10 research outputs found
Glucocerebrosidase expression patterns in the non-human primate brain
Glucocerebrosidase (GCase) is a lysosomal
enzyme encoded by the GBA1 gene. Mutations in GBA1
gene lead to Gaucher’s disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase
activity, therefore promoting the aggregation of alphasynuclein, a common neuropathological finding underlying
Parkinson’s disease (PD) and dementia with Lewy bodies.
However, it is also worth noting that a direct link between
GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date. Bearing in mind that a number of
strategies increasing GCase expression for the treatment of
PD are currently under development, here we sought to
analyze the baseline expression of GCase in the brain of
Macaca fascicularis, which has often been considered as
the gold-standard animal model of PD. Although as with
other lysosomal enzymes, GCase is expected to be ubiquitously expressed, here a number of regional variations
have been consistently found, together with several specific
neurochemical phenotypes expressing very high levels of
GCase. In this regard, the most enriched expression of
GCase was constantly found in cholinergic neurons from
the nucleus basalis of Meynert, dopaminergic cells in the
substantia nigra pars compacta, serotoninergic neurons
from the raphe nuclei, as well as in noradrenergic neurons
located in the locus ceruleus. Moreover, it is also worth
noting that moderate levels of expression were also found
in a number of areas within the paleocortex and archicortex, such as the entorhinal cortex and the hippocampal
formation, respectively
Estrogen and angiotensin interaction in the substantia nigra. Relevance to postmenopausal Parkinson's disease
Epidemiological studies have reported that the incidence of Parkinson's disease (PD) is higher in postmenopausal than in premenopausal women of similar age. Several laboratory observations have revealed that estrogen has protective effects against dopaminergic toxins. The mechanism by which estrogen protects dopaminergic neurons has not been clarified, although estrogen-induced attenuation of the neuroinflammatory response plays a major role. We have recently shown that activation of the nigral renin-angiotensin system (RAS), via type 1 (AT1) receptors, leads to NADPH complex and microglial activation and induces dopaminergic neuron death. In the present study we investigated the effect of ovariectomy and estrogen replacement on the nigral RAS and on dopaminergic degeneration induced by intrastriatal injection of 6-OHDA. We observed a marked loss of dopaminergic neurons in ovariectomized rats treated with 6-OHDA, which was significantly reduced by estrogen replacement or treatment with the AT1 receptor antagonist candesartan. We also observed that estrogen replacement induces significant downregulation of the activity of the angiotensin converting enzyme as well as downregulation of AT1 receptors, upregulation of AT2 receptors and downregulation of the NADPH complex activity in the substantia nigra in comparison with ovariectomized rats. The present results suggest that estrogen-induced down-regulation of RAS and NADPH activity may be associated with the reduced risk of PD in premenopausal women, and increased risk in conditions causing early reduction in endogenous estrogen, and that manipulation of brain RAS system may be an efficient approach for the prevention or coadjutant treatment of PD in estrogen-deficient women
Estrogen and angiotensin interaction in the substantia nigra. Relevance to postmenopausal Parkinson's disease
Epidemiological studies have reported that the incidence of Parkinson's disease (PD) is higher in postmenopausal than in premenopausal women of similar age. Several laboratory observations have revealed that estrogen has protective effects against dopaminergic toxins. The mechanism by which estrogen protects dopaminergic neurons has not been clarified, although estrogen-induced attenuation of the neuroinflammatory response plays a major role. We have recently shown that activation of the nigral renin-angiotensin system (RAS), via type 1 (AT1) receptors, leads to NADPH complex and microglial activation and induces dopaminergic neuron death. In the present study we investigated the effect of ovariectomy and estrogen replacement on the nigral RAS and on dopaminergic degeneration induced by intrastriatal injection of 6-OHDA. We observed a marked loss of dopaminergic neurons in ovariectomized rats treated with 6-OHDA, which was significantly reduced by estrogen replacement or treatment with the AT1 receptor antagonist candesartan. We also observed that estrogen replacement induces significant downregulation of the activity of the angiotensin converting enzyme as well as downregulation of AT1 receptors, upregulation of AT2 receptors and downregulation of the NADPH complex activity in the substantia nigra in comparison with ovariectomized rats. The present results suggest that estrogen-induced down-regulation of RAS and NADPH activity may be associated with the reduced risk of PD in premenopausal women, and increased risk in conditions causing early reduction in endogenous estrogen, and that manipulation of brain RAS system may be an efficient approach for the prevention or coadjutant treatment of PD in estrogen-deficient women
Location of prorenin receptors in primate substantia nigra: effects on dopaminergic cell death
Angiotensin II acts via angiotensin type 1 receptors and is a major inducer of inflammation and oxidative stress. Local renin-angiotensin systems play a major role in the development of age-related disorders in several tissues. These processes are delayed, but not totally abolished, by blockade of angiotensin signaling. A specific receptor for renin and its precursor prorenin has recently been identified. We previously showed that neurotoxin-induced dopaminergic (DA) cell loss is decreased by inhibition of angiotensin receptors, but the location and functional effects of prorenin receptor (PRR) in the brain, including the DA system, are unknown. In the substantia nigra of Macaca fascicularis and in rat primary mesencephalic cultures, double immunofluorescence analysis revealed PRR immunoreactivity in neurons (including DA neurons) and microglia, but not in astrocytes. Administration of the PRR blocker, handle region peptide, led to a significant decrease in 6-hydroxydopamine-induced DA cell death in the cultures,whereas administration of renin with simultaneous blockade of angiotensin receptors led to an increase in 6-hydroxydopamine-induced cell death. These results suggest that active agent angiotensin II-independent PRR intracellular signaling may contribute to exacerbation of DA cell death in vivo. Therefore, potential neuroprotective strategies for DA neurons in Parkinson disease should address both angiotensin and PRR signaling
Location of prorenin receptors in primate substantia nigra: effects on dopaminergic cell death
Angiotensin II acts via angiotensin type 1 receptors and is a major inducer of inflammation and oxidative stress. Local renin-angiotensin systems play a major role in the development of age-related disorders in several tissues. These processes are delayed, but not totally abolished, by blockade of angiotensin signaling. A specific receptor for renin and its precursor prorenin has recently been identified. We previously showed that neurotoxin-induced dopaminergic (DA) cell loss is decreased by inhibition of angiotensin receptors, but the location and functional effects of prorenin receptor (PRR) in the brain, including the DA system, are unknown. In the substantia nigra of Macaca fascicularis and in rat primary mesencephalic cultures, double immunofluorescence analysis revealed PRR immunoreactivity in neurons (including DA neurons) and microglia, but not in astrocytes. Administration of the PRR blocker, handle region peptide, led to a significant decrease in 6-hydroxydopamine-induced DA cell death in the cultures,whereas administration of renin with simultaneous blockade of angiotensin receptors led to an increase in 6-hydroxydopamine-induced cell death. These results suggest that active agent angiotensin II-independent PRR intracellular signaling may contribute to exacerbation of DA cell death in vivo. Therefore, potential neuroprotective strategies for DA neurons in Parkinson disease should address both angiotensin and PRR signaling
Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis
The putative presence of the cannabinoid receptor type 2 (CB(2)-R) in the central nervous system is still a matter of debate. Although first described in peripheral and immune tissues, evidence suggesting the existence of CB(2)-Rs in glial cells and even neurons has been made available more recently. By taking advantage of newly designed CB(2)-R mRNA riboprobes, we have demonstrated by in situ hybridization and PCR the existence of CB2-R transcripts in a variety of brain areas of the primate Macaca fascicularis, including the cerebral cortex and the hippocampus, as well as in the external and internal divisions of the globus pallidus, both pallidal segments showing the highest abundance of CB(2)-R transcripts. In this regard, the presence of the messenger coding CB(2)-Rs within the pallidal complex highlights their consideration as potential targets for the treatment of movement disorders of basal ganglia origin
Glucocerebrosidase expression patterns in the non-human primate brain
Glucocerebrosidase (GCase) is a lysosomal
enzyme encoded by the GBA1 gene. Mutations in GBA1
gene lead to Gaucher’s disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase
activity, therefore promoting the aggregation of alphasynuclein, a common neuropathological finding underlying
Parkinson’s disease (PD) and dementia with Lewy bodies.
However, it is also worth noting that a direct link between
GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date. Bearing in mind that a number of
strategies increasing GCase expression for the treatment of
PD are currently under development, here we sought to
analyze the baseline expression of GCase in the brain of
Macaca fascicularis, which has often been considered as
the gold-standard animal model of PD. Although as with
other lysosomal enzymes, GCase is expected to be ubiquitously expressed, here a number of regional variations
have been consistently found, together with several specific
neurochemical phenotypes expressing very high levels of
GCase. In this regard, the most enriched expression of
GCase was constantly found in cholinergic neurons from
the nucleus basalis of Meynert, dopaminergic cells in the
substantia nigra pars compacta, serotoninergic neurons
from the raphe nuclei, as well as in noradrenergic neurons
located in the locus ceruleus. Moreover, it is also worth
noting that moderate levels of expression were also found
in a number of areas within the paleocortex and archicortex, such as the entorhinal cortex and the hippocampal
formation, respectively
Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism
Abstract Although type 1 cannabinoid receptors (CB1-
Rs) are expressed abundantly throughout the brain, the
presence of type 2 cannabinoid receptors (CB2Rs) in neurons
is still somewhat controversial. Taking advantage of
newly designed CB1R and CB2R mRNA riboprobes, we
demonstrate by PCR and in situ hybridization that transcripts
for both cannabinoid receptors are present within
labeled pallidothalamic-projecting neurons of control and
MPTP-treated macaques, whereas the expression is markedly
reduced in dyskinetic animals. Moreover, an in situ
proximity ligation assay was used to qualitatively assess
the presence of CB1Rs and CB2Rs, as well as CB1R–CB2R
heteromers within basal ganglia output neurons in all
animal groups (control, parkinsonian and dyskinetic
macaques). A marked reduction in the number of CB1Rs,
CB2Rs and CB1R–CB2R heteromers was found in dyskinetic
animals, mimicking the observed reduction in CB1R
and CB2R mRNA expression levels. The fact that chronic
levodopa treatment disrupted CB1R–CB2R heteromeric
complexes should be taken into consideration when
designing new drugs acting on cannabinoid receptor
heteromers
Spanish cell therapy network (TerCel): 15 years of successful collaborative translational research
In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a
successful collaborative public initiative funded by the Spanish government for the support of nationwide
translational research in this important area. Thirty-two research groups organized in three programs
devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently
form the network. Each program has three working packages focused on basic science, pre-clinical studies
and clinical application. TerCel has contributed during this period to boost the translational research in cell
therapy in Spain, setting up a network of Good Manufacturing Practice certified cell manufacturing facilities and increasing the number of translational research projects, publications, patents and clinical trials of
the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product
approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on
the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice
for the benefit of patients
Spanish cell therapy network (TerCel): 15 years of successful collaborative translational research
In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a
successful collaborative public initiative funded by the Spanish government for the support of nationwide
translational research in this important area. Thirty-two research groups organized in three programs
devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently
form the network. Each program has three working packages focused on basic science, pre-clinical studies
and clinical application. TerCel has contributed during this period to boost the translational research in cell
therapy in Spain, setting up a network of Good Manufacturing Practice certified cell manufacturing facilities and increasing the number of translational research projects, publications, patents and clinical trials of
the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product
approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on
the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice
for the benefit of patients