En el presente estudio se analizaron los niveles de ansiedad despues de varias fases de la conduc... more En el presente estudio se analizaron los niveles de ansiedad despues de varias fases de la conducta sexual masculina en la rata. Los niveles de ansiedad se midieron en la prueba de conducta defensiva de enterramiento. No se encontraron diferencias en los niveles de ansiedad entre los grupos de animales control [sin prueba de conducta sexual] y los animales probados despues de cinco intromisiones de la primera serie copulatoria. Sin embargo, los animales probados durante el primer o segundo periodos posteyaculatorios o durante la ejecucion de la segunda serie copulatoria mostraron niveles de ansiedad menores que el grupo control. Estos resultados dan mas evidencia en favor de la idea de un incremento en la neurotransmision del acido gamma amino-butirico despues de la primera eyaculacion en la rata macho. Se discute respecto a la posible participacion de otros sistemas de neurotransmision en la mediacion de esta respuesta.
Despite the availability of various newly developed antiepileptic drugs (AEDs), pharmacoresistanc... more Despite the availability of various newly developed antiepileptic drugs (AEDs), pharmacoresistance remains a major challenge in epilepsy management. Unraveling the mechanisms underlying AED resistance has been the focus of intense efforts, in order to develop new rationally designed therapies for as yet refractory epilepsies. Based on experimental and clinical studies, one of the major neurobiological theories that has been put forward is the target hypothesis, which suggests that AEDs are not effective because of target alterations in the epileptogenic brain. Several studies have shown that seizure activity results in altered expression of gamma-aminobutyric acid (GABA) components such as GABA transporters (GATs) and GABA receptors. Indeed, changes in the composition of subunits expression appear to affect the functioning of GABAergic neurotransmission. Here, we review the current literature on epilepsy-associated changes in the GABA system conducted in experimental models and observations made in patients with treatment-resistant epilepsy, as well as genetic abnormalities in the GABA system in refractory human epilepsy.
Revista Médica del Hospital General de México, Oct 1, 2018
Background: The 5-hydroxytryptamine-1A receptors are known to be involved in the inhibition of se... more Background: The 5-hydroxytryptamine-1A receptors are known to be involved in the inhibition of seizures in epilepsy. Objective: The main aim of the present study is to determine the functional coupling to Gprotein of the 5-HT 1A receptor through 8-OH-DPAT-stimulated [ 35 S]GTP␥S binding assay in lateral temporal neocortex tissue of patients with mesial temporal lobe epilepsy (mTLE) and correlate it with clinical data. Material and methods: The activation of the G protein complex was determined by [ 35 S]GTP␥S binding assay. The temporal neocortex tissue was obtained from 5 patients with mTLE during epilepsy surgery and from 5 subjects (autopsies) who died due to an accident and without history of neurological disease. Results: We found that values of maximal stimulation (E max) of [ 35 S]GTP␥S binding significant decreased in the mTLE group (30.8%, p < .05) when compared to the autopsy samples (65.9%). The values of potency (pEC 50) were similar in both groups. However, we found no significant differences between the E max and age of patient, age of seizure onset, duration of epilepsy and frequency of seizures. Also, the pEC 50 values revealed no significant correlations with the clinical data.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Repressor Element-1 Silencing Transcription factor or Neuron-Restrictive Silencer Factor (RES... more The Repressor Element-1 Silencing Transcription factor or Neuron-Restrictive Silencer Factor (REST/NRSF) is a zinc finger repressor transcription factor of the Kruppel family. Several studies in experimental models have shown that overexpression of REST/NRSF occurs after the induction of seizures. In the present study, the expression of REST/NRSF (messenger ribonucleic acid (mRNA) and protein) was evaluated in the hippocampus of 28 patients with drug-resistant mesial temporal lobe epilepsy (MTLE) and their correlation with clinical variables and comorbid anxiety and depression. The REST/NRSF protein expression was augmented in an agedependent manner in the hippocampus of autopsied subjects. However, this condition was not observed in patients with MTLE, in whom overexpression of this transcription factor occurred at both the mRNA and protein levels. The correlations with clinical variables showed that the frequency of epileptic seizures was proportional to the protein expression of REST/NRSF. The results revealed that the overexpression of REST/NRSF was more evident in patients with MTLE without anxiety and depression. Our data indicate that the expression of REST/NRSF is modified in patients with MTLE. This condition has implications in the pathophysiology of this disorder, making it a potential candidate for the optimization of clinical treatments.
Blood-brain barrier (BBB) disruption has been associated with several acute and chronic brain dis... more Blood-brain barrier (BBB) disruption has been associated with several acute and chronic brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy. This represents a critical situation because damaged integrity of the BBB is related to the influx of immune mediators, plasma proteins and other outside elements from blood to the central nervous system (CNS) that may trigger a cascade of events that leads to neuroinflammation. In this review, evidence that mast cells and the release of factors such as histamine play an important role in the neuroinflammatory process associated with brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy is presented. Ó 2014 IMSS. Published by Elsevier Inc.
Mesial temporal lobe epilepsy (mTLE) is the most common epilepsy induced by previous cerebral inj... more Mesial temporal lobe epilepsy (mTLE) is the most common epilepsy induced by previous cerebral injury, and one out of three mTLE patients develops drug resistance (DR). AIM To assess the expression of Bcl-2, Caspase-3, Caspase-9, IL1-β, SEMA-3a, NT-3 and P-glycoprotein in the temporal cortex and their relationship with the progression of mTLE-DR clinical features in patients with mTLE-DR. METHOD Tissue samples from 17 patients were evaluated for protein expression by Western blot and the relationships of the evaluated proteins with the clinical features of the mTLE were assessed through hierarchical cluster analysis. RESULTS The mTLE-DR group showed significantly higher P-glycoprotein, Bcl-2 and Caspase-9 levels ***p < 0.0001, ****p < 0.0001 and ***p < 0.0002, respectively, than the autopsy control group. Four patient clusters were identified: Clusters 1 and 3 showed relationships among the age of mTLE onset, duration of mTLE-DR, average number of epileptic seizures per week, number of previous antiepileptic drugs (AEDs) and increased expression of Caspase-3, Caspase- 9, Neurotrophin-3 and Semaphorin-3a. Clusters 2 and 4 showed relationships among the mTLE onset age, current age, average number of epileptic seizures per week, number of previous AEDs and increased expression of IL1-β, Bcl-2, P-glycoprotein, Caspase-3 and NT-3. CONCLUSION The relationships among the clinical data (the age of mTLE onset, DR duration, number of previous AEDs, and average number of seizures per week and the expression of proteins involved in neuronal death, neuroinflammation and aberrant connection formation, as which are biological markers in the cerebral temporal cortex, are important factors in the progression and severity of mTLE-DR and support the intrinsic severity hypothesis.
A putative role of the brain-derived neurotrophic factor (BDNF) in epilepsy has emerged from in v... more A putative role of the brain-derived neurotrophic factor (BDNF) in epilepsy has emerged from in vitro and animal models, but few studies have analyzed human samples. We assessed the BDNF expression of transcripts with exons I (BDNFI), II (BDNFII), IV (BDNFIV) and VI (BDNFVI) and methylation levels of promoters 4 and 6 in the hippocampi of patients with pharmaco-resistant temporal lobe epilepsy (TLE) (n=24). Hippocampal sclerosis (HS) and pre-surgical pharmacological treatment were considered as clinical independent variables. A statistical significant increase for the BDNFVI (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) was observed in TLE patients compared to the autopsy control group (n=8). BDNFVI was also increased in anxiety/depression TLE (N=4) when compared to autopsies or to the remaining group of patients (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). In contrast, the use of the antiepileptic drug Topiramate (TPM) (N=3) was associated to a decrease in BDNFVI expression (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) when compared to the remaining group of patients. Methylation levels at the BDNF promoters 4 and 6 were similar between TLE and autopsies and in relation to the use of either Sertraline (SRT) or TPM. These results suggest an up-regulated expression of a specific BDNF transcript in patients with TLE, an effect that seems to be dependent on the use of specific drugs.
Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome... more Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome depends on the etiology. For instance, patients with posttraumatic FLE (PTE) have a worse surgical outcome compared to patients with FLE related to a tumoral lesion (TL). The present study focuses to determine if the FLE etiology is associated with the P-glycoprotein (P-gp) expression, a condition associated with drug resistance. P-gp expression and cellular localization were determined by Western Blot and immunohistochemical experiments in cortical brain samples obtained from patients with PTE (n = 5), TL (n = 5), and autopsies (n = 5). The neuronal count was estimated by Nissl and stereology procedure. Results showed that the autopsies tissue showed a neuronal count of 3514 ± 304.2 neurons per mm3. The P-gp expression ratio was 0.33 ± 0.02. Its expression was found in endothelial cells. Negligible P-gp expression was detected in neurons and astrocytes. Compared to the autopsies group, the TL group showed no changes in the neuronal count but, there was a decreased P-gp expression ratio (46%, p < 0.05). P-gp was located mainly in neurons, slight in astroglial, and endothelial cells. The PTE group showed a similar P-gp expression ratio compared to the autopsies group. P-gp was expressed in neurons, astrocytes, and endothelial cells in these samples. However, experiments revealed a high P-gp expression in a lower neuronal count (38%, p < 0.05 vs autopsy group). The present study reveals that patients with PTE present neuronal P-gp overexpression. This finding could underlie their worst surgical outcome.
Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopam... more Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DAN). Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson’s disease (PD) patients. We obtained DAN from hESCs and confirmed that they express dopaminergic markers, generate action potentials, and release dopamine (DA) in vitro. DAN were transplanted bilaterally in the putamen of parkinsonian NHPs. After grafting, animals improved motor behavior, evaluated by the HALLWAY task, and in agreement with this recovery, DA release was detected by microdialysis. Imaging techniques revealed changes in fractional anisotropy and mean diffusivity in magnetic resonance imaging and higher 11C-DTBZ binding in positron-emission tomography scans, associated with grafts. Postmortem analysis showed that transplanted DAN survived over ten months in the putamen, without developing tumors, in the immunosuppressed N...
En la ultima decada se ha relacionado la disfuncion del nucleo pedunculopontino (NPP) con la fisi... more En la ultima decada se ha relacionado la disfuncion del nucleo pedunculopontino (NPP) con la fisiopatologia de la enfermedad de Parkinson (EP); sin embargo, no se conocen los cambios que experimenta la liberacion de neurotransmisores en esta estructura. Estudiar los cambios en la liberacion de glutamato (GLU) y de acido g-aminobutirico (GABA) en el NPP de ratas hemiparkinsonianas, y evaluar la muerte celular en esa estructura, es el objetivo de esta investigacion. Se analizaron tres grupos de ratas Wistar: sanas (n = 12); lesionadas con 6-hidroxidopamina (6-OHDA) (n = 11); falsas lesionadas (n = 10). En todas las ratas se implanto una canula de microdialisis en el NPP derecho ipsilateral a la inyeccion de 6-OHDA, y los dializados se analizaron por tecnicas cromatograficas. La muerte celular en el NPP de los animales lesionados se evaluo por inmunohistoquimica TUNEL. Hubo un aumento significativo en las concentraciones de GLU y GABA en el NPP de las ratas hemiparkinsonianas (p < 0...
Introduction. In relation to drug-resistant temporal lobe epilepsy (DRTLE), the interrelation be... more Introduction. In relation to drug-resistant temporal lobe epilepsy (DRTLE), the interrelation between inflammation, oxidative stress, and neuronal death constitutes a topic increasingly researched into. Objectives: To expand the knowledge of the molecular mechanisms that participate in the pathophysiology of DRTLE by correlating clinical variables with immunological ones, oxidative stress and neuronal death. Methods. Immunocytochemistry techniques were used to measure the markers CD3, CD4, CD8, CD19, CD25, HLA-DR; Nephelometry was used for IgG, IgM, IgA, and Albumin; immunoenzymatic tests for IL-1β, IL-6, TNF-α, and nitric oxide. By means of western blot: NFκB, JNK, 4-hydroxy-2-nonenal, 3-nitrotyrosine; by means of spectrophotometry: malonildialdehyde, advanced glycation products, advanced protein oxidation products, uric acid, superoxide dismutase, glutathione, and vitamin C; by means of immunohistochemistry: Annexin V, TUNEL, synaptophysin, caspase 3, p53, and bcl-2; by means of...
Highlights Early intervention with Magnolia officinalis exerts a long-term neuroprotective effe... more Highlights Early intervention with Magnolia officinalis exerts a long-term neuroprotective effects on epileptogenesis. Magnolia officinalis decreases long-term excitability, neuronal damage, and reactive gliosis. Model of recurrent status epilepticus, where antiepileptic drug can be evaluated ABSTRACT During critical periods of neurodevelopment, the immature brain is susceptible to neuronal hyperexcitability, alterations such as hyperthermia, hypoxia, brain trauma or a preexisting neuroinflammatory condition can trigger, promote and prolong epileptiform activity and facilitate the development of epilepsy. The goal of the present study was to evaluate the long-term neuroprotective effects Magnolia officinalis extract, on a model of recurrent status epilepticus (SE) in immature rats. Sprague-Dawley rats were treated with kainic acid (KA) (3 mg/kg, dissolved in
Although there is evidence suggesting a relationship between parkinsonism and modifications to ga... more Although there is evidence suggesting a relationship between parkinsonism and modifications to gabaergic, cholinergic and opioid activities in the basal ganglia and related structures, so far studies are not conclusive, and the molecular mechanisms underlying ...
Neurochemical changes occurring in the nuclei of the basal ganglia as a consequence of the degene... more Neurochemical changes occurring in the nuclei of the basal ganglia as a consequence of the degeneration of the substantia nigra pars compacta (SNc) that typically occurs in the Parkinson's disease (PD), have been already studied (Zigmond et al., 2002). There are well-established experimental models of parkinsonism using intracerebral injection of 6-hydroxydopamine (6-OHDA) in rodents and systemic or intracarotid delivery of 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in non-human primates that have been instrumental in the investigation of these changes (Blum et al.
En el presente estudio se analizaron los niveles de ansiedad despues de varias fases de la conduc... more En el presente estudio se analizaron los niveles de ansiedad despues de varias fases de la conducta sexual masculina en la rata. Los niveles de ansiedad se midieron en la prueba de conducta defensiva de enterramiento. No se encontraron diferencias en los niveles de ansiedad entre los grupos de animales control [sin prueba de conducta sexual] y los animales probados despues de cinco intromisiones de la primera serie copulatoria. Sin embargo, los animales probados durante el primer o segundo periodos posteyaculatorios o durante la ejecucion de la segunda serie copulatoria mostraron niveles de ansiedad menores que el grupo control. Estos resultados dan mas evidencia en favor de la idea de un incremento en la neurotransmision del acido gamma amino-butirico despues de la primera eyaculacion en la rata macho. Se discute respecto a la posible participacion de otros sistemas de neurotransmision en la mediacion de esta respuesta.
Despite the availability of various newly developed antiepileptic drugs (AEDs), pharmacoresistanc... more Despite the availability of various newly developed antiepileptic drugs (AEDs), pharmacoresistance remains a major challenge in epilepsy management. Unraveling the mechanisms underlying AED resistance has been the focus of intense efforts, in order to develop new rationally designed therapies for as yet refractory epilepsies. Based on experimental and clinical studies, one of the major neurobiological theories that has been put forward is the target hypothesis, which suggests that AEDs are not effective because of target alterations in the epileptogenic brain. Several studies have shown that seizure activity results in altered expression of gamma-aminobutyric acid (GABA) components such as GABA transporters (GATs) and GABA receptors. Indeed, changes in the composition of subunits expression appear to affect the functioning of GABAergic neurotransmission. Here, we review the current literature on epilepsy-associated changes in the GABA system conducted in experimental models and observations made in patients with treatment-resistant epilepsy, as well as genetic abnormalities in the GABA system in refractory human epilepsy.
Revista Médica del Hospital General de México, Oct 1, 2018
Background: The 5-hydroxytryptamine-1A receptors are known to be involved in the inhibition of se... more Background: The 5-hydroxytryptamine-1A receptors are known to be involved in the inhibition of seizures in epilepsy. Objective: The main aim of the present study is to determine the functional coupling to Gprotein of the 5-HT 1A receptor through 8-OH-DPAT-stimulated [ 35 S]GTP␥S binding assay in lateral temporal neocortex tissue of patients with mesial temporal lobe epilepsy (mTLE) and correlate it with clinical data. Material and methods: The activation of the G protein complex was determined by [ 35 S]GTP␥S binding assay. The temporal neocortex tissue was obtained from 5 patients with mTLE during epilepsy surgery and from 5 subjects (autopsies) who died due to an accident and without history of neurological disease. Results: We found that values of maximal stimulation (E max) of [ 35 S]GTP␥S binding significant decreased in the mTLE group (30.8%, p < .05) when compared to the autopsy samples (65.9%). The values of potency (pEC 50) were similar in both groups. However, we found no significant differences between the E max and age of patient, age of seizure onset, duration of epilepsy and frequency of seizures. Also, the pEC 50 values revealed no significant correlations with the clinical data.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Repressor Element-1 Silencing Transcription factor or Neuron-Restrictive Silencer Factor (RES... more The Repressor Element-1 Silencing Transcription factor or Neuron-Restrictive Silencer Factor (REST/NRSF) is a zinc finger repressor transcription factor of the Kruppel family. Several studies in experimental models have shown that overexpression of REST/NRSF occurs after the induction of seizures. In the present study, the expression of REST/NRSF (messenger ribonucleic acid (mRNA) and protein) was evaluated in the hippocampus of 28 patients with drug-resistant mesial temporal lobe epilepsy (MTLE) and their correlation with clinical variables and comorbid anxiety and depression. The REST/NRSF protein expression was augmented in an agedependent manner in the hippocampus of autopsied subjects. However, this condition was not observed in patients with MTLE, in whom overexpression of this transcription factor occurred at both the mRNA and protein levels. The correlations with clinical variables showed that the frequency of epileptic seizures was proportional to the protein expression of REST/NRSF. The results revealed that the overexpression of REST/NRSF was more evident in patients with MTLE without anxiety and depression. Our data indicate that the expression of REST/NRSF is modified in patients with MTLE. This condition has implications in the pathophysiology of this disorder, making it a potential candidate for the optimization of clinical treatments.
Blood-brain barrier (BBB) disruption has been associated with several acute and chronic brain dis... more Blood-brain barrier (BBB) disruption has been associated with several acute and chronic brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy. This represents a critical situation because damaged integrity of the BBB is related to the influx of immune mediators, plasma proteins and other outside elements from blood to the central nervous system (CNS) that may trigger a cascade of events that leads to neuroinflammation. In this review, evidence that mast cells and the release of factors such as histamine play an important role in the neuroinflammatory process associated with brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy is presented. Ó 2014 IMSS. Published by Elsevier Inc.
Mesial temporal lobe epilepsy (mTLE) is the most common epilepsy induced by previous cerebral inj... more Mesial temporal lobe epilepsy (mTLE) is the most common epilepsy induced by previous cerebral injury, and one out of three mTLE patients develops drug resistance (DR). AIM To assess the expression of Bcl-2, Caspase-3, Caspase-9, IL1-β, SEMA-3a, NT-3 and P-glycoprotein in the temporal cortex and their relationship with the progression of mTLE-DR clinical features in patients with mTLE-DR. METHOD Tissue samples from 17 patients were evaluated for protein expression by Western blot and the relationships of the evaluated proteins with the clinical features of the mTLE were assessed through hierarchical cluster analysis. RESULTS The mTLE-DR group showed significantly higher P-glycoprotein, Bcl-2 and Caspase-9 levels ***p < 0.0001, ****p < 0.0001 and ***p < 0.0002, respectively, than the autopsy control group. Four patient clusters were identified: Clusters 1 and 3 showed relationships among the age of mTLE onset, duration of mTLE-DR, average number of epileptic seizures per week, number of previous antiepileptic drugs (AEDs) and increased expression of Caspase-3, Caspase- 9, Neurotrophin-3 and Semaphorin-3a. Clusters 2 and 4 showed relationships among the mTLE onset age, current age, average number of epileptic seizures per week, number of previous AEDs and increased expression of IL1-β, Bcl-2, P-glycoprotein, Caspase-3 and NT-3. CONCLUSION The relationships among the clinical data (the age of mTLE onset, DR duration, number of previous AEDs, and average number of seizures per week and the expression of proteins involved in neuronal death, neuroinflammation and aberrant connection formation, as which are biological markers in the cerebral temporal cortex, are important factors in the progression and severity of mTLE-DR and support the intrinsic severity hypothesis.
A putative role of the brain-derived neurotrophic factor (BDNF) in epilepsy has emerged from in v... more A putative role of the brain-derived neurotrophic factor (BDNF) in epilepsy has emerged from in vitro and animal models, but few studies have analyzed human samples. We assessed the BDNF expression of transcripts with exons I (BDNFI), II (BDNFII), IV (BDNFIV) and VI (BDNFVI) and methylation levels of promoters 4 and 6 in the hippocampi of patients with pharmaco-resistant temporal lobe epilepsy (TLE) (n=24). Hippocampal sclerosis (HS) and pre-surgical pharmacological treatment were considered as clinical independent variables. A statistical significant increase for the BDNFVI (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) was observed in TLE patients compared to the autopsy control group (n=8). BDNFVI was also increased in anxiety/depression TLE (N=4) when compared to autopsies or to the remaining group of patients (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). In contrast, the use of the antiepileptic drug Topiramate (TPM) (N=3) was associated to a decrease in BDNFVI expression (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) when compared to the remaining group of patients. Methylation levels at the BDNF promoters 4 and 6 were similar between TLE and autopsies and in relation to the use of either Sertraline (SRT) or TPM. These results suggest an up-regulated expression of a specific BDNF transcript in patients with TLE, an effect that seems to be dependent on the use of specific drugs.
Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome... more Frontal lobe epilepsy (FLE) is the second most frequent type of epilepsy and the surgical outcome depends on the etiology. For instance, patients with posttraumatic FLE (PTE) have a worse surgical outcome compared to patients with FLE related to a tumoral lesion (TL). The present study focuses to determine if the FLE etiology is associated with the P-glycoprotein (P-gp) expression, a condition associated with drug resistance. P-gp expression and cellular localization were determined by Western Blot and immunohistochemical experiments in cortical brain samples obtained from patients with PTE (n = 5), TL (n = 5), and autopsies (n = 5). The neuronal count was estimated by Nissl and stereology procedure. Results showed that the autopsies tissue showed a neuronal count of 3514 ± 304.2 neurons per mm3. The P-gp expression ratio was 0.33 ± 0.02. Its expression was found in endothelial cells. Negligible P-gp expression was detected in neurons and astrocytes. Compared to the autopsies group, the TL group showed no changes in the neuronal count but, there was a decreased P-gp expression ratio (46%, p < 0.05). P-gp was located mainly in neurons, slight in astroglial, and endothelial cells. The PTE group showed a similar P-gp expression ratio compared to the autopsies group. P-gp was expressed in neurons, astrocytes, and endothelial cells in these samples. However, experiments revealed a high P-gp expression in a lower neuronal count (38%, p < 0.05 vs autopsy group). The present study reveals that patients with PTE present neuronal P-gp overexpression. This finding could underlie their worst surgical outcome.
Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopam... more Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DAN). Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson’s disease (PD) patients. We obtained DAN from hESCs and confirmed that they express dopaminergic markers, generate action potentials, and release dopamine (DA) in vitro. DAN were transplanted bilaterally in the putamen of parkinsonian NHPs. After grafting, animals improved motor behavior, evaluated by the HALLWAY task, and in agreement with this recovery, DA release was detected by microdialysis. Imaging techniques revealed changes in fractional anisotropy and mean diffusivity in magnetic resonance imaging and higher 11C-DTBZ binding in positron-emission tomography scans, associated with grafts. Postmortem analysis showed that transplanted DAN survived over ten months in the putamen, without developing tumors, in the immunosuppressed N...
En la ultima decada se ha relacionado la disfuncion del nucleo pedunculopontino (NPP) con la fisi... more En la ultima decada se ha relacionado la disfuncion del nucleo pedunculopontino (NPP) con la fisiopatologia de la enfermedad de Parkinson (EP); sin embargo, no se conocen los cambios que experimenta la liberacion de neurotransmisores en esta estructura. Estudiar los cambios en la liberacion de glutamato (GLU) y de acido g-aminobutirico (GABA) en el NPP de ratas hemiparkinsonianas, y evaluar la muerte celular en esa estructura, es el objetivo de esta investigacion. Se analizaron tres grupos de ratas Wistar: sanas (n = 12); lesionadas con 6-hidroxidopamina (6-OHDA) (n = 11); falsas lesionadas (n = 10). En todas las ratas se implanto una canula de microdialisis en el NPP derecho ipsilateral a la inyeccion de 6-OHDA, y los dializados se analizaron por tecnicas cromatograficas. La muerte celular en el NPP de los animales lesionados se evaluo por inmunohistoquimica TUNEL. Hubo un aumento significativo en las concentraciones de GLU y GABA en el NPP de las ratas hemiparkinsonianas (p < 0...
Introduction. In relation to drug-resistant temporal lobe epilepsy (DRTLE), the interrelation be... more Introduction. In relation to drug-resistant temporal lobe epilepsy (DRTLE), the interrelation between inflammation, oxidative stress, and neuronal death constitutes a topic increasingly researched into. Objectives: To expand the knowledge of the molecular mechanisms that participate in the pathophysiology of DRTLE by correlating clinical variables with immunological ones, oxidative stress and neuronal death. Methods. Immunocytochemistry techniques were used to measure the markers CD3, CD4, CD8, CD19, CD25, HLA-DR; Nephelometry was used for IgG, IgM, IgA, and Albumin; immunoenzymatic tests for IL-1β, IL-6, TNF-α, and nitric oxide. By means of western blot: NFκB, JNK, 4-hydroxy-2-nonenal, 3-nitrotyrosine; by means of spectrophotometry: malonildialdehyde, advanced glycation products, advanced protein oxidation products, uric acid, superoxide dismutase, glutathione, and vitamin C; by means of immunohistochemistry: Annexin V, TUNEL, synaptophysin, caspase 3, p53, and bcl-2; by means of...
Highlights Early intervention with Magnolia officinalis exerts a long-term neuroprotective effe... more Highlights Early intervention with Magnolia officinalis exerts a long-term neuroprotective effects on epileptogenesis. Magnolia officinalis decreases long-term excitability, neuronal damage, and reactive gliosis. Model of recurrent status epilepticus, where antiepileptic drug can be evaluated ABSTRACT During critical periods of neurodevelopment, the immature brain is susceptible to neuronal hyperexcitability, alterations such as hyperthermia, hypoxia, brain trauma or a preexisting neuroinflammatory condition can trigger, promote and prolong epileptiform activity and facilitate the development of epilepsy. The goal of the present study was to evaluate the long-term neuroprotective effects Magnolia officinalis extract, on a model of recurrent status epilepticus (SE) in immature rats. Sprague-Dawley rats were treated with kainic acid (KA) (3 mg/kg, dissolved in
Although there is evidence suggesting a relationship between parkinsonism and modifications to ga... more Although there is evidence suggesting a relationship between parkinsonism and modifications to gabaergic, cholinergic and opioid activities in the basal ganglia and related structures, so far studies are not conclusive, and the molecular mechanisms underlying ...
Neurochemical changes occurring in the nuclei of the basal ganglia as a consequence of the degene... more Neurochemical changes occurring in the nuclei of the basal ganglia as a consequence of the degeneration of the substantia nigra pars compacta (SNc) that typically occurs in the Parkinson's disease (PD), have been already studied (Zigmond et al., 2002). There are well-established experimental models of parkinsonism using intracerebral injection of 6-hydroxydopamine (6-OHDA) in rodents and systemic or intracarotid delivery of 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in non-human primates that have been instrumental in the investigation of these changes (Blum et al.
Uploads
Papers by Luisa Rocha