Publications (156)549.9 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: 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.
- [Show abstract] [Hide abstract] ABSTRACT: 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. 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.
- [Show abstract] [Hide abstract] ABSTRACT: 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. 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.
- [Show abstract] [Hide abstract] ABSTRACT: 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 Parkinson's 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.
- [Show abstract] [Hide abstract] ABSTRACT: We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinson's 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.
- [Show abstract] [Hide abstract] ABSTRACT: Inflammatory processes described in Parkinson's 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.
- [Show abstract] [Hide abstract] ABSTRACT: Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
- [Show abstract] [Hide abstract] ABSTRACT: We show that intranigral lipopolysaccharide (LPS) injection, which provokes specific degeneration of DA neurons, induced caspase-3 activation in the rat ventral mesencephalon, which was mostly associated with glial cells. In contrast, nigral DA neurons exhibited AIF nuclear translocation in response to LPS. A significant decrease of the Bcl-2/Bax ratio in nigral tissue after LPS injection was observed. We next developed an in vitro co-culture system with the microglial BV2 and the DA neuronal MN9D murine cell lines. The silencing of caspase-3 or AIF by small interfering RNAs exclusively in the DA MN9D cells demonstrated the key role of AIF in the LPS-induced death of DA cells. In vivo chemical inhibition of caspases and poly(ADP-ribose)polymerase-1, an upstream regulator of AIF release and calpain, proved the central role of the AIF-dependent pathway in LPS-induced nigral DA cell death. We also observed nuclear translocation of AIF in the ventral mesencephalon of Parkinson's disease subjects.
- [Show abstract] [Hide abstract] ABSTRACT: We have searched for potential biomarkers in the cerebrospinal fluid (CSF) and plasma in an animal model of Parkinson's disease induced by inflammatory challenge. To achieve this, either unilateral or bilateral intranigral injection of lipopolysaccharide (LPS) was performed. CSF proteins were first analyzed either by 2D electrophoresis and MALDI-TOF at days 1 and 10 after the lesion to discern between potential prognosis and diagnosis protein markers. Most significant changes from this analysis were early increases of haptoglobin, transthyretin and different spots further identified as prostaglandin D synthase in response to LPS. These markers were then analyzed by western blotting in CSF and plasma using specific antibodies from samples obtained in animals receiving either LPS in substantia nigra or hippocampus and 6-OHDA in the medial forebrain bundle. This analysis confirmed the early increases of haptoglobin and transthyretin in response to intranigral injection of LPS or 6-OHDA in the bundle in plasma and CSF. We discuss the potential use of both biomarkers for the early diagnose of Parkinson's disease.
- [Show abstract] [Hide abstract] ABSTRACT: J. Neurochem. (2010) 114, 1687–1700. Peripheral inflammation could play a role in the origin and development of certain neurodegenerative disorders. To ascertain this possibility, a model of dopaminergic neurodegeneration based on the injection of the inflammatory agent lipopolysaccharide (LPS) within the substantia nigra was assayed in rats with ulcerative colitis (UC) induced by the ingestion of dextran sulphate sodium. We found an increase in the levels of inflammatory markers from serum (tumor necrosis factor-α, IL-1β, IL-6 and the acute phase protein C-reactive protein) and substantia nigra (tumor necrosis factor-α, IL-1β, IL-6, inducible nitric oxide synthase, intercellular adhesion molecule-1, microglial and astroglial populations) of rats with UC, as well as an alteration of the blood–brain barrier permeability and the loss of dopaminergic neurons. UC reinforced the inflammatory and deleterious effects of LPS. On the contrary, clodronate encapsulated in liposomes (ClodLip), which depletes peripheral macrophages, ameliorated the effect of LPS and UC. Peripheral inflammation might represent a risk factor in the development of Parkinson’s disease.
- [Show abstract] [Hide abstract] ABSTRACT: Anti-inflammatory strategies receive growing attention for their potential to prevent pathological deterioration in disorders such as Parkinson's disease, which is accompanied by inflammatory reactions that might play a critical role in the degeneration of nigral dopaminergic neurons. We investigated the influence of dexamethasone - a potent synthetic member of the glucocorticoids class of steroid hormones that acts as an anti-inflammatory - on the degeneration of the dopaminergic neurons of rats observed after intranigral injection of thrombin, a serine protease that induces inflammation through microglia proliferation and activation. We evaluated tyrosine hydroxylase (TH)-positive neurons as well as astroglial and microglial populations; dexamethasone prevented the loss of astrocytes but was unable to stop microglial proliferation induced by thrombin. Moreover, dexamethasone produced alterations in the levels of nexin and the thrombin receptor PAR-1, and facilitated accumulation of alpha-synuclein induced by thrombin in dopaminergic neurons. Dexamethasone increased oxidative stress and expression of monoamine oxidase A and B, along with changes on different MAP kinases related to degenerative processes, resulting in a bigger loss of dopaminergic neurons after intranigral injection of thrombin in dexamethasone-treated animals. It is interesting to ascertain that inhibition of monoamine oxidase by tranylcypromine prevented neurodegeneration of dopaminergic neurons, thus suggesting that the deleterious effects of dexamethasone might be mediated by monoamine oxidase.
- [Show abstract] [Hide abstract] ABSTRACT: Tissue-type plasminogen activator (tPA) is the only drug approved for the treatment of thromboembolic stroke, but it might lead to some neurotoxic side effects. tPA is a highly specific serine proteinase, one of the two principal plasminogen activators and one of the three trypsin-like serine proteinases of the tissue kallikrein family. We have observed that tPA injection in the SN leads to the degeneration of the dopaminergic neurons in a dose-dependent manner, without affecting the GABAergic neurons. We also found that tPA injected in the substantia nigra of rats produced the disruption of the blood-brain barrier (BBB) integrity, the induction of microglial activation, the loss of astroglia and the expression of aquaporin 4 (AQP4), as well as an increase in the expression of NMDA receptors and the brain derived neurothrophic factor (BDNF). All these effects, along with the changes produced in the phosphorylated forms of several MAP kinases and the transcription factor CREB, and the increase in the expression of nNOS and iNOS observed under our experimental conditions, could be involved in the loss of dopaminergic neurons.
- [Show abstract] [Hide abstract] ABSTRACT: 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. We have perfused different concentrations of LPS or 1 mM 1-methyl-4-phenylpyridinium ion (MPP+) in the rat's striatum, 24 h after implanting a brain microdialysis probe, both with and without Zocor Forte (simvastatin) treatment. Results show that LPS perfusion produced a decrease in the basal release of dopamine. Forty-eight hours after implanting the probe, we have perfused 1 mM MPP+ to check the integrity of the dopaminergic terminals present around the cannula. Our model to study toxicity in the striatal dopaminergic terminals suggests that Zocor Forte (simvastatin) could prevent the neurotoxic damage produced by LPS, but not that produced by MPP+.
- [Show abstract] [Hide abstract] ABSTRACT: The hippocampus is insensitive to strong inflammatory stimulus under normal conditions and one of the most severely affected areas in Alzheimer's disease. We have analyzed the effect of chronic stress for 9 days in the hippocampus unilaterally injected with LPS. In non-stressed rats, LPS injection failed to activate microglia although a subset of degenerating cells in the CA1 area was evident. This effect was not accompanied by loss of Neu-N positive neurons in the CA1 area. In stressed rats, LPS injection had a dramatic effect in activating microglia along with astrogliosis and BDNF mRNA induction. NeuN immunostaining demonstrated a loss of about 50% of CA1 pyramidal neurons under these conditions. Fluoro jade B histochemistry demonstrated the presence of degenerating cells in most of CA1 area. Mechanistically, combination of chronic stress and LPS resulted in prominent activation of MAPKs including JNK, p38 and ERK clearly different from LPS injection in controls. Further, LPS+stress induced a dramatic decrease in phosphorylated levels of both Akt and CREB, which fully supports a consistent deleterious state in the hippocampal system under these conditions. Treatment with RU486, a potent inhibitor of glucocorticoid receptor activation, significantly protected animals against the deleterious effects observed in LPS-stressed animals.
- [Show abstract] [Hide abstract] ABSTRACT: Axotomy is a powerful stimulus of axon growth and plastic changes. We investigated the potential role of BDNF/trkB signaling in the sprouting of dopaminergic nigral axons in response to axotomy of the medial forebrain bundle. Tyrosine hydroxylase immunohistochemistry revealed the existence of sprouting mechanisms in the axotomized substantia nigra (SN). Time-course changes of trkB mRNA expression demonstrated a robust increase in an area projecting from the rostral tip of the SN to the glial scar, which coincided with evidence of nigral dopaminergic sprouting. In addition, we found an early loss of this messenger in areas related to the knife cut, which recovered by 7 days postlesion. TrkB down-regulation appeared to be associated to the lesion-induced local damage, as it was restricted to an area showing Fluoro-Jade B- and TUNEL positive cells. In trkB-depleted areas, an inverse correlation between mRNA expressions of BDNF and trkB was apparent. Specific induction of BDNF mRNA was mostly seen in border of areas devoid of trkB mRNA. In contrast, in the areas exhibiting trkB mRNA expression, no BDNF mRNA was detected. We suggest that trkB levels could be a determinant element in regulating BDNF expression. Finally, the search for molecules involved in either promoting or inhibiting axonal growth, demonstrated up-regulation of GAP-43 and Nogo-A mRNA at sites close to the knife transections as early as 1 day postlesion. However, overall, Nogo-A induction was more robust than that seen for GAP-43.
- [Show abstract] [Hide abstract] ABSTRACT: We have performed intrastriatal injection of thrombin and searched for distant effects in the cell body region. In striatum, thrombin produced a slight loss of striatal neurons as demonstrated by neural nuclei immunostaining - a non-specific neuronal marker - and the expression of glutamic acid decarboxylase 67 mRNA, a specific marker for striatal GABAergic interneurons, the most abundant phenotype in this brain area. Interestingly, striatal neuropil contained many boutons immunostained for synaptic vesicle protein 2 and synaptophysin which colocalize with tyrosine hydroxylase (TH), suggesting a degenerative process with pre-synaptic accumulation of synaptic vesicles. When we studied the effects on substantia nigra, we found the disappearance of dopaminergic neurons, shown by loss of TH immunoreactivity, loss of expression of TH and dopamine transporter mRNAs, and disappearance of FluoroGold-labelled nigral neurons. The degeneration of substantia nigra dopaminergic neurons was produced through up-regulation of cFos mRNA, apoptosis and accumulation of alpha-synuclein shown by colocalization experiments. Thrombin effects could be mediated by protease-activated receptor 4 activation, as protease-activated receptor 4-activating peptide mimicked thrombin effects. Our results point out the possible relationship between synapse elimination and retrograde degeneration in the nigral dopaminergic system.
- [Show abstract] [Hide abstract] ABSTRACT: 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. We evaluated TH positive neurons, astroglial, and microglial populations and found that simvastatin prevented the inflammatory processes, as the induction of interleukin-1beta, tumor necrosis factor-alpha, and iNOS and the consequent dopaminergic degeneration induced by LPS. Moreover, simvastatin produced the activation of the neurotrophic factor BDNF, along with the prevention of the oxidative damage to proteins. Moreover, it also prevents the main changes produced by LPS on different mitogen-activated protein kinases, featured as increases of P-c-Jun N-terminal protein kinase, P-extracellular signal-regulated kinase, p-38, and P-glycogen synthase kinase and the decrease of the promotion of cell survival signals such as cAMP response element-binding protein and Akt. Our results suggest that statins could delay the progression of dopaminergic degeneration in disorders involving inflammatory processes.
- [Show abstract] [Hide abstract] ABSTRACT: 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. We increased the content of DA through the inhibition of its uptake by nomifensine or the inhibition of its catabolism by deprenyl. We found that although nomifensine and deprenyl enhanced the DA overflow produced by 3-NP perfusion, they protected against the damage induced by 3-NP in the DAergic terminals and the GABAergic neurons in the striatum. Moreover, there was a decrease of apoptotic cells, astrogliosis and activation of microglia as index of damage. We also found that depletion of DA by reserpine and alpha-methyl-p-tyrosine produced a significant reduction of the inhibition of the respiratory rate and of the production of superoxide radical induced by 3-NP in synaptosomes from the striatum. All these results suggest that endogenous dopamine within the dopaminergic terminals of the striatum enhances the mitochondrial production of radical oxygen species along with the respiratory inhibition produced by 3-NP and thus increases the toxicity produced by 3-NP in the striatum.
- [Show abstract] [Hide abstract] ABSTRACT: Stroke is the third leading cause of death and the leading cause of adult disability in the industrialized nations. One of the consequences of stroke is blood-brain barrier (BBB) leakage and subsequent edema, which is one of the causes of mortality in this pathology. Aquaporin-4 (AQP4) is the most abundant water channel in the brain. Studies in AQP4 knock-out mice have shown a prominent role of this water channel in edema development and resolution after ischemia. Here we have studied changes in AQP4 mRNA and protein expression in response to vascular endothelial growth factor (VEGF), a potent angiogenic factor. VEGF administration highly upregulated AQP4 mRNA and protein in the ventral midbrain. Perfusion of the animals with FITC-albumin prior to sacrifice demonstrated localization of AQP4 protein in close proximity to the VEGF-induced new blood vessels. Expression levels of AQP4 mRNA were maximum 7 days after VEGF injection whereas our previous report showed that BBB leakage is resolved at this time point. Therefore, we speculate a positive role of AQP4 in edema resolution, which may partially explain the previously reported beneficial effects of delayed VEGF administration in ischemic rats. Our results provide new insights into the molecular changes in the edematous brain and may help in future therapeutical directions.
Universidad de Sevilla
Hispalis, Andalusia, Spain
- Biochemistry and Molecular Biology