Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB.

Extract from Nasco pomace loaded in nutriosomes exerts anti-inflammatory effects in the MPTP mouse model of Parkinson's disease.

Neuroinflammation has recently emerged as a key event in Parkinson's disease (PD) pathophysiology and as a potential target for disease-modifying therapies. Plant-derived extracts, rich in bioactive phytochemicals with antioxidant properties, have shown potential in this regard. Yet their clinical utility is hampered by poor systemic availability and rapid metabolism.

Positive relation between dopamine neuron degeneration and metabolic connectivity disruption in the MPTP plus probenecid mouse model of Parkinson's disease.

The clinical manifestation of Parkinson's disease (PD) appears when neurodegeneration is already advanced, compromising the efficacy of disease-modifying treatment approaches. Biomarkers to identify the early stages of PD are therefore of paramount importance for the advancement of the therapy of PD. In the present study, by using a mouse model of PD obtained by subchronic treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the clearance inhibitor probenecid (MPTPp), we identified prodromal markers of PD by combining in vivo positron emission tomography (PET) imaging and ex vivo immunohistochemistry.

Neurobiology of Parkinson's Disease.

Parkinson's disease (PD) is one of the most rapidly growing neurological disorders [...

Serotonin 5-HT receptors and their interactions with adenosine A receptors in Parkinson's disease and dyskinesia.

The dopamine neuronal loss that characterizes Parkinson's Disease (PD) is associated to changes in neurotransmitters, such as serotonin and adenosine, which contribute to the symptomatology of PD and to the onset of dyskinetic movements associated to levodopa treatment. The present review describes the role played by serotonin 5-HT receptors and the adenosine A receptors on dyskinetic movements induced by chronic levodopa in PD. The focus is on preclinical and clinical results showing the interaction between serotonin 5-HT receptors and other receptors such as 5-HT receptors and adenosine A receptors.

Characterization of Nasco grape pomace-loaded nutriosomes and their neuroprotective effects in the MPTP mouse model of Parkinson's disease.

Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose FM06).

Influence of Age and Genetic Background on Ethanol Intake and Behavioral Response Following Ethanol Consumption and During Abstinence in a Model of Alcohol Abuse.

Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40-70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking.

Neuroinflammation and L-dopa-induced abnormal involuntary movements in 6-hydroxydopamine-lesioned rat model of Parkinson's disease are counteracted by combined administration of a 5-HT receptor agonist and A receptor antagonist.

Several lines of evidence have strongly implicated neuroinflammation in Parkinson's disease (PD) progression and l-dopa-induced dyskinesia. The present study investigated whether early subchronic pretreatment with the serotonin 5-HT receptor agonist eltoprazine plus the adenosine A receptor antagonist preladenant counteracted l-dopa-induced abnormal involuntary movements (AIMs, index of dyskinesia), and neuroinflammation, in unilateral 6-hydroxydopamine(6-OHDA)-lesioned rat model of PD. The immunoreactivity of glial fibrillary acidic protein (GFAP), and the colocalization of ionized calcium binding adaptor molecule-1 (IBA-1), with interleukin (IL)-1β, tumor-necrosis-factor-α (TNF-α) and IL-10 were evaluated in the denervated caudate-putamen (CPu) and substantia nigra pars-compacta (SNc).

Involvement of the Protein Ras Homolog Enriched in the Striatum, Rhes, in Dopaminergic Neurons' Degeneration: Link to Parkinson's Disease.

is one of the most interesting genes regulated by thyroid hormones that, through the inhibition of the striatal cAMP/PKA pathway, acts as a modulator of dopamine neurotransmission. is expressed at high levels in the dorsal striatum, with a medial-to-lateral expression gradient reflecting that of both dopamine D and adenosine A receptors. transcript is also present in the hippocampus, cerebral cortex, olfactory tubercle and bulb, substantia nigra pars compacta (SNc) and ventral tegmental area of the rodent brain.

Pharmacological interactions between adenosine A receptor antagonists and different neurotransmitter systems.

While Parkinson's disease (PD) is traditionally characterized by dopaminergic neuron degeneration, several neurotransmitters and neuromodulators besides dopamine are also involved in the onset and progression of the disease and its symptoms. The other principal neurotransmitters/neuromodulators known to control basal ganglia functions and, in particular, motor functions, are GABA, glutamate, serotonin (5-HT), noradrenaline, acetylcholine, adenosine and endocannabinoids. Among these, adenosine is the most relevant, acting through its adenosine A receptor.

Gender Differences in Neurodegeneration, Neuroinflammation and Na-Ca Exchangers in the Female A53T Transgenic Mouse Model of Parkinson's Disease.

Twelve-month-old male mice expressing the human A53T variant of α-synuclein (A53T) develop dopamine neuron degeneration, neuroinflammation, and motor deficits, along with dysfunctions of the mitochondrial Na-Ca exchanger (NCX) isoforms 1 (NCX1) and 3 (NCX3) in the nigrostriatal system. Since gender is thought to play a role in the etiology of Parkinson's disease (PD), we characterized neurochemical and behavioral alterations in 12-month-old female A53T transgenic mice. We investigated the presence of dopaminergic degeneration, astrogliosis and microgliosis using immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBA-1) in both the substantia nigra pars compacta (SNc) and striatum.

Fos expression induced by olanzapine and risperidone in the central extended amygdala.

The extended amygdala has been proposed to play an essential role in cognitive and affective processes and in neuropsychiatric disorders. In the present study, we examined the induction of Fos-like nuclei in the central amygdaloid nucleus (CeA), sublenticular extended amygdala (SLEA), interstitial nucleus of the posterior limb of the anterior commissure (IPAC), and bed nucleus of the stria terminalis (BSTL) of rodents to improve the knowledge regarding the pharmacological profile, therapeutic efficacy, and side-effects of olanzapine, an atypical antipsychotic drug and risperidone, a mixed atypical/typical antipsychotic drug in the rat brain. In addition, we evaluated the induction of Fos-like-nuclei in areas connected with these structures such as prefrontal cortex (PFCx), and nucleus accumbens shell, and in other important areas including the lateral septum and caudate-putamen that are involved in the therapeutic efficacy or side-effects of antipsychotic drugs.

Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age.

Ras homolog enriched in striatum (Rhes) is a protein that exerts important physiological functions and modulates psychostimulant drug effects. On this basis, the object of this study was to assess 3,4-methylenedioxymethamphetamine (MDMA) effects on microglial (CD11b) and astroglial (GFAP) activation and on dopamine neuron degeneration (TH) in wild-type (WT) and Rhes knockout (KO) male and female mice of different ages. Motor activity was also evaluated.

NCX1 and NCX3 as potential factors contributing to neurodegeneration and neuroinflammation in the A53T transgenic mouse model of Parkinson's Disease.

Na-Ca exchanger (NCX) isoforms constitute the major cellular Ca extruding system in neurons and microglia. We herein investigated the role of NCX isoforms in the pathophysiology of Parkinson's disease (PD). Their expression and activity were evaluated in neurons and glia of mice expressing the human A53T variant of α-synuclein (A53T mice), an animal model mimicking a familial form of PD.

Rhes Counteracts Dopamine Neuron Degeneration and Neuroinflammation Depending on Gender and Age.

We have recently shown that male Rhes knockout (KO) mice develop a mild form of spontaneous Parkinson's disease (PD)-like phenotype, characterized by motor impairment and a decrease in nigrostriatal dopamine (DA) neurons. Experimental evidence has implicated neuroinflammation in PD progression, and the presence of activated glial cells has been correlated with DA neuron degeneration. Despite this, several factors, such as gender, have been found to affect DAergic neuron degeneration and influence neuroinflammation, explaining the differences between men and women in the etiology of PD.

Dopaminergic neurodegeneration in a rat model of long-term hyperglycemia: preferential degeneration of the nigrostriatal motor pathway.

Epidemiological evidence suggests a correlation between diabetes and age-related neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Hyperglycemia causes oxidative stress in vulnerable tissues such as the brain. We recently demonstrated that elevated levels of glucose lead to the death of dopaminergic neurons in culture through oxidative mechanisms.

Role of adenosine A receptors in motor control: relevance to Parkinson's disease and dyskinesia.

Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A subtype are highly enriched in the caudate-putamen, which is richly innervated by dopamine.

Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson's disease.

Background: The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior.

Objectives: We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa's efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.

The Small GTP-Binding Protein Rhes Influences Nigrostriatal-Dependent Motor Behavior During Aging.

Background: Here we aimed to evaluate: (1) Rhes mRNA expression in mouse midbrain, (2) the effect of Rhes deletion on the number of dopamine neurons, (3) nigrostriatal-sensitive behavior during aging in knockout mice.

Methods: Radioactive in situ hybridization was assessed in adult mice. The beam-walking test was executed in 3-, 6- and 12-month-old mice.

Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease.

Background: Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release.

Dual target strategy: combining distinct non-dopaminergic treatments reduces neuronal cell loss and synergistically modulates L-DOPA-induced rotational behavior in a rodent model of Parkinson's disease.

The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A2A receptor (A2A R) represent major non-dopaminergic therapeutic targets in Parkinson's disease (PD) to improve motor symptoms and slow down/revert disease progression. The 6-hydroxydopamine rat model of PD was used to determine/compare the neuroprotective and behavioral impacts of single and combined administration of one mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), and two A2A R antagonists, (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl]propyl] (MSX-3) and 8-ethoxy-9-ethyladenine (ANR 94). Chronic treatment with MPEP or MSX-3 alone, but not with ANR 94, reduced the toxin-induced loss of dopaminergic neurons in the substantia nigra pars compacta.

Neuroprotective potential of adenosine A2A and cannabinoid CB1 receptor antagonists in an animal model of Parkinson disease.

The development of nondopaminergic therapeutic strategies that may improve motor and nonmotor deficits, while possibly slowing down the neurodegenerative process and associated neuroinflammation,is a primary goal of Parkinson disease (PD) research. We investigated the neuroprotective and anti-inflammatory potential of combined and single treatment with adenosine A2A and cannabinoid CB1 receptor antagonists MSX-3 and rimonabant, respectively, in a rodent model of PD. Rats bearing a unilateral intrastriatal 6-hydroxydopamine lesion were treated chronically with MSX-3 (0.

Adenosine A2A receptor antagonists in Parkinson's disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued.

Neurotransmitters other than dopamine, such as norepinephrine, 5-hydroxytryptamine, glutamate, adenosine and acetylcholine, are involved in Parkinson's disease (PD) and contribute to its symptomatology. Thus, the progress of non-dopaminergic therapies for PD has attracted much interest in recent years. Among new classes of drugs, adenosine A2A antagonists have emerged as promising candidates.