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1.  Deep hypothermia for the treatment of refractory status epilepticus 
Epilepsy & behavior : E&B  2015;49:313-317.
In a rat model of status epilepticus (SE) induced by lithium and pilocarpine and refractory to midazolam, deep hypothermia (20°C for 30 min.) reduced EEG power over 50-fold, stopped SE within 12 minutes, and reduced EEG spikes by 87%. Hypothermia deserves further investigation as a treatment of last resort for refractory SE.
doi:10.1016/j.yebeh.2015.06.028
PMCID: PMC4535418  PMID: 26198217
Status epilepticus; hypothermia; EEG power
2.  Neuroprotective effects of deep hypothermia in refractory status epilepticus 
Abstract
Objective
Pharmacoresistance develops quickly during repetitive seizures, and refractory status epilepticus (RSE) remains a therapeutic challenge. The outcome of RSE is poor, with high mortality and morbidity. New treatments are needed. Deep hypothermia (20°C) is used clinically during reconstructive cardiac surgery and neurosurgery, and has proved safe and effective in those indications. We tested the hypothesis that deep hypothermia reduces RSE and its long‐term consequences.
Methods
We used a model of SE induced by lithium and pilocarpine and refractory to midazolam. Several EEG measures were recorded in both hypothermic (n = 17) and normothermic (n = 20) animals. Neuronal injury (by Fluoro‐Jade B), cell‐mediated inflammation, and breakdown of the blood–brain barrier (BBB) (by immunohistochemistry) were studied 48 h following SE onset.
Results
Normothermic rats in RSE seized for 4.1 ± 1.1 h, and at 48 h they displayed extensive neuronal injury in many brain regions, including hippocampus, dentate gyrus, amygdala, entorhinal and pyriform cortices, thalamus, caudate/putamen, and the frontoparietal neocortex. Deep hypothermia (20°C) of 30 min duration terminated RSE within 12 min of initiation of hypothermia, reduced EEG power and seizure activity upon rewarming, and eliminated SE‐induced neuronal injury in most animals. Normothermic rats showed widespread breakdown of the BBB, and extensive macrophage infiltration in areas of neuronal injury, which were completely absent in animals treated with hypothermia.
Interpretation
These results suggest that deep hypothermia may open a new therapeutic avenue for the treatment of RSE and for the prevention of its long‐term consequences.
doi:10.1002/acn3.262
PMCID: PMC4693587  PMID: 26734661
3.  Trafficking of NMDA Receptors During Status Epilepticus: Therapeutic Implications 
Epilepsia  2013;54(0 6):78-80.
Summary
We used two models of status epilepticus (SE) to study trafficking of NMDA receptors (NMDAR). SE is associated with increased surface expression of NR1 subunits of NMDAR, and with an increase of NMDA synaptic and extrasynaptic currents suggesting an increase in number of functional NMDAR on dentate granule cells. The therapeutic implications of these results are discussed.
doi:10.1111/epi.12285
PMCID: PMC4551407  PMID: 24001081
NMDA receptor; receptor trafficking; status epilepticus; acute seizures; cholinergic seizures; epilepsy; monotherapy; hippocampus
4.  Rational Polytherapy in the Treatment of Acute Seizures and Status Epilepticus 
Epilepsia  2011;52(0 8):70-71.
doi:10.1111/j.1528-1167.2011.03243.x
PMCID: PMC4540642  PMID: 21967369
animal model; cholinergic seizures; drug toxicity; GABAergic inhibition; glutamatergic excitation; mortality; neuronal injury; seizure termination
5.  Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine 
Brain  2008;131(8):2071-2083.
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
comorbidity; depression; epilepsy; hippocampus; serotonin
6.  Depression after status epilepticus: behavioral and biochemical deficits, and effects of fluoxetine 
Brain : a journal of neurology  2008;131(Pt 8):2071-2083.
Summary
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioral and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naïve animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioral equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
Comorbidity; depression; epilepsy; hippocampus; serotonin
7.  In vivo interaction between serotonin and galanin type 1 and type 2 receptors in dorsal raphe: implication for limbic seizures 
Journal of neurochemistry  2005;95(5):1495-1503.
Neuropeptide galanin suppresses seizure activity in the hippocampus by inhibiting glutamatergic neurotransmission. Galanin may also modulate limbic seizures through interaction with other neurotransmitters in neuronal populations that project to the hippocampus. We examined the role of galanin receptors types 1 and 2 in the dorsal raphe in regulation serotonergic transmission and limbic seizures. Infusion of a mixed agonist of galanin receptors 1 and 2, galanin (1-29), into the dorsal raphe augmented the severity of limbic seizures both in rats and in wild type mice, and concurrently reduced serotonin concentration in dorsal raphe and in the hippocampus, measured by immunofluorescence, or HPLC. In contrast, injection of galanin 2 receptor agonist galanin (2-11), mitigated the severity of seizures in both species, and increased serotonin concentration in both areas. Injection of both galanin fragments into the dorsal raphe of galanin receptor 1 knockout mice exerted anticonvulsant effects. Both proconvulsant activity of galanin (1-29) and seizure suppression by galanin (2-11) were abolished in serotonin – depleted animals. Our data indicate that in the dorsal raphe, galanin 1 and 2 receptors modulate serotonergic transmission in a negative and a positive fashion respectively, and that these effects translate into either facilitation, or inhibition of limbic seizures.
doi:10.1111/j.1471-4159.2005.03498.x
PMCID: PMC1343489  PMID: 16219029
Serotonin; galanin receptor; dorsal raphe; hippocampus; seizures; 5-HIAA- 5-hydroxyindolacetic acid; 5-HT- serotonin; GalR1- galanin receptor type 1; GalR2- galanin receptor type 2; DR- dorsal raphe; i.p.- intraperitoneally; NA- norepinephrine; PCA- Parachloroamphetamine; PPS- perforant path stimulation; SE- status epilepticus

Results 1-7 (7)