Neurotensin as Modulator of Basal Ganglia- Thalamocortical Motor Circuit – Emerging Evidence for Neurotensin NTS1 Receptor as a Potential Target in Parkinson\u27s Disease

This chapter is focused on the putative role of neurotensin in the development of Parkinson’s disease, a neurodegenerative disorder mainly characterized by a progressive loss of nigrostriatal dopaminergic neurons (Schimpff et al., 2001). Although a direct causal role of neurotensin in Parkinson’s disease has not yet clearly demonstrated, some convincing animal and human studies support the potential role of the peptide in the etiopathogenesis of this motor disorder. Special emphasis is placed on the significance that neurotensin plays on basal ganglia neuroplasticity and neurodegeneration. This is mainly supported by recent findings clearly demonstrating that neurotensin enhances glutamate excitotoxicity in mesencephalic dopamine neurons and that neurotensin receptors are involved in the modulation of NMDA-induced excitotoxicity (Antonelli et al., 2002; 2004). Through these mechanisms neurotensin could contribute to the development and/or the progression of neurodegenerative disorders. The possible use of neurotensin receptor antagonists, in combination with conventional therapy, in the treatment of Parkinson’s disease, is also discussed

acute cocaine treatment enhances the antagonistic allosteric adenosine a2a dopamine d2 receptor receptor interactions in rat dorsal striatum without increasing significantly extracellular dopamine levels

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RV longitudinal deformation correlates with myocardial fibrosis in patients with end-stage heart failure

Objectives This study was performed to determine the accuracy of right ventricular (RV) longitudinal strain (LS) in predicting myocardial fibrosis in patients with severe heart failure (HF) undergoing heart transplantation. Background RVLS plays a key role in the evaluation of its systolic performance and clinical outcome in patients with refractory HF. Methods We studied 27 patients with severe systolic HF (ejection fraction 25% and New York Heart Association functional class III to IV, despite full medical therapy and cardiac resynchronization therapy) using echocardiography before heart transplantation. RV free wall LS, right atrial LS, sphericity index (SI), and tricuspid annular plane systolic excursion (TAPSE) were all measured. Upon removal of the heart, from the myocardial histologic analysis, the ratio of the fibrotic to the total sample area determined the extent of fibrosis (%). Results RV myocardial fibrosis correlated with RV free wall LS (r = 0.80; p < 0.0001), SI (r = 0.42; p = 0.01) and VO max (r = -0.41; p = 0.03), with a poor correlation with TAPSE (r = -0.34; p = 0.05) and right atrial LS (r = -0.37; p = 0.03). Stepwise multivariate analysis showed that RV free wall LS (β = 0.701, p < 0.0001) was independently associated with RV fibrosis (overall model R= 0.64, p < 0.0001). RV free wall LS was the main determinant of myocardial fibrosis. In the subgroup of patients with severe RV fibrosis, RV free wall LS had the highest diagnostic accuracy for detecting severe myocardial fibrosis (area under the curve = 0.87; 95% confidence interval: 0.80 to 0.94). Conclusions In late-stage HF patients, the right ventricle is enlarged, with reduced systolic function due to significant myocardial fibrosis. RV free wall myocardial deformation is the most accurate functional measure that correlates with the extent of RV myocardial fibrosis and functional capacity

Extrasynaptic Neurotransmission in the Modulation of Brain Function. Focus on the Striatal Neuronal–Glial Networks

Extrasynaptic neurotransmission is an important short distance form of volume transmission (VT) and describes the extracellular diffusion of transmitters and modulators after synaptic spillover or extrasynaptic release in the local circuit regions binding to and activating mainly extrasynaptic neuronal and glial receptors in the neuroglial networks of the brain. Receptor-receptor interactions in G protein-coupled receptor (GPCR) heteromers play a major role, on dendritic spines and nerve terminals including glutamate synapses, in the integrative processes of the extrasynaptic signaling. Heteromeric complexes between GPCR and ion-channel receptors play a special role in the integration of the synaptic and extrasynaptic signals. Changes in extracellular concentrations of the classical synaptic neurotransmitters glutamate and GABA found with microdialysis is likely an expression of the activity of the neuron-astrocyte unit of the brain and can be used as an index of VT-mediated actions of these two neurotransmitters in the brain. Thus, the activity of neurons may be functionally linked to the activity of astrocytes, which may release glutamate and GABA to the extracellular space where extrasynaptic glutamate and GABA receptors do exist. Wiring transmission (WT) and VT are fundamental properties of all neurons of the CNS but the balance between WT and VT varies from one nerve cell population to the other. The focus is on the striatal cellular networks, and the WT and VT and their integration via receptor heteromers are described in the GABA projection neurons, the glutamate, dopamine, 5-hydroxytryptamine (5-HT) and histamine striatal afferents, the cholinergic interneurons, and different types of GABA interneurons. In addition, the role in these networks of VT signaling of the energy-dependent modulator adenosine and of endocannabinoids mainly formed in the striatal projection neurons will be underlined to understand the communication in the striatal cellular networks

Brain dopamine transmission in health and Parkinson's disease: modulation of synaptic transmission and plasticity through volume transmission and dopamine heteroreceptors.

This perspective article provides observations supporting the view that nigro-striatal dopamine neurons and meso-limbic dopamine neurons mainly communicate through short distance volume transmission in the um range with dopamine diffusing into extrasynaptic and synaptic regions of glutamate and GABA synapses. Based on this communication it is discussed how volume transmission modulates synaptic glutamate transmission onto the D1R modulated direct and D2R modulated indirect GABA pathways of the dorsal striatum. Each nigro-striatal dopamine neuron was first calculated to form large numbers of neostriatal DA nerve terminals and then found to give rise to dense axonal arborizations spread over the neostriatum, from which dopamine is released. These neurons can through DA volume transmission directly influence not only the striatal GABA projection neurons but all the striatal cell types in parallel. It includes the GABA nerve cells forming the island-/striosome GABA pathway to the nigral dopamine cells, the striatal cholinergic interneurons and the striatal GABA interneurons. The dopamine modulation of the different striatal nerve cell types involves the five dopamine receptor subtypes, D1R to D5R receptors, and their formation of multiple extrasynaptic and synaptic dopamine homo and heteroreceptor complexes. These features of the nigro-striatal dopamine neuron to modulate in parallel the activity of practically all the striatal nerve cell types in the dorsal striatum, through the dopamine receptor complexes allows us to understand its unique and crucial fine-tuning of movements, which is lost in Parkinson's disease. Integration of striatal dopamine signals with other transmitter systems in the striatum mainly takes place via the receptor-receptor interactions in dopamine heteroreceptor complexes. Such molecular events also participate in the integration of volume transmission and synaptic transmission. Dopamine modulation of the glutamate synapses on the dorsal striato-pallidal GABA pathway involves D2R heteroreceptor complexes such as D2R-NMDAR, A2AR-D2R, and NTSR1-D2R heteroreceptor complexes. The dopamine modulation of glutamate synapses on the striato-entopeduncular/nigral pathway takes place mainly via D1R heteroreceptor complexes such as D1R-NMDAR, A2R-D1R, and D1R-D3R heteroreceptor complexes. Dopamine modulation of the island/striosome compartment of the dorsal striatum projecting to the nigral dopamine cells involve D4R-MOR heteroreceptor complexes. All these receptor-receptor interactions have relevance for Parkinson's disease and its treatment

Differential Effects of Palmitoylethanolamide against Amyloid-β Induced Toxicity in Cortical Neuronal and Astrocytic Primary Cultures from Wild-Type and 3xTg-AD Mice

BACKGROUND: Considering the heterogeneity of pathological changes occurring in Alzheimer's disease (AD), a therapeutic approach aimed both to neuroprotection and to neuroinflammation reduction may prove effective. Palmitoylethanolamide (PEA) has attracted attention for its anti-inflammatory/neuroprotective properties observed in AD animal models. OBJECTIVE AND METHODS: We evaluated the protective role of PEA against amyloid-β42 (Aβ42) toxicity on cell viability and glutamatergic transmission in primary cultures of cerebral cortex neurons and astrocytes from the triple-transgenic murine model of AD (3xTg-AD) and their wild-type littermates (non-Tg) mice. RESULTS: Aβ42 (0.5 μM; 24 h) affects the cell viability in cultured cortical neurons and astrocytes from non-Tg mice, but not in those from 3xTg-AD mice. These effects were counteracted by the pretreatment with PEA (0.1 μM). Basal glutamate levels in cultured neurons and astrocytes from 3xTg-AD mice were lower than those observed in cultured cells from non-Tg mice. Aβ42-exposure reduced and increased glutamate levels in non-Tg mouse cortical neurons and astrocytes, respectively. These effects were counteracted by the pretreatment with PEA. By itself, PEA did not affect cell viability and glutamate levels in cultured cortical neuron and astrocytes from non-Tg or 3xTg-AD mice. CONCLUSION: The exposure to Aβ42 induced toxic effects on cultured cortical neurons and astrocytes from non-Tg mice, but not in those from 3xTg-AD mice. Furthermore, PEA exerts differential effects against Aβ42-induced toxicity in primary cultures of cortical neurons and astrocytes from non-Tg and 3xTg-AD mice. In particular, PEA displays protective properties in non-Tg but not in 3xTg-AD mouse neuronal cultured cells overexpressing Aβ

GET73 prevents ethanol-induced neurotoxicity in primary cultures of rat hippocampal neurons

Aims: N-[(4-trifluoromethyl) benzyl] 4-methoxybutyramide (GET73) may be considered a promising therapeutic agent for the treatment of alcohol use disorders. The compound displayed anti-alcohol and anxiolytic properties in rat. In the present study, an in vitro experimental model of chronic ethanol treatment was used to investigate the ability of the compound to counteract the ethanol-induced neurotoxicity. Methods: Primary cultures of rat hippocampal neurons were exposed to ethanol (75 mM; 4 days) and the neuroprotective effects of GET73 were assessed by evaluating cell viability, cell morphology, glutamate levels and reactive oxygen species production. Results: The exposure to ethanol induced a reduction of cell viability, an alteration of cytoskeleton, a decrease in extracellular glutamate levels and an increase of reactive oxygen species production. The addiction of GET73 (1 and 10 μM) 1 h before and during chronic ethanol exposure prevented all the above ethanol-induced effects. Based on the proposed GET73 mechanism of action, the effects of mGlu5 receptor negative allosteric modulator, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), on ethanol-induced reduction of cell viability were also assessed. The results indicated that the addiction of MPEP (100 μM) 1 h before and during chronic ethanol exposure prevented the ethanol-induced cell viability reduction. Conclusion: The present findings provide the first evidence that GET73 shows a neuroprotective role against ethanol-induced neurotoxicity in primary cultures of rat hippocampal neurons. Together with previous findings, these results suggest that GET73 possesses multifaceted properties thus lending further support to the significance of developing GET73 as a therapeutic tool for use in the treatment of alcohol use disorders

CONSEGUENZE A BREVE E LUNGO TERMINE INDOTTE DAL CONSUMO DI MARIJUANA DURANTE LA GRAVIDANZA E/O L'ALLATTAMENTO SULLE FUNZIONI COGNITIVE NEUROCHIMICHE E COMPORTAMENTALI DELLA PROLE.

The present chapter summarizes integrated neurochemical, morphological and neurobehavioural evidence, in particular from our laboratory, which emphasize the short- and long-term consequences of prenatal exposure to cannabinoids on rat glutamate transmission and cognitive functions. In addition, in order to clarify the scientific context in which the work has been developed, a summary of the human studies focused on the postnatal consequences of maternal marijuana use during pregnancy and/or lactation in neurobehavioral and cognitive functioning in the offspring, is reported in the first part of the chapter. The results obtained provide evidence that maternal exposure to the cannabinoids receptor agonist WIN55,212-2 induces an impairment of cognitive capacities in the offspring. This impairment is associated with alterations of cortical and hippocampal glutamate outflow, cortical neuron morphology and hippocampal long term potentiation. These findings are in line with clinical data showing that the consumption of marijuana by women during pregnancy has negative consequences on the cognitive functions of their children. Thus, although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of glutamate transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported

Reversal of clonidine effect on acetylcholine release during morphine tolerance.

Effect of clonidine on acetylcholine release during morphine tolerance