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Wolfgang Loscher - One of the best experts on this subject based on the ideXlab platform.
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effective termination of status epilepticus by rational polypharmacy in the lithium pilocarpine model in rats window of opportunity to prevent epilepsy and prediction of epilepsy by biomarkers
Neurobiology of Disease, 2015Co-Authors: Claudia Brandt, Sonja Broer, Rebecca Klee, Kathrin Tollner, Wolfgang LoscherAbstract:Abstract The pilocarpine rat model, in which status epilepticus (SE) leads to epilepsy with spontaneous recurrent seizures (SRS), is widely used to study the mechanisms of epileptogenesis and develop strategies for epilepsy prevention. SE is commonly interrupted after 30–90 min by high-dose diazepam or other anticonvulsants to reduce mortality. It is widely believed that SE duration of 30–60 min is sufficient to induce hippocampal damage and epilepsy. However, resistance to diazepam develops during SE, so that an SE that is longer than 30 min is difficult to terminate, and SE typically recurs several hours after diazepam, thus forming a bias for studies on epileptogenesis or antiepileptogenesis. We developed a drug cocktail, consisting of diazepam, phenobarbital, and scopolamine that allows complete and persistent SE termination in the lithium–pilocarpine model. A number of novel findings were obtained with this cocktail. (a) In contrast to previous reports with incomplete SE suppression, a SE of 60 min duration did not induce epilepsy, whereas epilepsy with SRS developed after 90 or 120 min SE; (b) by comparing groups of rats with 60 and 90 min of SE, development of epilepsy could be predicted by behavioral hyperexcitability and decrease in seizure threshold, indicating that these read-outs are suited as biomarkers of epileptogenesis; (c) CA1 damage was prevented by the cocktail, but rats exhibited cell loss in the Dentate Hilus, which was related to development of epilepsy. These data demonstrate that the duration of SE needed for induction of epileptogenesis in this model is longer than previously thought.
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the intrahippocampal kainate model of temporal lobe epilepsy revisited epileptogenesis behavioral and cognitive alterations pharmacological response and hippoccampal damage in epileptic rats
Epilepsy Research, 2013Co-Authors: Marta Rattka, Claudia Brandt, Wolfgang LoscherAbstract:Systemic or intracerebral (e.g., intrahippocampal or intraamygdalar) administration of kainate, a potent neurotoxic analog of glutamate, is widely used to induce status epilepticus (SE) and subsequent development of epilepsy in rats. However, in apparent contrast to systemic administration, following intracerebral injection the proportion of rats that have been observed to generate spontaneous recurrent seizures (SRS) and the frequency of the SRS are comparatively low. More recently, it has been shown that these problems can be resolved by injecting kainate into the dorsal hippocampus of awake rats, thus avoiding the insult-modifying effects of anesthesia, which had often been used for intracerebral injection of this convulsant in previous studies. For further characterization of this model, we injected kainate (0.4 μg) unilaterally into the CA3 of the posterior hippocampus in awake rats, which induced limbic SE (ranging from 4 to 20 h) in all rats without mortality. Repeated video-EEG monitoring (24h/day, 7 days/week) for periods of 1-2.5 weeks from 1 to 8 months after SE demonstrated that 91% of the rats developed epilepsy, and that seizure frequency significantly increased over the course of the disease. Epilepsy was associated with increased behavioral excitability and impaired learning and memory in a water maze, most likely as a result of hippocampal pathology, which was characterized by extensive neuronal loss in CA3 and Dentate Hilus and dispersion of granule cells in the ipsilateral hippocampus. A drug trial with phenobarbital showed that all epileptic rats used in this trial responded to treatment with suppression of SRS. The data substantiate that intrahippocampal kainate injection in awake rats offers an excellent model of human temporal lobe epilepsy and indicate that this model may have particular advantages for studying mechanisms of injury-induced epilepsy and comorbidities as targets for antiepileptic and antiepileptogenic therapies.
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therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive ampa receptor antagonist ns1209 following status epilepticus in rats
Neuropharmacology, 2011Co-Authors: Melanie Langer, Claudia Brandt, Christina Zellinger, Wolfgang LoscherAbstract:Epileptogenesis, i.e., the process leading to epilepsy, is a presumed consequence of brain insults including head trauma, stroke, infections, tumors, status epilepticus (SE), and complex febrile seizures. Typically, brain insults produce morphological and functional alterations in the hippocampal formation, including neurodegeneration in CA1, CA3, and, most consistently, the Dentate Hilus. Most of these alterations develop gradually, over several days, after the insult, providing a therapeutic window of opportunity for neuroprotective agents in the immediate post-injury period. We have previously reported that prolonged (four weeks) treatment with the antiepileptic drug valproate (VPA) after SE prevents hippocampal damage and most of the behavioral alterations that occur after brain insult, but not the development of spontaneously occurring seizures. These data indicated that VPA, although not preventing epilepsy, might be an effective disease-modifying treatment following brain insult. The present study was designed to (1) determine the therapeutic window for the neuroprotective effect of VPA after SE; (2) compare the efficacy of different intermittent i.p. versus continuous i.v. VPA treatment protocols; and (3) compare VPA with the glutamate (AMPA) receptor antagonist NS1209. As in our previous study with VPA, SE was induced by sustained electrical stimulation of the basolateral amygdala in rats and terminated after 4 h by diazepam. In vehicle controls, >90% of the animals developed significant neurodegeneration in the Dentate Hilus, whereas damage in CA1 and CA3 was more variable. Hilar parvalbumin-expressing interneurons were more sensitive to the effects of seizures than somatostatin-stained hilar interneurons or hilar mossy cells. Among the various VPA treatment protocols, continuous infusion of VPA for 24 immediately following the SE was the most effective neuroprotective treatment, preventing most of the neuronal damage. Infusion with NS1209 for 24 h exhibited similar neuroprotective efficacy. These data demonstrate that short treatment after SE with either VPA or NS1209 is powerfully neuroprotective, and may be disease-modifying treatments following brain insult.
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treatment with valproate after status epilepticus effect on neuronal damage epileptogenesis and behavioral alterations in rats
Neuropharmacology, 2006Co-Authors: Claudia Brandt, Alexandra M Gastens, Mei Zhen Sun, Maria Hausknecht, Wolfgang LoscherAbstract:Epileptogenesis, i.e. the process leading to epilepsy with spontaneous recurrent seizures, can be initiated by a number of brain damaging insults, including traumatic brain injury, status epilepticus (SE), and stroke. Such acquired epilepsy is often associated with memory impairment and behavioral problems. There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection and prevention or modification of epileptogenesis induced by such brain insults. One promising candidate in this respect is valproic acid (VPA), a widely used AED that has been reported to exert neuroprotective activity in a number of in vitro and in vivo models. The present study investigated whether VPA reduces brain damage and improves functional outcome in a rat model of post-SE epilepsy. A self-sustaining SE was induced by prolonged electrical stimulation of the basal amygdala via a depth electrode. SE was terminated after 4 h by diazepam, immediately followed by onset of treatment with VPA. VPA was injected i.p. at a bolus dose of 400 mg/kg, followed by three times daily administration of 200 mg/kg for 4 weeks. A control group received vehicle instead of VPA after SE. Spontaneous seizures were recorded in all rats of both groups following termination of treatment, without significant inter-group difference in seizure frequency or severity. However, treatment with VPA after SE prevented the hyperexcitability and locomotor hyperactivity observed in vehicle-treated epileptic rats. Furthermore, VPA completely counteracted the neuronal damage in the hippocampal formation, including the Dentate Hilus. The data demonstrate that, although VPA does not prevent the occurrence of spontaneous seizures after SE, it exerts powerful neuroprotective effects and prevents part of the behavioral alterations, demonstrating that administration of VPA immediately after SE exerts a favorable effect on long-term functional outcome.
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antiepileptic drug resistant rats differ from drug responsive rats in hippocampal neurodegeneration and gabaa receptor ligand binding in a model of temporal lobe epilepsy
Neurobiology of Disease, 2006Co-Authors: Holger A Volk, Claudia Brandt, Dimitrula Arabadzisz, Jeanmarc Fritschy, Kerstin Bethmann, Wolfgang LoscherAbstract:The disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to antiepileptic drugs (AEDs). The biological basis of this refractoriness is unknown but may include alterations in AED targets in the epileptogenic brain tissue, reduced AED penetration to the seizure focus, and neuropathological brain alterations such as hippocampal sclerosis typically found in patients with refractory TLE. In the present study, we used a rat model of TLE to examine whether AED responders differ from non-responders in their structural alterations and GABAA receptor characteristics in the hippocampal formation. In this model, spontaneous recurrent seizures develop after a status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video/EEG monitoring before, during, and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders and non-responders. The severity or duration of the initial brain insult (the status epilepticus) did not differ between responders and non-responders, indicating that the difference between the two subgroups is genetically determined. Subsequent histological examination showed a significant loss of neurons in the CA1, CA3c/CA4, and Dentate Hilus of non-responders, whereas responders did not differ in this respect from non-epileptic controls. The morphological alterations in the non-responders were associated with striking alterations in autoradiographic imaging of diazepam-sensitive and diazepam-insensitive GABAA receptor binding in the Dentate gyrus with a significant shift to enhanced diazepam-insensitive binding. The present data indicate that neurodegeneration and associated GABAA receptor changes in the Dentate gyrus are critically involved in the mechanisms underlying refractoriness of seizures in TLE.
Claudia Brandt - One of the best experts on this subject based on the ideXlab platform.
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effective termination of status epilepticus by rational polypharmacy in the lithium pilocarpine model in rats window of opportunity to prevent epilepsy and prediction of epilepsy by biomarkers
Neurobiology of Disease, 2015Co-Authors: Claudia Brandt, Sonja Broer, Rebecca Klee, Kathrin Tollner, Wolfgang LoscherAbstract:Abstract The pilocarpine rat model, in which status epilepticus (SE) leads to epilepsy with spontaneous recurrent seizures (SRS), is widely used to study the mechanisms of epileptogenesis and develop strategies for epilepsy prevention. SE is commonly interrupted after 30–90 min by high-dose diazepam or other anticonvulsants to reduce mortality. It is widely believed that SE duration of 30–60 min is sufficient to induce hippocampal damage and epilepsy. However, resistance to diazepam develops during SE, so that an SE that is longer than 30 min is difficult to terminate, and SE typically recurs several hours after diazepam, thus forming a bias for studies on epileptogenesis or antiepileptogenesis. We developed a drug cocktail, consisting of diazepam, phenobarbital, and scopolamine that allows complete and persistent SE termination in the lithium–pilocarpine model. A number of novel findings were obtained with this cocktail. (a) In contrast to previous reports with incomplete SE suppression, a SE of 60 min duration did not induce epilepsy, whereas epilepsy with SRS developed after 90 or 120 min SE; (b) by comparing groups of rats with 60 and 90 min of SE, development of epilepsy could be predicted by behavioral hyperexcitability and decrease in seizure threshold, indicating that these read-outs are suited as biomarkers of epileptogenesis; (c) CA1 damage was prevented by the cocktail, but rats exhibited cell loss in the Dentate Hilus, which was related to development of epilepsy. These data demonstrate that the duration of SE needed for induction of epileptogenesis in this model is longer than previously thought.
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the intrahippocampal kainate model of temporal lobe epilepsy revisited epileptogenesis behavioral and cognitive alterations pharmacological response and hippoccampal damage in epileptic rats
Epilepsy Research, 2013Co-Authors: Marta Rattka, Claudia Brandt, Wolfgang LoscherAbstract:Systemic or intracerebral (e.g., intrahippocampal or intraamygdalar) administration of kainate, a potent neurotoxic analog of glutamate, is widely used to induce status epilepticus (SE) and subsequent development of epilepsy in rats. However, in apparent contrast to systemic administration, following intracerebral injection the proportion of rats that have been observed to generate spontaneous recurrent seizures (SRS) and the frequency of the SRS are comparatively low. More recently, it has been shown that these problems can be resolved by injecting kainate into the dorsal hippocampus of awake rats, thus avoiding the insult-modifying effects of anesthesia, which had often been used for intracerebral injection of this convulsant in previous studies. For further characterization of this model, we injected kainate (0.4 μg) unilaterally into the CA3 of the posterior hippocampus in awake rats, which induced limbic SE (ranging from 4 to 20 h) in all rats without mortality. Repeated video-EEG monitoring (24h/day, 7 days/week) for periods of 1-2.5 weeks from 1 to 8 months after SE demonstrated that 91% of the rats developed epilepsy, and that seizure frequency significantly increased over the course of the disease. Epilepsy was associated with increased behavioral excitability and impaired learning and memory in a water maze, most likely as a result of hippocampal pathology, which was characterized by extensive neuronal loss in CA3 and Dentate Hilus and dispersion of granule cells in the ipsilateral hippocampus. A drug trial with phenobarbital showed that all epileptic rats used in this trial responded to treatment with suppression of SRS. The data substantiate that intrahippocampal kainate injection in awake rats offers an excellent model of human temporal lobe epilepsy and indicate that this model may have particular advantages for studying mechanisms of injury-induced epilepsy and comorbidities as targets for antiepileptic and antiepileptogenic therapies.
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therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive ampa receptor antagonist ns1209 following status epilepticus in rats
Neuropharmacology, 2011Co-Authors: Melanie Langer, Claudia Brandt, Christina Zellinger, Wolfgang LoscherAbstract:Epileptogenesis, i.e., the process leading to epilepsy, is a presumed consequence of brain insults including head trauma, stroke, infections, tumors, status epilepticus (SE), and complex febrile seizures. Typically, brain insults produce morphological and functional alterations in the hippocampal formation, including neurodegeneration in CA1, CA3, and, most consistently, the Dentate Hilus. Most of these alterations develop gradually, over several days, after the insult, providing a therapeutic window of opportunity for neuroprotective agents in the immediate post-injury period. We have previously reported that prolonged (four weeks) treatment with the antiepileptic drug valproate (VPA) after SE prevents hippocampal damage and most of the behavioral alterations that occur after brain insult, but not the development of spontaneously occurring seizures. These data indicated that VPA, although not preventing epilepsy, might be an effective disease-modifying treatment following brain insult. The present study was designed to (1) determine the therapeutic window for the neuroprotective effect of VPA after SE; (2) compare the efficacy of different intermittent i.p. versus continuous i.v. VPA treatment protocols; and (3) compare VPA with the glutamate (AMPA) receptor antagonist NS1209. As in our previous study with VPA, SE was induced by sustained electrical stimulation of the basolateral amygdala in rats and terminated after 4 h by diazepam. In vehicle controls, >90% of the animals developed significant neurodegeneration in the Dentate Hilus, whereas damage in CA1 and CA3 was more variable. Hilar parvalbumin-expressing interneurons were more sensitive to the effects of seizures than somatostatin-stained hilar interneurons or hilar mossy cells. Among the various VPA treatment protocols, continuous infusion of VPA for 24 immediately following the SE was the most effective neuroprotective treatment, preventing most of the neuronal damage. Infusion with NS1209 for 24 h exhibited similar neuroprotective efficacy. These data demonstrate that short treatment after SE with either VPA or NS1209 is powerfully neuroprotective, and may be disease-modifying treatments following brain insult.
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treatment with valproate after status epilepticus effect on neuronal damage epileptogenesis and behavioral alterations in rats
Neuropharmacology, 2006Co-Authors: Claudia Brandt, Alexandra M Gastens, Mei Zhen Sun, Maria Hausknecht, Wolfgang LoscherAbstract:Epileptogenesis, i.e. the process leading to epilepsy with spontaneous recurrent seizures, can be initiated by a number of brain damaging insults, including traumatic brain injury, status epilepticus (SE), and stroke. Such acquired epilepsy is often associated with memory impairment and behavioral problems. There has been a growing interest in the use of antiepileptic drugs (AEDs) for neuroprotection and prevention or modification of epileptogenesis induced by such brain insults. One promising candidate in this respect is valproic acid (VPA), a widely used AED that has been reported to exert neuroprotective activity in a number of in vitro and in vivo models. The present study investigated whether VPA reduces brain damage and improves functional outcome in a rat model of post-SE epilepsy. A self-sustaining SE was induced by prolonged electrical stimulation of the basal amygdala via a depth electrode. SE was terminated after 4 h by diazepam, immediately followed by onset of treatment with VPA. VPA was injected i.p. at a bolus dose of 400 mg/kg, followed by three times daily administration of 200 mg/kg for 4 weeks. A control group received vehicle instead of VPA after SE. Spontaneous seizures were recorded in all rats of both groups following termination of treatment, without significant inter-group difference in seizure frequency or severity. However, treatment with VPA after SE prevented the hyperexcitability and locomotor hyperactivity observed in vehicle-treated epileptic rats. Furthermore, VPA completely counteracted the neuronal damage in the hippocampal formation, including the Dentate Hilus. The data demonstrate that, although VPA does not prevent the occurrence of spontaneous seizures after SE, it exerts powerful neuroprotective effects and prevents part of the behavioral alterations, demonstrating that administration of VPA immediately after SE exerts a favorable effect on long-term functional outcome.
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antiepileptic drug resistant rats differ from drug responsive rats in hippocampal neurodegeneration and gabaa receptor ligand binding in a model of temporal lobe epilepsy
Neurobiology of Disease, 2006Co-Authors: Holger A Volk, Claudia Brandt, Dimitrula Arabadzisz, Jeanmarc Fritschy, Kerstin Bethmann, Wolfgang LoscherAbstract:The disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to antiepileptic drugs (AEDs). The biological basis of this refractoriness is unknown but may include alterations in AED targets in the epileptogenic brain tissue, reduced AED penetration to the seizure focus, and neuropathological brain alterations such as hippocampal sclerosis typically found in patients with refractory TLE. In the present study, we used a rat model of TLE to examine whether AED responders differ from non-responders in their structural alterations and GABAA receptor characteristics in the hippocampal formation. In this model, spontaneous recurrent seizures develop after a status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video/EEG monitoring before, during, and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders and non-responders. The severity or duration of the initial brain insult (the status epilepticus) did not differ between responders and non-responders, indicating that the difference between the two subgroups is genetically determined. Subsequent histological examination showed a significant loss of neurons in the CA1, CA3c/CA4, and Dentate Hilus of non-responders, whereas responders did not differ in this respect from non-epileptic controls. The morphological alterations in the non-responders were associated with striking alterations in autoradiographic imaging of diazepam-sensitive and diazepam-insensitive GABAA receptor binding in the Dentate gyrus with a significant shift to enhanced diazepam-insensitive binding. The present data indicate that neurodegeneration and associated GABAA receptor changes in the Dentate gyrus are critically involved in the mechanisms underlying refractoriness of seizures in TLE.
Makoto Shibutani - One of the best experts on this subject based on the ideXlab platform.
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relationship between brain accumulation of manganese and aberration of hippocampal adult neurogenesis after oral exposure to manganese chloride in mice
Toxicology, 2015Co-Authors: Yoh Kikuchihara, Liyun Wang, Hajime Abe, Yoshiaki Ikarashi, Takeshi Tanaka, Mizuho Kato, Toshinori Yoshida, Makoto ShibutaniAbstract:We previously found persistent aberration of hippocampal adult neurogenesis, along with brain manganese (Mn) accumulation, in mouse offspring after developmental exposure to 800-ppm dietary Mn. Reduction of parvalbumin (Pvalb)(+) γ-aminobutyric acid (GABA)-ergic interneurons in the Hilus of the Dentate gyrus along with promoter region hypermethylation are thought to be responsible for this aberrant neurogenesis. The present study was conducted to examine the relationship between the induction of aberrant neurogenesis and brain Mn accumulation after oral Mn exposure as well as the responsible mechanism in young adult animals. We used two groups of mice with 28- or 56-day exposure periods to oral MnCl2·xH2O at 800 ppm as Mn, a dose sufficient to lead to aberrant neurogenesis after developmental exposure. A third group of mice received intravenous injections of Mn at 5-mg/kg body weight once weekly for 28 days. The 28-day oral Mn exposure did not cause aberrations in neurogenesis. In contrast, 56-day oral exposure caused aberrations in neurogenesis suggestive of reductions in type 2b and type 3 progenitor cells and immature granule cells in the Dentate subgranular zone. Brain Mn accumulation in 56-day exposed cases, as well as in directly Mn-injected cases occurred in parallel with reduction of Pvalb(+) GABAergic interneurons in the Dentate Hilus, suggesting that this may be responsible for aberrant neurogenesis. For reduction of Pvalb(+) interneurons, suppression of brain-derived neurotrophic factor-mediated signaling of mature granule cells may occur via suppression of c-Fos-mediated neuronal plasticity due to direct Mn-toxicity rather than promoter region hypermethylation of Pvalb.
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disruptive neuronal development by acrylamide in the hippocampal Dentate Hilus after developmental exposure in rats
Archives of Toxicology, 2011Co-Authors: Bunichiro Ogawa, Liyun Wang, Kunitoshi Mitsumori, Takumi Ohishi, Miwa Takahashi, Eriko Taniai, Hitomi Hayashi, Makoto ShibutaniAbstract:To examine whether developmental exposure to acrylamide (AA) impairs neuronal development, pregnant Sprague–Dawley rats were treated with AA at 0, 25, 50 or 100 ppm in drinking water from gestational day 6 until weaning on postnatal day 21. Offspring were immunohistochemically examined at the end of exposure. We investigated the expression of Reelin (a molecule regulating neuronal migration and positioning) in the Hilus of the hippocampal Dentate gyrus. As a positive control for direct exposure, AA (50 mg/kg body weight) was administered to pups by intraperitoneal injection 3 times per week during the lactation period. As well as pups directly injected with AA, maternally exposed offspring decreased body weight at 100 ppm; increased dose-dependently the number of Reelin-immunoreactive cells (from 25 ppm AA) and glutamic acid decarboxylase 67-immunoreactive cells (from 50 ppm AA), confirming an increase in γ-aminobutyric acid-ergic interneurons. We also noted decreased apoptosis in the neuroblast-producing subgranular zone of the Dentate gyrus of maternally exposed pups at 100 ppm, as well as in directly AA-injected pups. These results suggest that a compensatory regulatory mechanism exists to correct impaired neurogenesis and mismigration caused by maternal exposure to AA during neuronal development. The lowest-observed-adverse-effect level of AA was determined to be 25 ppm (3.72 mg/kg body weight/day).
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no effect of sustained systemic growth retardation on the distribution of reelin expressing interneurons in the neuron producing hippocampal Dentate gyrus in rats
Reproductive Toxicology, 2010Co-Authors: Takumi Ohishi, Liyun Wang, Kunitoshi Mitsumori, Bunichiro Ogawa, Eriko Taniai, Hitomi Hayashi, Kenichi Fujisawa, Makoto ShibutaniAbstract:Reelin signaling plays a role in neuronal migration and positioning during brain development. To clarify the effect of systemic growth retardation on the distribution of Reelin-expressing interneurons in the Hilus of the hippocampal Dentate gyrus, pregnant rats were fed a synthetic diet with either a normal (20% casein) or low (10% casein) protein concentration from gestational day 10 to postnatal day (PND) 21 at weaning. Male offspring were immunohistochemically examined at PND 21 and on PND 77. Protein-restricted offspring displayed systemic growth retardation through PND 77 and had decreased absolute brain weights and an increased number of external granular cells in the cerebellar cortex, suggestive of retarded brain growth at weaning. However, maternal protein restriction did not change the cellular distribution of immunoreactivity for Reelin, Calbindin-D-28K, or glutamic acid decarboxylase 67 or of NeuN-positive postmitotic neurons in the Dentate Hilus either at PND 21 or PND 77, which suggests that the population of γ-aminobutyric acid-ergic interneurons involving synthesis of Reelin was not affected. Furthermore, as well as the distribution of hilar neurons expressing neurogenesis-related FoxG1, cell proliferation and apoptosis in the subgranular zone were unaffected through PND 77. These results suggest that systemic growth retardation caused by maternal protein restriction does not affect neuronal migration and postnatal neurogenesis of the Dentate gyrus resulting in unaltered distribution of Reelin-synthesizing interneurons.
Flemming Fryd Johansen - One of the best experts on this subject based on the ideXlab platform.
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stereological cell counts of gabaergic neurons in rat Dentate Hilus following transient cerebral ischemia
Experimental Brain Research, 2001Co-Authors: Georg Johannes Muller, Arne Moller, Flemming Fryd JohansenAbstract:We have previously demonstrated a 60–80% ischemic loss of somatostatinergic neurons in the dorsal Dentate Hilus of the rat. However, several studies have failed to demonstrate ischemic loss of GABAergic neurons in Hilus, although one study reports that 96% of the somatostatinergic neurons in the dorsal Hilus colocalize GABA. In order to understand this paradox, we have now estimated, using unbiased stereology, the total number of neurons immunohistochemically stained against glutamic acid decarboxylase-65 (GAD65) and GAD67 in the dorsal Dentate Hilus. Rats were divided into groups subjected to either sham operation (n=8) or 8 min of transient global ischemia during systemical hypotension (n=8) and allowed to survive for 7–9 days. Results from cell counts (mean ± SD) in sham rats demonstrated that the dorsal Hilus contains 9,189±3,957 GAD65 neurons and 6,991±2,784 GAD67 neurons. After ischemia, corresponding cell counts demonstrated 10,216±4,866 GAD65 neurons and 10,119±5,906 GAD67 neurons, and these results were not significantly different (P>0.05) from results in sham rats. Power analysis of the t-test informs that losses less than 80% are not significant and reflects the excessive variance in our material. For comparison, we estimated a total of 21% ischemic neuron death in the dorsal Hilus on cresyl violet-stained sections from other corresponding sham (n=7) and ischemic rats (n=7). This explains why ischemic loss of hilar GABAergic neurons can only be detected by counts of the vulnerable subpopulation colocalizing somatostatin. Our investigation has demonstrated a surprisingly high variation between rats in a number of GAD-immunopositive neurons located in the dorsal Dentate Hilus, which is related to variations between the individual rats and neurons in their endogenous GAD expression.
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effects of the ampa receptor antagonist nbqx on neuron loss in Dentate Hilus of the hippocampal formation after 8 10 or 12 min of cerebral ischemia in the rat
Journal of Cerebral Blood Flow and Metabolism, 1997Co-Authors: Nils Henrik Diemer, Torben Bruhn, Flemming Fryd JohansenAbstract:The alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), offers protection to hippocampal CA1 pyramidal cells after short episodes of transient cerebral ischemia. Besides CA1 pyramidal cells, neurons containing somatostatin (SS) and located in the Dentate Hilus of the hippocampal formation are lost after cerebral ischemia. We studied the protective effects of NBQX on SS neurons in the Hilus and on hippocampal CA1 pyramidal cells following 8, 10, or 12 min of four-vessel occlusion ischemia during systemic hypotension. NBQX was administered 3 x 30 mg/kg at 0, 10, and 25 after induction of ischemia or sham, and all rats survived for 7 days. NBQX given to control rats without ischemia had no influence on number or morphology of hilar SS neurons and CA1 pyramidal cells. After 8 min of ischemia, NBQX prevented loss of hilar SS neurons. After 10 and 12 min of ischemia, NBQX had no significant effects on loss of SS neurons in the Dentate Hilus. However, in all ischemic groups, NBQX significantly reduced loss of CA1 pyramidal cells as compared to control rats. This neuroprotective effect decreased gradually and significantly as the time of ischemia increased. Our results support the observation that SS neurons in Hilus are among the most ischemia-vulnerable neurons in the brain. We found that administration of NBQX in generally accepted dosages can protect the rapidly dying SS neurons in Hilus from only brief episodes of ischemia.
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Hypothermia protects somatostatinergic neurons in rat Dentate Hilus from zinc accumulation and cell death after cerebral ischemia.
Molecular and chemical neuropathology, 1993Co-Authors: Flemming Fryd Johansen, Niels Tønder, M. Berg, Jens Zimmer, Nils Henrik DiemerAbstract:We have previously shown that somatostatin (SS) immunoreactive (-i) neurons, located in the rat Dentate Hilus, are vulnerable to cerebral ischemia (Johansen et al., 1987). Within 40 h after ischemia, the cells show clear signs of cell death. At the same time, we observed that dying cells, located in the projection field of the mossy fibers (Dentate Hilus and CA3 mossy fiber layer), accumulate free zinc. We now demonstrate that the hilar cells, accumulating zinc after ischemia, are SS-i cells. Since it is known that hypothermia can ameliorate ischemic brain damage, we furthermore studied whether hypothermia (29 degrees C) protects the vulnerable SS-i neurons in Hilus from zinc accumulation and ischemic cell death. We found that hypothermia both prevented ischemia-induced neuronal zinc accumulation and cell death. We speculate that hilar SS-i cells are highly vulnerable to ischemia, and develop rapid ischemic cell death, because they accumulate zinc shortly after ischemia.
Teresa A Milner - One of the best experts on this subject based on the ideXlab platform.
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chronic stress differentially alters mrna expression of opioid peptides and receptors in the dorsal hippocampus of female and male rats
The Journal of Comparative Neurology, 2021Co-Authors: Megan A Johnson, Bruce S Mcewen, Teresa A Milner, Natalina H Contoreggi, Batsheva R Rubin, Jason D Gray, Mary Jeanne Kreek, Joshua F Kogan, Matthew BrysonAbstract:Chronic immobilization stress (CIS) results in sex-dependent changes in opioid peptide levels and receptor subcellular distributions within the rat dorsal hippocampus which are paralleled with an inability for males to acquire conditioned place preference (CPP) to oxycodone. Here, RNAScope in situ hybridization was used to determine the expression of hippocampal opioid peptides and receptors in unstressed (US) and CIS estrus female and male adult (~ 14 wk) Sprague Dawley rats. In all groups, Dentate granule cells expressed PENK and PDYN; additionally, numerous interneurons expressed PENK. OPRD1 and OPRM1 were primarily expressed in interneurons, and to a lesser extent, in pyramidal and granule cells. OPRK1-was expressed in sparsely distributed interneurons. There were few baseline sex differences: US females compared to US males had more PENK-expressing and fewer OPRD1-expressing granule cells and more OPRM1-expressing CA3b interneurons. Several expression differences emerged after CIS. Both CIS females and males compared to their US counterparts had elevated: 1) PENK-expressing Dentate granule cells and interneurons in CA1 and CA2/3a; 2) OPRD1 probe number and cell expression in CA1, CA2/3a and CA3b and the Dentate gyrus; and 3) OPRK1-expressing interneurons in the Dentate Hilus. Also, CIS males compared to US males had elevated: 1) PDYN expression in granule cells; 2) OPRD1 probe and interneuron expression in CA2/3a; 3) OPRM1 in granule cells; and 4) OPRK1 interneuron expression in CA2/3a. The sex-specific changes in hippocampal opioid gene expression may impact network properties and synaptic plasticity processes that may contribute to the attenuation of oxycodone CPP in CIS males. This article is protected by copyright. All rights reserved.
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sex differences in neuroplasticity and stress related gene expression and protein levels in the rat hippocampus following oxycodone conditioned place preference
Neuroscience, 2019Co-Authors: Matthew Randesi, Bruce S Mcewen, Teresa A Milner, Natalina H Contoreggi, Yan Zhou, Batsheva R Rubin, Julia R Bellamy, Jason D Gray, Mary Jeanne KreekAbstract:Prescription opioid abuse is a serious public health issue. Recently, we showed that female and male Sprague-Dawley rats acquire conditioned place preference (CPP) to the mu opioid receptor agonist oxycodone. Anatomical analysis of the hippocampus from these rats unveiled sex differences in the opioid system in a way that would support excitation and opiate associative learning processes especially in females. In this study, we examined the expression and protein densities of opioid, plasticity, stress and related kinase and signaling molecules in the hippocampus of female and male rats following oxycodone CPP. Oxycodone CPP females have: a) increases in ARC (activity regulated cytoskeletal-associated protein)-immunoreactivity (ir) in CA3 pyramidal cells; b) decreases in Npy (neuropeptide Y) gene expression in the medial hippocampus but higher numbers of NPY-containing hilar interneurons compared to males; c) increases in Crhr2 (corticotropin releasing factor receptor 2) expression in CA2/3; d) increases in Akt1 (AKT serine/threonine kinase 1) expression in medial hippocampus; and e) decreases in phosphorylated MAPK (mitogen activated protein kinase)-ir in CA1 and Dentate gyrus. Oxycodone CPP males have: a) increases in Bdnf (brain derived-neurotrophic factor) expression, which is known to be produced in granule cells, relative to females; b) elevated Mapk1 expression and pMAPK-ir in the Dentate Hilus which harbors newly generated granule cells; and c) increases in CRHR1-ir in CA3 pyramidal cell soma. These sex-specific changes in plasticity, stress and kinase markers in hippocampal circuitry parallel previously observed sex differences in the opioid system after oxycodone CPP.
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sex differences in subcellular distribution of delta opioid receptors in the rat hippocampus in response to acute and chronic stress
Neurobiology of Stress, 2016Co-Authors: Sanoara Mazid, Bruce S Mcewen, Baila S Hall, Shannon C Odell, Khalifa Stafford, Andreina D Dyer, Tracey A Van Kempen, Jane Selegean, Elizabeth M Waters, Teresa A MilnerAbstract:Abstract Drug addiction requires associative learning processes that critically involve hippocampal circuits, including the opioid system. We recently found that acute and chronic stress, important regulators of addictive processes, affect hippocampal opioid levels and mu opioid receptor trafficking in a sexually dimorphic manner. Here, we examined whether acute and chronic stress similarly alters the levels and trafficking of hippocampal delta opioid receptors (DORs). Immediately after acute immobilization stress (AIS) or one-day after chronic immobilization stress (CIS), the brains of adult female and male rats were perfusion-fixed with aldehydes. The CA3b region and the Dentate Hilus of the dorsal hippocampus were quantitatively analyzed by light microscopy using DOR immunoperoxidase or dual label electron microscopy for DOR using silver intensified immunogold particles (SIG) and GABA using immunoperoxidase. At baseline, females compared to males had more DORs near the plasmalemma of pyramidal cell dendrites and about 3 times more DOR-labeled CA3 dendritic spines contacted by mossy fibers. In AIS females, near-plasmalemmal DOR-SIGs decreased in GABAergic hilar dendrites. However, in AIS males, near-plasmalemmal DOR-SIGs increased in CA3 pyramidal cell and hilar GABAergic dendrites and the percentage of CA3 dendritic spines contacted by mossy fibers increased to about half that seen in unstressed females. Conversely, after CIS, near-plasmalemmal DOR-SIGs increased in hilar GABA-labeled dendrites of females whereas in males plasmalemmal DOR-SIGs decreased in CA3 pyramidal cell dendrites and near-plasmalemmal DOR-SIGs decreased hilar GABA-labeled dendrites. As CIS in females, but not males, redistributed DOR-SIGs near the plasmalemmal of hilar GABAergic dendrites, a subsequent experiment examined the acute affect of oxycodone on the redistribution of DOR-SIGs in a separate cohort of CIS females. Plasmalemmal DOR-SIGs were significantly elevated on hilar interneuron dendrites one-hour after oxycodone (3 mg/kg, I.P.) administration compared to saline administration in CIS females. These data indicate that DORs redistribute within CA3 pyramidal cells and Dentate hilar GABAergic interneurons in a sexually dimorphic manner that would promote activation and drug related learning in males after AIS and in females after CIS.
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enkephalin levels and the number of neuropeptide y containing interneurons in the hippocampus are decreased in female cannabinoid receptor 1 knock out mice
Neuroscience Letters, 2016Co-Authors: Sophie A Rogers, Tracey A Van Kempen, Virginia M Pickel, Teresa A MilnerAbstract:Drug addiction requires learning and memory processes that are facilitated by activation of cannabinoid-1 (CB1) and opioid receptors in the hippocampus. This involves activity-dependent synaptic plasticity that is partially regulated by endogenous opioid (enkephalin and dynorphin) and non-opioid peptides, specifically cholecystokinin, parvalbumin and neuropeptide Y, the neuropeptides present in inhibitory interneurons that co-express CB1 or selective opioid receptors. We tested the hypothesis that CB1 receptor expression is a determinant of the availability of one or more of these peptide modulators in the hippocampus. This was achieved by quantitatively analyzing the immunoperoxidase labeling for each of these neuropeptide in the dorsal hippocampus of female wild-type (CB1+/+) and cannabinoid receptor 1 knockout (CB1-/-) C57/BL6 mice. The levels of Leu(5)-enkephalin-immunoreactivity were significantly reduced in the Hilus of the Dentate gyrus and in stratum lucidum of CA3 in CB1-/- mice. Moreover, the numbers of neuropeptide Y-immunoreactive interneurons in the Dentate Hilus were significantly lower in the CB1-/- compared to wild-type mice. However, CB1+/+ and CB1-/- mice did not significantly differ in expression levels of either dynorphin or cholecystokinin, and showed no differences in numbers of parvalbumin-containing interneurons. These findings suggest that the cannabinoid and opioid systems have a nuanced, regulatory relationship that could affect the balance of excitation and inhibition in the hippocampus and thus processes such as learning that rely on this balance.