EASL-EORTC clinical practice guidelines : management of hepatocellular carcinoma

▪ Abstract In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.

Pharmacology and functions of metabotropic glutamate receptors.

Naturally occurring variations in maternal care alter the expression of genes that regulate behavioral and endocrine responses to stress, as well as hippocampal synaptic development. These effects form the basis for the development of stable, individual differences in stress reactivity and certain forms of cognition. Maternal care also influences the maternal behavior of female offspring, an effect that appears to be related to oxytocin receptor gene expression, and which forms the basis for the intergenerational transmission of individual differences in stress reactivity. Patterns of maternal care that increase stress reactivity in offspring are enhanced by stressors imposed on the mother. These findings provide evidence for the importance of parental care as a mediator of the effects of environmental adversity on neural development.

Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations.

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

Cortical glutamatergic fibres and cholinergic inputs arising from large aspiny interneurons converge on striatal spiny neurons and play a major role in the control of motor activity. We have investigated the interaction between excitatory amino acids and acetylcholine (ACh) on striatal spiny neurons by utilizing intracellular recordings, both in current- and in voltage-clamp mode in rat brain slices. Muscarine (0.3-10 microM) produced a reversible and dose-dependent increase in the membrane depolarizations/inward currents induced by brief applications of N-methyl-D-aspartate (NMDA), while it did not affect the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-induced responses. These concentrations of muscarine did not alter the membrane potential and the current-voltage relationship of the recorded cells. Neostigmine (0.3-10 microM), an ACh-esterase inhibitor, mimicked this facilitatory effect. The facilitatory effects of muscarine and neostigmine were antagonized either by scopolamine (3 microM) or by pirenzepine (10-100 nM), an antagonist of M1-like muscarinic receptors, but not by methoctramine (300 nM), an antagonist of M2-like muscarinic receptor. Accordingly, these facilitatory effects were mimicked by McN-A-343 (1-10 microM), an agonist of M1-like muscarinic receptors, but not by oxotremorine (300 nM), an agonist of M2-like receptors. Tetrodotoxin (TTX) did not block the facilitatory effect produced by the activation of muscarinic receptors suggesting that this effect is postsynaptically mediated. The action of neostigmine was prevented either by the intracellular calcium (Ca2+) chelator BAPTA (200 mM) or by preincubating the slices with inhibitors of protein kinase C (PKC) (staurosporine 100 nM or calphostin C 1 microM). McN-A-343 did not alter the excitatory post synaptic potentials (EPSPs) evoked by corticostriatal stimulation in the presence of physiological concentration of magnesium (Mg2+ 1.2 mM), while it enhanced the duration of these EPSPs recorded in the absence of external magnesium. Our data show that endogenous striatal ACh exerts a positive modulatory action on NMDA responses via M1-like muscarinic receptors and PKC activation.

Endogenous ACh enhances striatal NMDA-responses via M1-like muscarinic receptors and PKC activation.

Changing the strength of synaptic connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. Plastic changes appear to follow a regional specialization and underlie the specific type of memory mediated by the brain area in which plasticity occurs. Thus, long-term changes occurring at excitatory corticostriatal synapses should be critically involved in motor learning. Indeed, repetitive stimulation of the corticostriatal pathway can cause either a long-lasting increase or an enduring decrease in synaptic strength, respectively referred to as long-term potentiation (LTP), and long-term depression, both requiring a complex sequence of biochemical events. Once established, LTP can be reversed to control levels by a low-frequency stimulation protocol, an active phenomenon defined "synaptic depotentiation," required to erase redundant information. In the 6-hydroxydopamine rat model of Parkinson's disease (PD), striatal synaptic plasticity has been shown to be impaired, although chronic treatment with levodopa was able to restore it. Of interest, a consistent number of L-dopa-treated animals developed involuntary movements, resembling human dyskinesias. Strikingly, electrophysiological recordings from the dyskinetic group of rats demonstrated a selective impairment of synaptic depotentiation. This survey will provide an overview of plastic changes occurring at striatal synapses. The potential relevance of these findings in the control of motor function and in the pathogenesis both of PD and L-dopa-induced motor complications will be discussed.

Striatal synaptic plasticity: implications for motor learning and Parkinson's disease.

High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson's disease patients.

Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia

Parkin is the most common causative gene of juvenile and early-onset familial Parkinson's diseases and is thought to function as an E3 ubiquitin ligase in the ubiquitin-proteasome system. However, it remains unclear how loss of Parkin protein causes dopaminergic dysfunction and nigral neurodegeneration. To investigate the pathogenic mechanism underlying these mutations, we used parkin-/- mice to study its physiological function in the nigrostriatal circuit. Amperometric recordings showed decreases in evoked dopamine release in acute striatal slices of parkin-/- mice and reductions in the total catecholamine release and quantal size in dissociated chromaffin cells derived from parkin-/- mice. Intracellular recordings of striatal medium spiny neurons revealed impairments of long-term depression and long-term potentiation in parkin-/- mice, whereas long-term potentiation was normal in the Schaeffer collateral pathway of the hippocampus. Levels of dopamine receptors and dopamine transporters were normal in the parkin-/- striatum. These results indicate that Parkin is involved in the regulation of evoked dopamine release and striatal synaptic plasticity in the nigrostriatal pathway, and suggest that impairment in evoked dopamine release may represent a common pathophysiological change in recessive parkinsonism.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2009.06152.x

Antonio Pisani

Papers

Endogenous ACh enhances striatal NMDA-responses via M1-like muscarinic receptors and PKC activation.

Striatal synaptic plasticity: implications for motor learning and Parkinson's disease.

High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson's disease patients.

Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia

Impaired dopamine release and synaptic plasticity in the striatum of Parkin−/− mice