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

Time of Day-Dependent Alterations in Hippocampal Kynurenic Acid, Glutamate, and GABA in Adult Rats Exposed to Elevated Kynurenic Acid During Neurodevelopment

Hypofunction of glutamatergic signaling is causally linked to neurodevelopmental disorders, including psychotic disorders like schizophrenia and bipolar disorder. Kynurenic acid (KYNA) has been found to be elevated in postmortem brain tissue and cerebrospinal fluid of patients with psychotic illnesses and may be involved in the hypoglutamatergia and cognitive dysfunction experienced by these patients. As insults during the prenatal period are hypothesized to be linked to the pathophysiology of psychotic disorders, we presently utilized the embryonic kynurenine (EKyn) paradigm to induce a prenatal hit. Pregnant Wistar dams were fed chow laced with kynurenine to stimulate fetal brain KYNA elevation from embryonic day 15 to embryonic day 22. Control dams (ECon) were fed unlaced chow. Plasma and hippocampal tissue from young adult (postnatal day 56) ECon and EKyn male and female offspring were collected at the beginning of the light (Zeitgeber time, ZT 0) and dark (ZT 12) phases to assess kynurenine pathway metabolites. Hippocampal tissue was also collected at ZT 6 and ZT 18. In separate animals, in vivo microdialysis was conducted in the dorsal hippocampus to assess extracellular KYNA, glutamate, and gamma-aminobutyric acid (GABA). Biochemical analyses revealed no changes in peripheral metabolites, yet hippocampal tissue KYNA levels were significantly impacted by EKyn treatment, and increased in male EKyn offspring at ZT 6. Interestingly, extracellular hippocampal KYNA levels were only elevated in male EKyn offspring during the light phase. Decreases in extracellular glutamate levels were found in the dorsal hippocampus of EKyn male and female offspring, while decreased GABA levels were present only in males during the dark phase. The current findings suggest that the EKyn paradigm may be a useful tool for investigation of sex- and time-dependent changes in hippocampal neuromodulation elicited by prenatal KYNA elevation, which may influence behavioral phenotypes and have translational relevance to psychotic disorders

Biological activity of new bioactive steroids deriving from biotransformation of cortisone

Cortisone is a metabolite belonging to the corticosteroid class that is used pharmaceutically directly as a drug or prodrug. In addition to its large consumption, its use is linked to several side effects, so pharmaceutical research aims to develop effective drugs with low or no side effects, alternative compounds to cortisone are part of an active investment in ongoing research on drug discovery. Since biotransformation can be considered a source of new molecules with potential therapeutic use, the present work focuses on a preliminary in vitro study aimed at evaluating the mutagenic, anti-inflammatory, antioxidant and neuroprotective activity of SCA and SCB molecules obtained from the biotransformation of cortisone using Rh. Rhodnii strain DSM 43960. The results obtained are very encouraging due to the safety of biotransformed compounds with reference to genotoxicity checked by Ames test, to the very high antioxidant capacity and to the anti-inflammatory activity. In fact, thecompounds inhibited both the TNF alpha-stimulated expression and secretion of NFkB target cytokines, and COX activity, and can activate the glucocorticoid receptor. Finally SCA and SCB exhibited neuroprotective properties

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

n/

Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder

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

Climate mediates the effects of disturbance on ant assemblage structure

Many studies have focused on the impacts of climate change on biological assemblages, yet little is known about howclimate interacts with other major anthropogenic influences on biodiversity, such as habitat disturbance. Using a unique global database of 1128 local ant assemblages, we examined whether climate mediates the effects of habitat disturbance on assemblage structure at a global scale. Species richness and evenness were associated positively with temperature, and negatively with disturbance. However, the interaction among temperature, precipitation and disturbance shaped species richness and evenness. The effectwas manifested through a failure of species richness to increase substantially with temperature in transformed habitats at low precipitation. At low precipitation levels, evenness increased with temperature in undisturbed sites, peaked at medium temperatures in disturbed sites and remained low in transformed sites. In warmer climates with lower rainfall, the effects of increasing disturbance on species richness and evenness were akin to decreases in temperature of up to 98C. Anthropogenic disturbance and ongoing climate change may interact in complicated ways to shape the structure of assemblages, with hot, arid environments likely to be at greatest risk. © 2015 The Author(s) Published by the Royal Society. All rights reserved

Palmitoylethanolamide (PEA) as a Potential Therapeutic Agent in Alzheimer's Disease

N-Palmitoylethanolamide (PEA) is a non-endocannabinoid lipid mediator belonging to the class of the N-acylethanolamine phospolipids and was firstly isolated from soy lecithin, egg yolk, and peanut meal. Either preclinical or clinical studies indicate that PEA is potentially useful in a wide range of therapeutic areas, including eczema, pain, and neurodegeneration. PEA-containing products are already licensed for use in humans as a nutraceutical, a food supplement, or a food for medical purposes, depending on the country. PEA is especially used in humans for its analgesic and anti-inflammatory properties and has demonstrated high safety and tolerability. Several preclinical in vitro and in vivo studies have proven that PEA can induce its biological effects by acting on several molecular targets in both central and peripheral nervous systems. These multiple mechanisms of action clearly differentiate PEA from classic anti-inflammatory drugs and are attributed to the compound that has quite unique anti(neuro) inflammatory properties. According to this view, preclinical studies indicate that PEA, especially in micronized or ultramicronized forms (i.e., formulations that maximize PEA bioavailability and efficacy), could be a potential therapeutic agent for the effective treatment of different pathologies characterized by neurodegeneration, (neuro) inflammation, and pain. In particular, the potential neuroprotective effects of PEA have been demonstrated in several experimental models of Alzheimer's disease. Interestingly, a single-photon emission computed tomography (SPECT) case study reported that a mild cognitive impairment (MCI) patient, treated for 9 months with ultramicronized-PEA/luteolin, presented an improvement of cognitive performances. In the present review, we summarized the current preclinical and clinical evidence of PEA as a possible therapeutic agent in Alzheimer's disease. The possible PEA neuroprotective mechanism(s) of action is also described