Inflammatory bowel disease induces pathological α-synuclein aggregation in the human gut and brain.

Aims: According to Braak's hypothesis, it is plausible that Parkinson's disease (PD) originates in the enteric nervous system (ENS) and spreads to the brain through the vagus nerve. In this work, we studied whether inflammatory bowel diseases (IBDs) in humans can progress with the emergence of pathogenic α-synuclein (α-syn) in the gastrointestinal tract and midbrain dopaminergic neurons.

Methods: We have analysed the gut and the ventral midbrain from subjects previously diagnosed with IBD and form a DSS-based rat model of gut inflammation in terms of α-syn pathology.

Galectin-3 Deletion Reduces LPS and Acute Colitis-Induced Pro-Inflammatory Microglial Activation in the Ventral Mesencephalon.

Parkinson's disease is a highly prevalent neurological disorder for which there is currently no cure. Therefore, the knowledge of risk factors as well as the development of new putative molecular targets is mandatory. In this sense, peripheral inflammation, especially the originated in the colon, is emerging as a predisposing factor for suffering this disease.

Antioxidant Effect of Hydroxytyrosol, Hydroxytyrosol Acetate and Nitrohydroxytyrosol in a Rat MPP Model of Parkinson's Disease.

3,4-Dihydroxyphenyl ethanol, known as hydroxytyrosol (HTy), is a phenylpropanoid found in diverse vegetable species. Several studies have demonstrated that HTy is a potent antioxidant. Thus, our study is aimed to evaluate the antioxidant effect of HTy and its derivatives, hydroxytyrosol acetate (HTyA) and nitrohydroxytyrosol (HTyN), in a model of oxidative stress induced by 1-methyl-4-phenylpyridinium (MPP) in rats.

Hydroxycinnamic acid derivatives isolated from hempseed and their effects on central nervous system enzymes.

New neuroprotective treatments of natural origin are being investigated. Both, plant extracts and isolated compounds have shown bioactive effects. Hempseed is known for its composition of fatty acids, proteins, fibre, vitamins, as well as a large number of phytochemical compounds.

Selective deletion of Caspase-3 gene in the dopaminergic system exhibits autistic-like behaviour.

Apoptotic caspases are thought to play critical roles in elimination of excessive and non-functional synapses and removal of extra cells during early developmental stages. Hence, an impairment of this process may thus constitute a basis for numerous neurological and psychiatric diseases. This view is especially relevant for dopamine due to its pleiotropic roles in motor control, motivation and reward processing.

Reformulating Pro-Oxidant Microglia in Neurodegeneration.

In neurodegenerative diseases, microglia-mediated neuroinflammation and oxidative stress are central events. Recent genome-wide transcriptomic analyses of microglial cells under different disease conditions have uncovered a new subpopulation named disease-associated microglia (DAM). These studies have challenged the classical view of the microglia polarization state's proinflammatory M1 (classical activation) and immunosuppressive M2 (alternative activation).

Peripheral Inflammation Enhances Microglia Response and Nigral Dopaminergic Cell Death in an MPTP Model of Parkinson's Disease.

The impact of systemic inflammation in nigral dopaminergic cell loss remains unclear. Here, we have investigated the role of peripheral inflammation induced by systemic lipopolysaccharide (LPS) administration in the MPTP-based model of Parkinson's disease. Brain inflammation, microglia and astroglia activation, disruption of the blood-brain barrier (BBB) and integrity of the nigrostriatal dopaminergic system were evaluated in response to i.

Effect of intracerebral hydroxytyrosol and its nitroderivatives on striatal dopamine metabolism: A study by in vivo microdialysis.

Aims: The natural phenolic oil compound hydroxytyrosol (HTy) is widely studied because of its antioxidant and neuroprotective properties. Nitroderivatives of HTy have been studied in order to evaluate their putative effects on catechol-O-methyltransferase (COMT) activity.

Main Methods: To study its effect on dopamine metabolism, nitrohydroxytyrosol and its lipophilic derivatives (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether), were administered into the rat corpus striatum through a microdialysis probe.

In vivo striatal measurement of hydroxytyrosol, and its metabolite (homovanillic alcohol), compared with its derivative nitrohydroxytyrosol.

Phenolic compounds were measured by in vivo brain microdialysis in rat striatum. Basal extracellular levels of hydroxytyrosol, homovanillic alcohol and nitro-hydroxytyrosol were not detectable by HPLC with electrochemical detection. However, systemic administration of hydroxytyrosol (20 and 40mg/kg, i.

In vivo effect of apomorphine and haloperidol on MPP neurotoxicity.

The involvement of dopaminergic (DAergic) receptor drugs in the neuroprotection against the neurotoxic action of 1-methyl-4-phenylpyridinium (MPP(+)) in the DAergic terminals in striatum was studied using an intracerebral microdialysis technique. Twenty-four hours after surgery (day 1), apomorphine and haloperidol, alone or with 1 mmol/l of MPP(+) perfusion through the microdialysis probe, were systemically administered. Forty-eight hours after surgery (day 2), 1 mmol/l of MPP(+) was perfused for 15 min in all groups of animals and the output of dopamine was measured.

Role of dopamine in the recruitment of immune cells to the nigro-striatal dopaminergic structures.

Research indicates that inflammation and microglial activation are involved in the initiation and progression of Parkinson's disease (PD). Neuroinflammation contributes to the infiltration of peripheral immune cells and blood-brain barrier (BBB) leakage, linking peripheral and central inflammatory events in the pathogenesis of PD. Dopamine (DA) likely plays a role in this process.

Peripheral inflammation increases the deleterious effect of CNS inflammation on the nigrostriatal dopaminergic system.

Evidence supports the role of inflammation in the development of neurodegenerative diseases. In this work, we are interested in inflammation as a risk factor by itself and not only as a factor contributing to neurodegeneration. We tested the influence of a mild to moderate peripheral inflammation (injection of carrageenan into the paws of rats) on the degeneration of dopaminergic neurons in an animal model based on the intranigral injection of lipopolysaccharide (LPS), a potent inflammatory agent.

Striatal ablation of GABAergic neurons prevents the in vivo neuroprotective effect of DCG-IV against the MPP+-induced neurotoxicity on dopaminergic nerve terminals.

In previous studies we found that intrastriatal DCG-IV administration, an agonist for group II metabotropic glutamate receptor: (i) protected striatal dopaminergic terminals against MPP(+)-induced neurotoxicity (Matarredona et al., 2001); (ii) selectively destroyed striatal GABAergic neurons (Venero et al., 2002) and (iii) induced early robust up-regulation of brain-derived neurotrophic factor (BDNF) in nigral dopaminergic neurons afferents in a target-dependent manner (Rite et al.

Effect of in vivo striatal perfusion of lipopolysaccharide on dopamine metabolites.

We have used the microdialysis technique to perfuse different concentrations of LPS in the rat's striatum 24h after the implantation of a microdialysis probe. Dopamine metabolites in the dialysate obtained from the rat brain were measured by HPLC using electrochemical detection. Results show that intrastriatal perfusion of different concentrations of LPS produced a dose-dependent decrease in the extracellular DOPAC output, with no effect on the extracellular HVA output.

Zocor Forte (simvastatin) has a neuroprotective effect against LPS striatal dopaminergic terminals injury, whereas against MPP+ does not.

Due to their potential role in preventing further deterioration of Parkinson's disease, anti-inflammatory strategies have attracted great interest. In this context, some studies point out the possible protective effect of anti-inflammatory compounds against the in vivo degeneration of dopaminergic neurons produced by lipopolysaccharide (LPS)-induced inflammatory processes and others. We have investigated the effect of the treatment of Zocor Forte (simvastatin) in LPS and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurodegenerative models to identify neuroprotective drugs for Parkinson's disease.

Endogenous dopamine enhances the neurotoxicity of 3-nitropropionic acid in the striatum through the increase of mitochondrial respiratory inhibition and free radicals production.

3-Nitropropionic acid (3-NP), an inhibitor of the mitochondrial enzyme succinate dehydrogenase, induces neuronal degeneration in the striatum. It is known that dopamine (DA) enhances this toxic effect. In this work, we study how the increase of DA influences the toxic effect of 3-NP on DAergic terminals, GABAergic neurons, astroglia and microglia in the striatum.

Simvastatin prevents the inflammatory process and the dopaminergic degeneration induced by the intranigral injection of lipopolysaccharide.

Anti-inflammatory strategies have attracted much interest for their potential to prevent further deterioration of Parkinson's disease. Recent experimental and clinical evidence indicate that statins - extensively used in medical practice as effective lipid-lowering agents - have also anti-inflammatory effects. In this study, we investigated the influence of simvastatin on the degenerative process of the dopaminergic neurons of the rat following intranigral injection of lipopolysaccharide (LPS), a potent inductor of inflammation that we have previously used as an animal model of Parkinson's disease.

Organogel formation by coaggregation of adaptable amidocarbamates and their tetraamide analogues.

Mixtures of derivatives of Hanabusa's bolaamphiphilic amidocarbamates containing two Z-valinyl subunits and aliphatic spacers that range from ethylenic to octamethylenic are able to form organogels. A coassembly of them is observed in their acetonitrile and toluene gels; namely, the concentration of a given compound at which a gel is formed is lowered by the presence of equimolar quantities of any other compound in the series. The aggregates were studied by wide-angle X-ray diffraction (WAXD) and the results can be rationalized if the gel fibers are formed by supramolecular copolymers.

Evidence for dopamine-derived hydroxyl radical formation in the nigrostriatal system in response to axotomy.

We have evaluated the ability of the injured nigrostriatal dopaminergic system to produce highly reactive hydroxyl radicals ((*)OH) by the electrochemical detection of salicylate hydroxylation. Unilateral transection of the medial forebrain bundle transiently increased the formation of (*)OH in substantia nigra (SN) but not in striatum during the first 48 h postlesion, when most relevant changes in terms of oxidatively modified proteins take place. Short-term adaptive axotomy-induced changes in substantia nigra included downregulation of nigral tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression and more intense TH immunoreactivity.