Background Traumatic brain injury (TBI) is one of the most important causes of acquired structura... more Background Traumatic brain injury (TBI) is one of the most important causes of acquired structural epilepsy, post-traumatic epilepsy (PTE), however, efficient preventative measures and treatment are still not available to patients. Preclinical studies indicated biperiden, an anticholinergic drug, as a potential drug to modify the epileptogenic process. The main objective of this clinical trial is to evaluate the efficacy of biperiden as an antiepileptogenic agent in patients that suffered TBI. Methods This prospective multicenter (n = 10) interventional study will include 312 adult patients admitted to emergency care units with a diagnosis of moderate or severe TBI. Following inclusion and exclusion criteria, patients will be randomized, using block randomization, to receive double-blind treatment with placebo or biperiden for 10 days. Follow-up will occur at specific time windows up to 2 years. Main outcomes are incidence of PTE after TBI and occurrence of severe adverse events. Ot...
In this work, we show extensive phosphorylation of the alpha subunit of translation initiation fa... more In this work, we show extensive phosphorylation of the alpha subunit of translation initiation factor 2 (eIF2alpha) occurring in the brain of mice subjected to 30 min of status epilepticus induced by pilocarpine. eIF2alpha(P) immunoreactivity was detected in the hippocampal pyramidal layer CA1 and CA3, cortex layer V, thalamus and amygdala. After 2 h of recovery, there was a marked decrease in total brain eIF2alpha(P), with the cortex layer V showing the most pronounced loss of anti-eIF2alpha(P) labeling, whereas the CA1 subregion had a significant increase in eIF2alpha(P). These results indicate that inhibition of protein synthesis in experimental models of epilepsy might be due to low levels of eIF2-GTP caused by the phosphorylation of eIF2alpha, and suggest that translational control may contribute to cell fate in the affected areas.
Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR... more Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.
Supragranular mossy fiber sprouting (MFS), aberrant axonal projections from dentate granule cells... more Supragranular mossy fiber sprouting (MFS), aberrant axonal projections from dentate granule cells to the area immediately above the granule cell layer, might be the best characterized form of aberrant synaptic plasticity in the mammalian brain. Starting with its initial description in epileptic tissue in 1985, a huge amount of information at all levels has been accumulated over the past two decades. Yet, despite this intense research effort, there is still important debate on the relative contribution of MFS to the hyperexcitability in temporal lobe epilepsy, and even less agreement about its role in seizure generation. Using cycloheximide to block the development of MFS after status epilepticus, we directly address some of the relevant issues in the field.
This study aimed to determine whether preemptive fentanyl administration in neonatal rats reduces... more This study aimed to determine whether preemptive fentanyl administration in neonatal rats reduces the impact of a nociceptive stimulus initiated during the first day of life (P1) on hippocampal neurogenesis, behavior, and learning. At P1, Wistar rat pups received either a subcutaneous injection of fentanyl (F) before intraplantar injection of complete Freund’s adjuvant (CFA) (CFA + F group), an isolated injection of CFA (CFA group), or subcutaneous injection of fentanyl without CFA injection (F). Control animals received saline injections using the same route and volume as the treatment groups. Hippocampal neurogenesis was evaluated by 5′ –bromo-2′-deoxyuridine (BrdU) staining on P10 and P39 to assess neuronal proliferation and survival, respectively. Anxiety behavior in adulthood was assessed using an open field test (OF) and an elevated plus maze test (EPM). Spatial memory was assessed on a Morris water maze test (MWM), where the animals were trained for seven days, beginning on P...
International Journal of Developmental Neuroscience, 2021
Maternal separation and neonatal manipulation of pups produce changes in maternal behavior after ... more Maternal separation and neonatal manipulation of pups produce changes in maternal behavior after the dam–pup reunion. Here, we examined whether continuous versus alternating days of neonatal manipulation during the first 8 postnatal days produces differential changes in maternal and non‐maternal behaviors in rats. We found that both maternal separation protocols increased anogenital licking after dam–pup reunion, reflecting increased maternal care of pups.
Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic br... more Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies.
Background Traumatic brain injury (TBI) is one of the most important causes of acquired structura... more Background Traumatic brain injury (TBI) is one of the most important causes of acquired structural epilepsy, post-traumatic epilepsy (PTE), however, efficient preventative measures and treatment are still not available to patients. Preclinical studies indicated biperiden, an anticholinergic drug, as a potential drug to modify the epileptogenic process. The main objective of this clinical trial is to evaluate the efficacy of biperiden as an antiepileptogenic agent in patients that suffered TBI. Methods This prospective multicenter (n = 10) interventional study will include 312 adult patients admitted to emergency care units with a diagnosis of moderate or severe TBI. Following inclusion and exclusion criteria, patients will be randomized, using block randomization, to receive double-blind treatment with placebo or biperiden for 10 days. Follow-up will occur at specific time windows up to 2 years. Main outcomes are incidence of PTE after TBI and occurrence of severe adverse events. Ot...
In this work, we show extensive phosphorylation of the alpha subunit of translation initiation fa... more In this work, we show extensive phosphorylation of the alpha subunit of translation initiation factor 2 (eIF2alpha) occurring in the brain of mice subjected to 30 min of status epilepticus induced by pilocarpine. eIF2alpha(P) immunoreactivity was detected in the hippocampal pyramidal layer CA1 and CA3, cortex layer V, thalamus and amygdala. After 2 h of recovery, there was a marked decrease in total brain eIF2alpha(P), with the cortex layer V showing the most pronounced loss of anti-eIF2alpha(P) labeling, whereas the CA1 subregion had a significant increase in eIF2alpha(P). These results indicate that inhibition of protein synthesis in experimental models of epilepsy might be due to low levels of eIF2-GTP caused by the phosphorylation of eIF2alpha, and suggest that translational control may contribute to cell fate in the affected areas.
Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR... more Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.
Supragranular mossy fiber sprouting (MFS), aberrant axonal projections from dentate granule cells... more Supragranular mossy fiber sprouting (MFS), aberrant axonal projections from dentate granule cells to the area immediately above the granule cell layer, might be the best characterized form of aberrant synaptic plasticity in the mammalian brain. Starting with its initial description in epileptic tissue in 1985, a huge amount of information at all levels has been accumulated over the past two decades. Yet, despite this intense research effort, there is still important debate on the relative contribution of MFS to the hyperexcitability in temporal lobe epilepsy, and even less agreement about its role in seizure generation. Using cycloheximide to block the development of MFS after status epilepticus, we directly address some of the relevant issues in the field.
This study aimed to determine whether preemptive fentanyl administration in neonatal rats reduces... more This study aimed to determine whether preemptive fentanyl administration in neonatal rats reduces the impact of a nociceptive stimulus initiated during the first day of life (P1) on hippocampal neurogenesis, behavior, and learning. At P1, Wistar rat pups received either a subcutaneous injection of fentanyl (F) before intraplantar injection of complete Freund’s adjuvant (CFA) (CFA + F group), an isolated injection of CFA (CFA group), or subcutaneous injection of fentanyl without CFA injection (F). Control animals received saline injections using the same route and volume as the treatment groups. Hippocampal neurogenesis was evaluated by 5′ –bromo-2′-deoxyuridine (BrdU) staining on P10 and P39 to assess neuronal proliferation and survival, respectively. Anxiety behavior in adulthood was assessed using an open field test (OF) and an elevated plus maze test (EPM). Spatial memory was assessed on a Morris water maze test (MWM), where the animals were trained for seven days, beginning on P...
International Journal of Developmental Neuroscience, 2021
Maternal separation and neonatal manipulation of pups produce changes in maternal behavior after ... more Maternal separation and neonatal manipulation of pups produce changes in maternal behavior after the dam–pup reunion. Here, we examined whether continuous versus alternating days of neonatal manipulation during the first 8 postnatal days produces differential changes in maternal and non‐maternal behaviors in rats. We found that both maternal separation protocols increased anogenital licking after dam–pup reunion, reflecting increased maternal care of pups.
Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic br... more Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies.
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