Hippocampal damage after intra-amygdala kainic acid-induced status epilepticus and seizure preconditioning-mediated neuroprotection in SJL mice
ABSTRACT Exposure of the brain to a stressful stimulus that is sub-threshold for permanent injury can temporarily protect against cell death during a subsequent and otherwise damaging insult. One or more brief, non-harmful seizure episode(s) (seizure preconditioning) can dramatically reduce hippocampal damage when given prior to status epilepticus (epileptic tolerance). We recently reported that status epilepticus-induced hippocampal damage in C57BL/6 mice could be reduced by approximately 50% when preceded 24h earlier by a brief, non-injurious generalized seizure induced by 15mg/kg systemic kainic acid (KA). Since other mouse strains might display different vulnerability to either seizure preconditioning or status epilepticus, we investigated whether epileptic tolerance could be acquired in another strain. SJL mice, reported to display greater seizure sensitivity to systemic KA, received intra-amygdala microinjection of KA to trigger status epilepticus. Intracerebral recordings confirmed evoked seizures involved the ipsilateral hippocampus. Status epilepticus produced hippocampal damage which mainly affected the ipsilateral CA3 and hilus; a pattern similar to C57BL/6 mice. The damage extended through the full rostro-caudal extent of the hippocampal formation. Seizure preconditioning using 20mg/kg systemic KA, but not 15mg/kg, significantly reduced hippocampal damage after status epilepticus by 37% in the dorsal hippocampus and by 65% in the ventral hippocampus. These studies suggest status epilepticus induced by intra-amygdala KA in SJL mice models aspects of the pathophysiology of human mesial temporal sclerosis. Moreover, seizure preconditioning effectively produces neuroprotection in SJL mice, further establishing epileptic tolerance as a conserved endogenous neuroprotection paradigm.
Radiotherapy and Oncology 05/2011; 99. DOI:10.1016/S0167-8140(11)71478-5 · 4.86 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: 14-3-3 proteins are ubiquitous molecular chaperones that are abundantly expressed in the brain where they regulate cell functions including metabolism, the cell cycle and apoptosis. Brain levels of several 14-3-3 isoforms are altered in diseases of the nervous system, including epilepsy. The 14-3-3 zeta (ζ) isoform has been linked to endoplasmic reticulum (ER) function in neurons, with reduced levels provoking ER stress and increasing vulnerability to excitotoxic injury. Here we report that transgenic overexpression of 14-3-3ζ in mice results in selective changes to the unfolded protein response pathway in the hippocampus, including down-regulation of glucose-regulated proteins 78 and 94, activating transcription factors 4 and 6, and Xbp1 splicing. No differences were found between wild-type mice and transgenic mice for levels of other 14-3-3 isoforms or various other 14-3-3 binding proteins. 14-3-3ζ overexpressing mice were potently protected against cell death caused by intracerebroventricular injection of the ER stressor tunicamycin. 14-3-3ζ overexpressing mice were also potently protected against neuronal death caused by prolonged seizures. These studies demonstrate that increased 14-3-3ζ levels protect against ER stress and seizure-damage despite down-regulation of the unfolded protein response. Delivery of 14-3-3ζ may protect against pathologic changes resulting from prolonged or repeated seizures or where injuries provoke ER stress.PLoS ONE 01/2013; 8(1):e54491. DOI:10.1371/journal.pone.0054491 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Epilepsy is the most common and chronic neurological disorder characterized by recurrent unprovoked seizures. The key aim in treating patients with epilepsy is the suppression of seizures. An understanding of focal changes that are involved in epileptogenesis may therefore provide novel approaches for optimal treatment of the seizure. Although the actual pathogenesis of epilepsy is still uncertain, recently growing lines of evidence declare that microglia and astrocyte activation, oxidative stress and reactive oxygen species (ROS) production, mitochondria dysfunction, and damage of blood-brain barrier (BBB) are involved in its pathogenesis. Impaired GABAergic function in the brain is probably the most accepted hypothesis regarding the pathogenesis of epilepsy. Clinical neuroimaging of patients and experimental modeling have demonstrated that seizures may induce neuronal apoptosis. Apoptosis signaling pathways are involved in the pathogenesis of several types of epilepsy such as temporal lobe epilepsy (TLE). The quality of life of patients is seriously affected by treatment-related problems and also by unpredictability of epileptic seizures. Moreover, the available antiepileptic drugs (AED) are not significantly effective to prevent epileptogenesis. Thus, novel therapies that are proficient to control seizure in people who are suffering from epilepsy are needed. The preconditioning method promises to serve as an alternative therapeutic approach because this strategy has demonstrated the capability to curtail epileptogenesis. For this reason, understanding of molecular mechanisms underlying brain tolerance induced by preconditioning is crucial to delineate new neuroprotective ways against seizure damage and epileptogenesis. In this review, we summarize the work to date on the pathogenesis of epilepsy and discuss recent therapeutic strategies in the treatment of epilepsy. We will highlight that novel therapy targeting such as preconditioning process holds great promise. In addition, we will also highlight the role of gene reprogramming and mitochondrial biogenesis in the preconditioning-mediated neuroprotective events.Molecular Neurobiology 09/2014; DOI:10.1007/s12035-014-8876-5 · 5.29 Impact Factor