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1.
Eur J Pharmacol ; 771: 29-39, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26681545

ABSTRACT

The tetracycline antibiotic minocycline can exert strong anti-inflammatory, antioxidant, and antiapoptotic effects. There is cumulating evidence that epileptogenic brain insults trigger neuroinflammation and anti-inflammatory concepts can modulate the process of epileptogenesis. Based on the mechanisms of action discussed for minocycline, the compound is of interest for intervention studies as it can prevent the polarization of microglia into a pro-inflammatory state. Here, we assessed the efficacy of sub-chronic minocycline administration initiated immediately following an electrically-induced status epilepticus in rats. The treatment did not affect the development of spontaneous seizures. However, minocycline attenuated behavioral long-term consequences of status epilepticus with a reduction in hyperactivity and hyperlocomotion. Furthermore, the compound limited the spatial learning deficits observed in the post-status epilepticus model. The typical status epilepticus-induced neuronal cell loss was evident in the hippocampus and the piriform cortex. Minocycline exposure selectively protected neurons in the piriform cortex and the hilus, but not in the hippocampal pyramidal layer. In conclusion, the data argue against an antiepileptogenic effect of minocycline in adult rats. However, the findings suggest a disease-modifying impact of the tetracycline affecting the development of behavioral co-morbidities, as well as long-term consequences on spatial learning. In addition, minocycline administration resulted in a selective neuroprotective effect. Although strong anti-inflammatory effects have been proposed for minocycline, we could not verify these effects in our experimental model. Considering the multitude of mechanisms claimed to contribute to minocycline's effects, it is of interest to further explore the exact mechanisms underlying the beneficial effects in future studies.


Subject(s)
Anticonvulsants/therapeutic use , Minocycline/therapeutic use , Status Epilepticus/drug therapy , Animals , Behavior, Animal/drug effects , Cerebral Cortex/pathology , Electric Stimulation , Female , Hippocampus/pathology , Maze Learning/drug effects , Microglia/drug effects , Motor Activity/drug effects , Neurons/drug effects , Neuroprotective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Seizures/drug therapy
2.
Brain Behav Immun ; 53: 138-158, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26685804

ABSTRACT

Detailed knowledge about the patterns of molecular alterations during epileptogenesis is a presupposition for identifying targets for preventive or disease-modifying approaches, as well as biomarkers of the disease. Large-scale differential proteome analysis can provide unique and novel perspectives based on comprehensive data sets informing about the complex regulation patterns in the disease proteome. Thus, we have completed an elaborate differential proteome analysis based on label-free LC-MS/MS in a rat model of epileptogenesis. Hippocampus and parahippocampal cortex tissues were sampled and analyzed separately at three key time points chosen for monitoring disease development following electrically-induced status epilepticus, namely, the early post-insult phase, the latency phase, and the chronic phase with spontaneous recurrent seizures. We focused the bioinformatics analysis on proteins linked to immune and inflammatory responses, because of the emerging evidence of the specific pathogenic role of inflammatory signalings during epileptogenesis. In the early post-insult and the latency phases, pathway enrichment analysis revealed an extensive over-representation of Toll-like receptor signaling, pro-inflammatory cytokines, heat shock protein regulation, and transforming growth factor beta signaling and leukocyte transendothelial migration. The inflammatory response in the chronic phase proved to be more moderate with differential expression in the parahippocampal cortex exceeding that in the hippocampus. The data sets provide novel information about numerous differentially expressed proteins, which serve as interaction partners or modulators in key disease-associated inflammatory signaling events. Noteworthy, a set of proteins which act as modulators of the ictogenic Toll-like receptor signaling proved to be differentially expressed. In addition, we report novel data demonstrating the regulation of different Toll-like receptor ligands during epileptogenesis. Taken together, the findings deepen our understanding of modulation of inflammatory signaling during epileptogenesis providing an excellent and comprehensive basis for the identification of target and biomarker candidates.


Subject(s)
Epilepsy/metabolism , Inflammation/metabolism , Animals , Biomarkers/metabolism , Cerebral Cortex/metabolism , Cytokines/metabolism , Disease Models, Animal , Epilepsy/etiology , Epilepsy/genetics , Female , Gene Expression Profiling , Hippocampus/metabolism , Inflammation/genetics , Parahippocampal Gyrus/metabolism , Proteome/metabolism , Proteomics/methods , Rats , Rats, Sprague-Dawley , Receptors, Purinergic/metabolism , Signal Transduction , Tandem Mass Spectrometry/methods , Toll-Like Receptors/metabolism
3.
Neurosci Lett ; 604: 151-6, 2015 Sep 14.
Article in English | MEDLINE | ID: mdl-26259695

ABSTRACT

The neuroprotective and anti-inflammatory effects of the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone are of particular interest for disease-modifying and antiepileptogenic approaches. We studied the expression of PPARγ and the impact of rosiglitazone on the consequences of status epilepticus (SE) in a rat post-SE model. Immunohistochemical analysis revealed a selective overexpression of PPARγ in the piriform cortex of rats with spontaneous seizures. Rosiglitazone administration initiated following SE failed to exert relevant effects on the development of spontaneous seizures and neuronal cell loss. Whereas spatial learning in the Morris water maze was delayed in SE animals with vehicle administration, the learning curve of rosiglitazone-treated SE rats showed no significant difference to that of controls. The study provides first evidence arguing against a robust antiepileptogenic effect. However, the findings in the spatial learning paradigm indicate disease-modifying effects.


Subject(s)
PPAR gamma/metabolism , Status Epilepticus/metabolism , Animals , Behavior, Animal , Electric Stimulation , Female , Gene Expression Regulation , Hippocampus/drug effects , Hippocampus/pathology , Maze Learning , Neurons/drug effects , Neurons/pathology , PPAR gamma/agonists , Parietal Lobe/drug effects , Parietal Lobe/pathology , Piriform Cortex/drug effects , Piriform Cortex/metabolism , Piriform Cortex/pathology , Rats, Sprague-Dawley , Rosiglitazone , Seizures/physiopathology , Spatial Learning , Status Epilepticus/pathology , Status Epilepticus/physiopathology , Thiazolidinediones/pharmacology
4.
Eur J Pharmacol ; 740: 72-80, 2014 Oct 05.
Article in English | MEDLINE | ID: mdl-25016931

ABSTRACT

Blockade of KCa3.1 channels has been suggested as a novel strategy to reduce microglia activation. The concept has been confirmed by neuroprotective effects in a rat brain ischemia-reperfusion model and reduced microglia activation surrounding glioblastomas. Cumulating evidence exists that microglia activation significantly contributes to epileptogenesis as well as intrinsic severity in the chronic epileptic brain. Taken together these data raised the question whether the KCa3.1 channel blocker triarylmethane-34 (TRAM-34) might also exert beneficial effects in chronic epilepsy models. In a rat post-status epilepticus model TRAM-34 treatment following the insult did not result in neuroprotective effects. Whereas status epilepticus-associated neurodegeneration remained unaffected in the piriform cortex, loss of pyramidal cells in the hippocampal CA1 and CA3a region and of neuropeptide Y-positive interneurons in the hilus proved to be exacerbated by pharmacological KCa3.1 blockade. The development of spontaneous seizures and of behavioral and cognitive alterations was comparable in animals receiving TRAM-34 treatment or the respective vehicle. The kindling model of temporal lobe epilepsy with a massive stimulation paradigm with frequent seizure elicitation in fully kindled rats was used to assess a putative disease-modifying effect. However, sub-chronic TRAM-34 treatment failed to exert relevant effects on seizure generation and thresholds. In conclusion, the data obtained in two different chronic epilepsy models argue against using KCa3.1 blockers as disease-modifying or antiepileptogenic agents. Exacerbation of neuronal cell loss in TRAM-34 pre-treated epileptic animals rather indicates that translational development of the compound needs to carefully consider the pathophysiological mechanisms associated with different brain insults.


Subject(s)
Epilepsy, Temporal Lobe/drug therapy , Intermediate-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Potassium Channel Blockers/therapeutic use , Pyrazoles/therapeutic use , Status Epilepticus/drug therapy , Animals , Epilepsy, Temporal Lobe/pathology , Female , Hippocampus/drug effects , Hippocampus/pathology , Microglia/metabolism , Neurons/drug effects , Neurons/pathology , Potassium Channel Blockers/pharmacology , Pyrazoles/pharmacology , Rats, Sprague-Dawley , Status Epilepticus/pathology
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