Manuel Sarmiento

Ulcerative colitis exacerbates lipopolysaccharide-induced damage to the nigral dopaminergic system: potential risk factor in Parkinson`s disease.

J. Neurochem. (2010) 114, 1687–1700.

Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation

BackgroundParkinson’s disease is an irreversible neurodegenerative disease linked to progressive movement disorders and is accompanied by an inflammatory reaction that is believed to contribute to its pathogenesis. Since sensitivity to inflammation is not the same in all brain structures, the aim of this work was to test whether physiological conditions as stress could enhance susceptibility to inflammation in the substantia nigra, where death of dopaminergic neurons takes place in Parkinson’s disease.MethodsTo achieve our aim, we induced an inflammatory process in nonstressed and stressed rats (subject to a chronic variate stress) by a single intranigral injection of lipopolysaccharide, a potent proinflammogen. The effect of this treatment was evaluated on inflammatory markers as well as on neuronal and glial populations.ResultsData showed a synergistic effect between inflammation and stress, thus resulting in higher microglial activation and expression of proinflammatory markers. More important, the higher inflammatory response seen in stressed animals was associated with a higher rate of death of dopaminergic neurons in the substantia nigra, the most characteristic feature seen in Parkinson’s disease. This effect was dependent on glucocorticoids.ConclusionsOur data demonstrate that stress sensitises midbrain microglia to further inflammatory stimulus. This suggests that stress may be an important risk factor in the degenerative processes and symptoms of Parkinson’s disease.

Chronic stress as a risk factor for Alzheimer’s disease

Abstract This review aims to point out that chronic stress is able to accelerate the appearance of Alzheimer’s disease (AD), proposing the former as a risk factor for the latter. Firstly, in the introduction we describe some human epidemiological studies pointing out the possibility that chronic stress could increase the incidence, or the rate of appearance of AD. Afterwards, we try to justify these epidemiological results with some experimental data. We have reviewed the experiments studying the effect of various stressors on different features in AD animal models. Moreover, we also point out the data obtained on the effect of chronic stress on some processes that are known to be involved in AD, such as inflammation and glucose metabolism. Later, we relate some of the processes known to be involved in aging and AD, such as accumulation of β-amyloid, TAU hyperphosphorylation, oxidative stress and impairement of mitochondrial function, emphasizing how they are affected by chronic stress/glucocorticoids and comparing with the description made for these processes in AD. All these data support the idea that chronic stress could be considered a risk factor for AD.

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. Overall, the treatment with carrageenan increased the effect of the intranigral injection of LPS on the loss of dopaminergic neurons in the SN along with all the other parameters studied, including: serum levels of the inflammatory markers TNF-α, IL-1β, IL-6 and C-reactive protein; activation of microglia, expression of proinflammatory cytokines, the adhesion molecule ICAM and the enzyme iNOS, loss of astrocytes and damage to the blood brain barrier (BBB). The possible implication of BBB rupture in the increased loss of dopaminergic neurons has been studied using another Parkinsons disease animal model based on the intraperitoneal injection of rotenone. In this experiment, loss of dopaminergic neurons was also strengthened by carrageenan, without affecting the BBB. In conclusion, our data show that a mild to moderate peripheral inflammation can exacerbate the degeneration of dopaminergic neurons caused by a harmful stimulus.

Peripheral inflammation increases the damage in animal models of nigrostriatal dopaminergic neurodegeneration: possible implication in Parkinson's disease incidence.

Inflammatory processes described in Parkinsons disease (PD) and its animal models appear to be important in the progression of the pathogenesis, or even a triggering factor. Here we review that peripheral inflammation enhances the degeneration of the nigrostriatal dopaminergic system induced by different insults; different peripheral inflammations have been used, such as IL-1β and the ulcerative colitis model, as well as insults to the dopaminergic system such as 6-hydroxydopamine or lipopolysaccharide. In all cases, an increased loss of dopaminergic neurons was described; inflammation in the substantia nigra increased, displaying a great activation of microglia along with an increase in the production of cytokines such as IL-1β and TNF-α. Increased permeability or disruption of the BBB, with overexpression of the ICAM-1 adhesion molecule and infiltration of circulating monocytes into the substantia nigra, is also involved, since the depletion of circulating monocytes prevents the effects of peripheral inflammation. Data are reviewed in relation to epidemiological studies of PD.

Inflammatory animal model for parkinson’s disease: the intranigral injection of LPS induced the inflammatory process along with the selective degeneration of nigrostriatal dopaminergic neurons

We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinsons disease (PD). The implication of neuroinflammation on this disease was originally established in 1988, when the presence of activated microglia in the substantia nigra (SN) of parkinsonians was reported by McGeer et al. Neuroinflammation could be involved in the progression of the disease or even has more direct implications. We injected 2 μg of the potent proinflammatory compound lipopolysaccharide (LPS) in different areas of the CNS, finding that SN displayed the highest inflammatory response and that dopaminergic (body) neurons showed a special and specific sensitivity to this process with the induction of selective dopaminergic degeneration. Neurodegeneration is induced by inflammation since it is prevented by anti-inflammatory compounds. The special sensitivity of dopaminergic neurons seems to be related to the endogenous dopaminergic content, since it is overcome by dopamine depletion. Compounds that activate microglia or induce inflammation have similar effects to LPS. This model suggest that inflammation is an important component of the degeneration of the nigrostriatal dopaminergic system, probably also in PD. Anti-inflammatory treatments could be useful to prevent or slow down the rate of dopaminergic degeneration in this disease.

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 Parkinsons 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. In the present study, the dopaminergic toxin 6-hydroxydopamine (6-OHDA) was used to damage dopaminergic neurons. Injection of 6-OHDA within the nigrostriatal pathway produced loss of astrocytes, disruption of the BBB, microglia activation and a reduction in osteopontin (OPN) immunoreactivity. Depletion of DA content by alpha-methylparatyrosine (α-MPT, a tyrosine hydroxylase inhibitor) reduced the infiltration of peripheral macrophages as well as the 6-OHDA-induced increase in microglial cells. DA could therefore be relevant in sustaining inflammation and lymphocyte recruitment induced by 6-OHDA, supporting DA implication in the degeneration of dopaminergic neurons induced by inflammatory processes.

Synergistic Deleterious Effect of Chronic Stress and Sodium Azide in the Mouse Hippocampus

Alzheimers disease is the most common cause of dementia in the elderly. Although the primary cause of the disease is presently unknown, to date several risk factors have been described. Evidence suggests that one of these risk factors could be chronic stress. The aim of this work is to demonstrate that chronic stress is able to induce Alzheimers disease features after the administration of nontoxic doses of sodium azide. We found that chronic stress increases the levels of several proteins involved in Alzheimers disease pathogenesis, such as presenilin 1, presenilin 2, and S100β, besides inducing the aggregation of Tau, ubiquitin, and β-amyloid proteins in the hippocampus. More important, our work shows a synergistic effect of stress and sodium azide treatment leading to significant neuronal death in the mouse hippocampus. Our results point out that chronic stress is a risk factor contributing to amplify and accelerate Alzheimers disease features in the hippocampus.

Respiratory response to systemic inhibition of the Na+/H+ exchanger type 3 in intact rats

The Na+/H+ exchangers (NHEs) are a family of antiporters involved in the maintenance of neural steady-state intracellular pH. The NHE3 seems to be the predominant subtype in central chemosensitive cells. We aimed to analyze the effect of a selective NHE3 inhibition on the respiratory pattern in spontaneously breathing rats with intact vagi. Rats were intravenously infused for 10 min with the selective NHE3 inhibitor AVE1599 (Aventis Pharma Deustchland, 0.5 and 2 mg/kg) or with phosphate buffer. Whole-body plethysmography was used to monitor breathing pattern before, during, and up to 30 min after the drug infusion. Immunohistochemistry for the c-Fos protein was performed in the animal brains and c-Fos-positive cells were counted along the brainstem. Selective NHE3 inhibition induced a significant increase in the respiratory frequency and in the number of c-Fos immunopositive cells in the lateral parabrachial nucleus, the pre-Bötzinger complex and a rostral extension of the retrotrapezoid nucleus/parapyramidal region (p<0.05, ANOVA). We conclude that systemic administration of AVE1599 increases respiratory frequency and activates ponto-medullary areas implicated in the central control of breathing and chemoreception.

Systemic Inhibition of the Na+/H+ Exchanger Type 3 in Intact Rats Activates Brainstem Respiratory Regions

Selective inhibition of the Na(+)/H(+) exchanger type 3 (NHE3) increases the firing rate of brainstem ventrolateral CO(2)/H(+) sensitive neurons, resembling the responses evoked by hypercapnic stimuli. In anesthetized animals, NHE3 inhibition has also been shown to stimulate the central chemosensitive drive. We aimed to analyze the respiratory-related brainstem regions affected by NHE3 inhibition in anaesthetized spontaneously-breathing rats with intact peripheral afferents. For that, c-Fos immunopositive cells were counted along the brainstem in rats intravenously infused with the selective NHE3 inhibitor AVE1599. A rostral extension of the ventral respiratory column which includes the pre-Bötzinger complex was activated by the NHE3 inhibitor. In addition, the number of c-Fos positive cells resulted significantly increased in the most rostral extension of the retrotrapezoid nucleus/parapyramidal region. In the pons, the intravenous infusion of AVE1599 activated the lateral parabrachial and Kölliker-Fuse nuclei. Thus, selective NHE3 inhibition in anaesthetized rats activates the respiratory network and evokes a pattern of c-Fos expressing cells similar to that induced by hypercapnia.