arrays.

J Negat Results Biomed. 2007;6:3

Authors: Wagenaar DA, Pine J, Potter SM

PMID: 17288610 [PubMed - in process]

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Cannabinoid & opioid

Involvement of cannabinoid (CB(1))-receptors in the development and maintenance of opioid tolerance.

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Involvement of cannabinoid (CB(1))-receptors in the development and maintenance of opioid tolerance.

Neuroscience. 2007 Mar 27;

Authors: Trang T, Sutak M, Jhamandas K

Sustained exposure to opioid agonists such as morphine increases levels of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn, a response implicated in the development of opioid tolerance and physical dependence. Recent evidence suggests that both the opioid-induced increase in CGRP and the development of opioid physical dependence are suppressed by blockade of spinal cannabinoid (CB(1))-receptors. The present study examined whether CB(1)-receptor activity also has a role in the development of opioid tolerance. In rats implanted with spinal catheters, repeated acute injections of morphine (15 mug) delivered over 4 h resulted in a rapid decline of thermal and mechanical antinociception and a significant loss of analgesic potency, reflecting development of acute opioid tolerance. In another set of experiments, chronic administration of spinal morphine (15 mug) once daily for 5 days produced a similar loss of analgesic effect and a marked increase in CGRP-immunoreactivity in the superficial laminae of the dorsal horn. Consistent with the in vivo findings, primary cultures of adult dorsal root ganglion (DRG) neurons exposed to morphine for 5 days showed a significant increase in the number of CGRP-immunoreactive neurons. Co-administration of acute or chronic morphine with a CB(1)-receptor antagonist/inverse agonist, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM-251), inhibited the development of both acute and chronic analgesic tolerance. In animals already exhibiting tolerance to morphine, intervention with AM-251 restored morphine analgesic potency. Co-administration with AM-251 attenuated the morphine-induced increase in CGRP-immunoreactivity in the spinal cord and in DRG cultured neurons. Collectively, the results of this study suggest that activity of endocannabinoids, mediated via CB(1)-receptors, contributes to both the development and maintenance of opioid tolerance by influencing the opioid-induced increase in spinal CGRP.

PMID: 17395382 [PubMed - as supplied by publisher]

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