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1.
Neuroscience ; 170(1): 28-41, 2010 Sep 29.
Article in English | MEDLINE | ID: mdl-20621164

ABSTRACT

Recent data support the involvement of the endocannabinoid signaling in early brain development, as well as a key role of cannabinoid receptors (CBR) in pathological conditions associated with unbalanced neuronal excitability and inflammation. Using immunocytochemistry, we explored the expression and cellular pattern of CBR 1 and 2 (CB1 and CB2) during prenatal human cortical development, as well as in focal malformations of cortical development associated with intractable epilepsy (focal cortical dysplasia; cortical tubers in patients with the tuberous sclerosis complex and glioneuronal tumors). Strong CB1 immunoreactivity was detected in the cortical plate in developing human brain from the earliest stages tested (gestational week 9) and it persisted throughout prenatal development. Both cannabinoid receptors were not detected in neural progenitor cells located in the ventricular zone. Only CB1 was expressed in the subventricular zone and in Cajal-Retzius cells in the molecular zone of the developing neocortex. CB2 was detected in cells of the microglia/macrophage lineage during development. In malformations of cortical development, prominent CB1 expression was demonstrated in dysplastic neurons. Both CBR were detected in balloon/giant cells, but CB2 appeared to be more frequently expressed than CB1 in these cell types. Reactive astrocytes were mainly stained with CB1, whereas cells of the microglia/macrophage lineage were stained with CB2. These findings confirm the early expression pattern of cannabinoid receptors in the developing human brain, suggesting a function for CB1 in the early stages of corticogenesis. The expression patterns in malformations of cortical development highlight the role of cannabinoid receptors as mediators of the endocannabinoid signaling and as potential pharmacological targets to modulate neuronal and glial cell function in epileptogenic developmental pathologies.


Subject(s)
Cerebral Cortex/growth & development , Epilepsy/metabolism , Epilepsy/pathology , Gene Expression Regulation, Developmental , Receptor, Cannabinoid, CB1/biosynthesis , Receptor, Cannabinoid, CB2/biosynthesis , Adult , Cell Lineage/genetics , Cerebral Cortex/embryology , Cerebral Cortex/pathology , Child , Child, Preschool , Epilepsy/genetics , Female , Humans , Infant , Infant, Newborn , Macrophages/cytology , Macrophages/metabolism , Male , Microglia/cytology , Microglia/metabolism , Middle Aged , Receptor, Cannabinoid, CB1/genetics , Receptor, Cannabinoid, CB2/genetics , Young Adult
2.
Neuroscience ; 167(3): 929-45, 2010 May 19.
Article in English | MEDLINE | ID: mdl-20219643

ABSTRACT

A growing body of evidence demonstrates the involvement of plasminogen activators (PAs) in a number of physiologic and pathologic events in the CNS. Induction of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) has been observed in different experimental models of epilepsy and tPA has been implicated in the mechanisms underlying seizure activity. We investigated the expression and the cellular distribution of tPA and uPA in several epileptogenic pathologies, including hippocampal sclerosis (HS; n=6), and developmental glioneuronal lesions, such as focal cortical dysplasia (FCD, n=6), cortical tubers in patients with the tuberous sclerosis complex (TSC; n=6) and in gangliogliomas (GG; n=6), using immuno-cytochemical, western blot and real-time quantitative PCR analysis. TPA and uPA immunostaining showed increased expression within the epileptogenic lesions compared to control specimens in both glial and neuronal cells (hippocampal neurons in HS and dysplastic neurons in FCD, TSC and GG specimens). Confocal laser scanning microscopy confirmed expression of both proteins in astrocytes and microglia, as well as in microvascular endothelium. Immunoblot demonstrated also up-regulation of the uPA receptor (uPAR; P<0.05). Increased expression of tPA, uPA, uPAR and tissue PA inhibitor type mRNA levels was also detected by PCR analysis in different epileptogenic pathologies (P<0.05). Our data support the role of PA system components in different human focal epileptogenic pathologies, which may critically influence neuronal activity, inflammatory response, as well as contributing to the complex remodeling of the neuronal networks occurring in epileptogenic lesions.


Subject(s)
Brain Neoplasms/metabolism , Brain/metabolism , Epilepsy/metabolism , Nervous System Malformations/metabolism , Tissue Plasminogen Activator/metabolism , Urokinase-Type Plasminogen Activator/metabolism , Adolescent , Adult , Astrocytes/metabolism , Biomarkers/metabolism , Blotting, Western , Brain/abnormalities , Brain/pathology , Brain Neoplasms/complications , Brain Neoplasms/physiopathology , Child , Epilepsy/etiology , Epilepsy/physiopathology , Female , Ganglioglioma/complications , Ganglioglioma/metabolism , Ganglioglioma/physiopathology , Hippocampus/metabolism , Hippocampus/pathology , Hippocampus/physiopathology , Humans , Immunohistochemistry , Male , Malformations of Cortical Development/complications , Malformations of Cortical Development/metabolism , Malformations of Cortical Development/physiopathology , Microglia/metabolism , Middle Aged , Nervous System Malformations/complications , Nervous System Malformations/physiopathology , RNA, Messenger/metabolism , Receptors, Urokinase Plasminogen Activator/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tissue Plasminogen Activator/analysis , Tissue Plasminogen Activator/genetics , Tuberous Sclerosis/complications , Tuberous Sclerosis/metabolism , Tuberous Sclerosis/physiopathology , Urokinase-Type Plasminogen Activator/analysis , Urokinase-Type Plasminogen Activator/genetics , Young Adult
3.
Eur J Neurosci ; 31(6): 1100-7, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20214679

ABSTRACT

Increasing evidence supports the involvement of inflammatory and immune processes in temporal lobe epilepsy (TLE). MicroRNAs (miRNA) represent small regulatory RNA molecules that have been shown to act as negative regulators of gene expression controlling different biological processes, including immune-system homeostasis and function. We investigated the expression and cellular distribution of miRNA-146a (miR-146a) in a rat model of TLE as well as in human TLE. miR-146a analysis in rat hippocampus was performed by polymerase chain reaction and immunocytochemistry at 1 week and 3-4 months after induction of status epilepticus (SE). Prominent upregulation of miR-146a activation was evident at 1 week after SE and persisted in the chronic phase. The miR-146a expression was confirmed to be present in reactive astrocytes. In human TLE with hippocampal sclerosis, increased astroglial expression of miR-146a was observed mainly in regions where neuronal cell loss and reactive gliosis occurred. The increased and persistent expression of miR-146a in reactive astrocytes supports the possible involvement of miRNAs in the modulation of the astroglial inflammatory response occurring in TLE and provides a target for future studies aimed at developing strategies against pro-epileptogenic inflammatory signalling.


Subject(s)
Epilepsy, Temporal Lobe/metabolism , Gene Expression Regulation/physiology , MicroRNAs/metabolism , Adult , Animals , Disease Models, Animal , Electric Stimulation/adverse effects , Epilepsy, Temporal Lobe/etiology , Epilepsy, Temporal Lobe/pathology , Female , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Humans , Male , MicroRNAs/genetics , Middle Aged , Neuroglia/metabolism , Rats , Rats, Sprague-Dawley , Statistics, Nonparametric , Time Factors , Young Adult
4.
Neurobiol Dis ; 36(1): 81-95, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19596445

ABSTRACT

An increasing number of observations suggest an important role for voltage-gated potassium (Kv) channels in epilepsy. We studied the cell-specific distribution of Kv4.2, phosphorylated (p) Kv4.2 and the Kv4.2 interacting protein NCS-1 using immunocytochemistry in different epilepsy-associated focal lesions. In hippocampal sclerosis (HS), Kv4.2 and pKv4.2 immunoreactivity (IR) was reduced in the neuropil in regions with prominent neuronal cell loss. In both HS and malformations of cortical development (MCD), intense labeling was found in neuronal somata, but not in dendrites. Strong NCS-1 IR was observed in neurons in all lesion types. Western blot analysis demonstrated an increase of total Kv4.2 in all lesions and activation of the ERK pathway in HS and ganglioglioma. These findings indicate that Kv4.2 is expressed in both neuronal and glial cells and its regulation may involve potassium channel interacting proteins, alterations in the subcellular localization of the channel, as well as phosphorylation-mediated posttranslational modifications.


Subject(s)
Epilepsy/pathology , Hippocampus/metabolism , Hippocampus/pathology , Malformations of Cortical Development/metabolism , Shal Potassium Channels/metabolism , Adolescent , Adult , Animals , Child , Child, Preschool , Epilepsy/complications , Female , Humans , Male , Malformations of Cortical Development/complications , Malformations of Cortical Development/pathology , Nerve Tissue Proteins/metabolism , Neuroglia/metabolism , Neurons/metabolism , Postmortem Changes , Rats , Sclerosis/complications , Sclerosis/pathology , Young Adult
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