1,721,004 research outputs found
Bcl-2 expression in thalamus, brainstem, cerebellum and visual cortex of adult primate
No full textDue to the functional importance of Bcl-2, which acts as an anti-apoptotic protein that also affects neural differentiation and adult neurogenesis, we undertook a detailed immunohistochemical study of the distribution of this protein in the brain of squirrel monkeys. The present study describes findings obtained at thalamic, brainstem, cerebellum and visual cortex levels, and the data are compared with our previous results gathered in the same species. At thalamic level, Bcl-2-positive neurons occur in anterior, rostral intralaminar, midline and lateral habenular nuclei. The protein is also expressed in several structures associated with the ventricular system, including the subventricular zone (SVZ), the subcommissural organ, and the periventricular grey at rostral and caudal tips of the fourth ventricle. At brainstem and cerebellar levels, Bcl-2-positive neurons occur in the dorsal raphe nucleus, inferior olivary complex, and in molecular and granular layers of the cerebellum. Finally, neurons of layer IV of the striate cortex display a very strong Bcl-2 immunoreactivity that contrasts with the poor labeling of neurons in adjacent parastriate and peristriate cortices. These finding suggests that Bcl-2 plays a role in the plasticity and structural maintenance of various structures in the primate brain and indicate that the mitotically active SVZ might be more extended along the rostrocaudal axis in primates than in rodents
Expression pattern of voltage-dependent calcium channel subunits in hippocampal inhibitory neurons in mice
No full textDifferent subtypes of voltage-dependent calcium channels (VDCCs) generate various types of calcium currents that play important role in neurotransmitter release, membrane excitability, calcium transients and gene expression. Well-established differences in the physiological properties and variable sensitivity of hippocampal GABAergic inhibitory neurons to excitotoxic insults suggest that the calcium homeostasis, thus VDCC subunits expression pattern is likely different in subclasses of inhibitory cells. Using double-immunohistochemistry, here we report that in mice: 1) Cav2.1 and Cav3.1 subunits are expressed in almost all inhibitory neurons; 2) subunits responsible for the L-type calcium current (Cav1.2 and Cav1.3) are infrequently co-localized with calretinin inhibitory cell marker while Cav1.3 subunit, at least in part, tends to compensate for the low expression of Cav1.2 subunit in parvalbumin-, metabotropic glutamate receptor 1alpha- and somatostatin-immunopositive inhibitory neurons; 3) Cav2.2 subunit is expressed in the majority of inhibitory neurons except in calbindin-reactive inhibitory cells; 4) Cav2.3 subunit is expressed in the vast majority of the inhibitory cells except in parvalbumin- and calretinin-immunoreactive neurons where the proportion of expression of this subunit is considerably lower. These data indicate that VDCC subunits are differentially expressed in hippocampal GABAergic interneurons, which could explain the diversity in their electrophysiological properties, the existence of synaptic plasticity in certain inhibitory neurons and their vulnerability to stressful stimuli
Ischemic-hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus
No full textStatus epilepticus (SE) is one of the recognized primary precipitating events that can lead to temporal lobe epilepsy (TLE) associated with hippocampal sclerosis. This type of epilepsy is characterized by poor response to drug treatment, often requiring surgical intervention to remove the mesial temporal regions involved in the seizure onset. However, even neurosurgery may not be completely successful. Thus, the prevention of hippocampal damage and epileptogenesis is currently evaluated as a possible alternative therapeutic approach to prevent the development of pharmacoresistant TLE. Lines of evidence suggest that ischemic-hypoxic lesions might occur in different brain regions, including the hippocampus, during SE. Especially in the hippocampal CA3 region, an ischemic-like lesion develops in the stratum lacunosum-moleculare and is mainly characterized by a loss of astrocytes and neuronal processes and increased immunostaining of pimonidazole which probes areas exposed to hypoxia. Interestingly, these mechanisms can contribute to neuronal cell loss and may be counteracted by drugs that can afford vascular protection, as in the case of ligands of the ghrelin receptor. Notably, some of the ghrelin receptor ligands possess a double edge effect, since they are anticonvulsant and vascular-protective, thus, potentially representing new tools to counteract the consequences of SE. This article is part of a Special Issue entitled Status Epilepticus
Differential expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor subunits by calretinin-immunoreactive neurons in the human striatum
No full textWe recently reported the existence of medium and large intemeurons immunoreactive for the calcium-binding protein calretinin in the human striatum. We also showed a selective sparing of all medium, but not all large, calretinin-immunoreactive striatal neurons in Huntington's disease striatum. Because glutamate receptor-mediated excitotoxicity has been implicated in the massive loss of striatal projection neurons that characterizes Huntington's disease, we have applied a double-antigen localization procedure to post mortem tissue from eight normal human subjects to determine the expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor subunits 1/2/4 by the calretinin-immunoreactive interneurons. The two types of calretinin-immunoreactive neurons were found to display various patterns of glutamate receptor subunit expression and a specific regionalization was also noted in the expression of these glutamate receptor subunits. Approximately half of the large calretinin-immunoreactive neurons displayed immunoreactivity for glutamate receptor subunits 1 and 2, and about the same proportion of medium calretinin-immunoreactive neurons expressed glutamate receptor subunits 1 and 4. These double-labeled neurons were rather uniformly distributed in the caudate nucleus and putamen. In contrast, as much as 70.1% of the large calretinin-immunoreactive neurons displayed glutamate receptor subunit 4 immunoreactivity in the postcommissural portion of the putamen, an area that corresponds to the sensorimotor striatal territory. For their part, the medium calretinin-immunoreactive neurons were markedly enriched with glutamate receptor subunit 2, 76% of them being double labeled in the caudate nucleus, which corresponds to the striatal associative territory, compared with 85.5% in the postcommissural putamen. Receptor subunit composition plays a key role in determining the functional properties of glutamate receptors, including their permeability to calcium and susceptibility to excitotoxic insults. Thus, the differential expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor subunits reported here may help to explain the selective sparing of certain types of calretinin-immunoreactive striatal interneurons in Huntington's disease, although other factors, such as post-transcriptional editing, are also likely to be involved
Characterization of the subventricular zone of the adult human brain: evidence for the involvement of Bcl-2
No full textThe subventricular zone (SVZ) is an embryonic remnant that persists and remains mitotically active throughout adulthood. The rodent SVZ harbors neuronal precursors, principally in its anterior part, and generates neuroblasts that migrate tangentially into the olfactory bulb, thus forming the so-called rostral migratory stream. This study aimed at characterizing the SVZ in the human brain. Antibodies raised against the widely used SVZ molecular markers nestin, glial fibrillary acidic protein, beta-tubulin-III and polysialylated neural cell adhesion molecule, have allowed us to characterize in detail a zone similar to the rodent SVZ in humans. Virtually all portions of the lateral ventricle, as well as the ventral (hypothalamic) sector of the third ventricle, displayed immunoreactivity for most of the molecular markers. The midline region of the septum (septal recess) and the ventral portion of the SVZ displayed a particularly intense immunostaining for all SVZ markers. These two regions may represent zones of adult neurogenesis that are unique to primates. Furthermore, the anti-apoptotic protein Bcl-2 was found to be actively synthesized and co-expressed with all the other markers throughout the entire SVZ. This study reveals that a well-developed SVZ exists in the adult human brain and suggests that Bcl-2 might play an important role in the functional organization of such a system
Repeated 6-Hz corneal stimulation progressively increases FosB/∆FosB levels in the lateral amygdala and induces seizure generalization to the hippocampus.
No full textExposure to repetitive seizures is known to promote convulsions which depends on specific patterns of network activity. We aimed at evaluating the changes in seizure phenotype and neuronal network activation caused by the modified 6-Hz corneal stimulation model of psychomotor seizures. Mice received up to 4 sessions of 6-Hz corneal stimulation with fixed current amplitude of 32 mA and an inter-stimulation interval of 72 h. Video-electroencephalography showed that evoked seizures were characterized by a motor component and a non-motor component. Seizures appeared always in frontal cortex, but only at the fourth stimulation they involved the hippocampus. Duration of non-motor seizures progressively decreased after the second session, whereas convulsive seizures remained unchanged. In addition, a more severe seizure phenotype, consisting of tonic-clonic generalized convulsions, was predominant after the second session. Immunohistochemistry and double immunofluorescence experiments revealed a significant increase in neuronal activity occurring in the lateral amygdala after the fourth session most likely due to activity of principal cells. These findings suggest a predominant role of amygdala in promoting progressively more severe convulsions
Protective but not anticonvulsive effects of ghrelin and JMV-1843 in the pilocarpine model of status epilepticus.
No full textIn models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagogue-receptor 1a (GHS-R1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45 ± 0.07 mm(2) in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P<0.05) and JMV-1843 (P<0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P<0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus
Neurosteroids And Epileptogenesis
No full textEpileptogenesis is defined as the latent period at the end of which spontaneous recurrent seizures occur. This concept has been recently re-evaluated to include exacerbation of clinically-manifested epilepsy. Thus, in patients affected by pharmacoresistant seizures, the progression toward a worse condition may be viewed as the result of a durable epileptogenic process. However, the mechanism potentially responsible for this progression remains unclear. Neuroinflammation has been consistently detected both in the latent period and in the chronic phase of epilepsy, especially when brain damage is present. This phenomenon is accompanied by glial cell reaction, leading to gliosis. We have previously described rats presenting an increased expression of the cytochrome P450 cholesterol side-chain cleavage (P450scc) enzyme, during the latent period, in glial cells of the hippocampus. The P450scc enzyme is critically involved in the synthesis of neurosteroids and its upregulation is associated with a delayed appearance of spontaneous recurrent seizures in rats that experienced status epilepticus (SE) induced by pilocarpine. Moreover, by decreasing the synthesis of neurosteroids able to promote inhibition, such as allopregnanolone, through administration of the 5α-reductase blocker finasteride, it is possible to terminate the latent period in pilocarpine-treated rats. Finasteride was also found to promote seizures in the chronic period of epileptic rats, suggesting that neurosteroids are continuously produced to counteract seizures. In humans, exacerbation of epilepsy has been also described in patients occasionally exposed to finasteride. Overall, these findings suggest a major role of neurosteroids in the progression of epilepsy and a possible antiepileptogenic role of allopregnanolone and cognate molecules
Pathophysiogenesis of Mesial Temporal Lobe Epilepsy: Is Prevention of Damage Antiepileptogenic?
No full textTemporal lobe epilepsy (TLE) is frequently associated with hippocampal sclerosis, possibly caused by a primary
brain injury that occurred a long time before the appearance of neurological symptoms. This type of epilepsy is
characterized by refractoriness to drug treatment, so to require surgical resection of mesial temporal regions involved in
seizure onset. Even this last therapeutic approach may fail in giving relief to patients. Although prevention of hippocampal
damage and epileptogenesis after a primary event could be a key innovative approach to TLE, the lack of clear data on
the pathophysiological mechanisms leading to TLE does not allow any rational therapy. Here we address the current
knowledge on mechanisms supposed to be involved in epileptogenesis, as well as on the possible innovative treatments
that may lead to a preventive approach. Besides loss of principal neurons and of specific interneurons, network rearrangement
caused by axonal sprouting and neurogenesis are well known phenomena that are integrated by changes in receptor
and channel functioning and modifications in other cellular components. In particular, a growing body of evidence
from the study of animal models suggests that disruption of vascular and astrocytic components of the blood-brain barrier
takes place in injured brain regions such as the hippocampus and piriform cortex. These events may be counteracted by
drugs able to prevent damage to the vascular component, as in the case of the growth hormone secretagogue ghrelin and
its analogues. A thoroughly investigation on these new pharmacological tools may lead to design effective preventive
therapies
Cloning of mouse Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) and characterization of CaMKKbeta and CaMKKalpha distribution in the adult mouse brain.
No full textThe Ca(2+)/calmodulin-dependent protein kinase kinases alpha and beta (CaMKKs alpha and beta) are novel members of the CaM kinase family. The CaMKKbeta was cloned from mouse brain. The deduced amino acid sequence shared 96.43% homology with the rat CaMKKbeta. Both the alpha and beta isoforms were widely distributed throughout the adult mouse brain. Additionally, all peripheral tissues examined displayed CaMKK alpha and beta expression
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