Increased expression and activity of urokinase-type plasminogen activator during epileptogenesis

Our recent large-scale molecular profiling study revealed a sevenfold upregulation in the expression of urokinase-type plasminogen activator (uPA) during epileptogenesis. uPA is a member of the plasminogen activation system, which is a major contributor to the reorganization of neuronal circuits after trauma. Here, we investigated the expression and activity of uPA in normal and epileptogenic rat hippocampus to test a hypothesis that the expression of uPA is altered in brain areas that undergo epilepsy-related circuitry reorganization. Epileptogenesis was triggered by inducing status epilepticus (SE) with electrical stimulation of the amygdala in rats. Continuous video-electroencephalogram recordings were used to monitor the development of SE and the occurrence of spontaneous seizures. Animals were killed at 1, 4 or 14 days after SE, and brains were processed for immunohistochemistry or protein extraction. Confocal microscopy analysis of double-immunolabelled preparations indicated that SE triggered an increased expression of uPA in hippocampal astrocytes, neurons, white matter and blood vessels. Zymography revealed that the expression of uPA protein is associated with increased levels of enzymatically active uPA during epileptogenesis. uPA expression and enzymatic activity peaked within 1-4 days after SE, that is, before the occurrence of spontaneous seizures, and remained elevated for at least 2 weeks. These data suggest that uPA is involved in the reorganization of neuronal tissue during the epileptogenic process.     

Fear conditioning is impaired in systemic kainic acid and amygdala-stimulation models of epilepsy

PURPOSE: The lateral nucleus of the amygdala is critical for fear conditioning, a paradigm of emotional learning, which requires recognition of an unconditioned stimulus as aversive and association of conditioned stimuli with an unconditioned stimulus. Some patients with temporal lobe epilepsy have amygdaloid damage associated with impaired emotional learning. Fear conditioning also is impaired at least in some animal models of epilepsy. We studied whether contextual or tone-cued fear conditioning is impaired in two status epilepticus models of epilepsy and whether impairment correlates with the extent of damage in the lateral nucleus of the amygdala. METHODS: We induced epilepsy in rats by either systemic kainic acid administration or electrical amygdala stimulation. Behavioral reactions in all phases of fear conditioning were analyzed from videotapes. Damage to the lateral nucleus of the amygdala was analyzed from thionin-stained sections both histologically and by volumetry. RESULTS: Immediate reflexive responses to unconditioned and conditioned stimuli were preserved, whereas the freezing response to an unconditioned stimulus was reduced. Contextual conditioning was severely impaired, whereas tone-cued conditioning was better preserved. The lateral nucleus pathology did not correlate with impaired fear conditioning. CONCLUSIONS: These data suggest that processing of complex contextual stimuli is severely affected in experimental epilepsy, whereas conditioning to simple cues is better preserved.     

Quantitative T2 mapping as a potential marker for the initial assessment of the severity of damage after traumatic brain injury in rat

Severity of traumatic brain injury (TBI) positively correlates with the risk of post-traumatic epilepsy (PTE). Studies on post-traumatic epileptogenesis would greatly benefit from markers that at acute phase would reliably predict the extent and severity of histologic brain damage caused by TBI in individual subjects. Currently in experimental models, severity of TBI is determined by the pressure of applied load that does not directly reflect the extent of inflicted brain injury, mortality within experimental population, or impairment in behavioral tests that are laborious to perform. We aimed to compare MRI markers measured at acute post-injury phase to previously used indicators of injury severity in the ability to predict the extent of histologically determined post-traumatic tissue damage. We used lateral fluid-percussion injury model in rat that is a clinically relevant model of closed head injury in humans, and results in PTE in severe cases. Rats (48 injured, 12 controls) were divided into moderate (mTBI) and severe (sTBI) groups according to impact strength. MRI data (T2, T2*, lesion volume) were acquired 3 days post-injury. Motor deficits were analysed using neuroscore (NS) and beam balance (BB) tests 2 and 3 days post-injury, respectively. Histological evaluation of lesion volume (Fluoro-Jade B) was used as the reference outcome measure, and was performed 2 weeks after TBI. From MRI parameters studied, quantitative T2 values of cortical lesion not only correlated with histologic lesion volume (P < 0.001, r = 0.6, N = 34), as well as NS (P < 0.01, r = − 0.5, N = 34) and BB (P < 0.01, r = − 0.5, N = 34) results, but also successfully differentiated animals with mTBI from those with sTBI 70.6 ± 6.2 6.2 ms vs. 75.9 ± 2.6 ms, P < 0.001). Quantitative T2 of the lesion early after TBI can serve as an indicator of the severity of post-traumatic cortical damage and neuro-motor impairment, and has a potential as a clinical marker for identification of individuals with elevated risk of PTE.     

Cavernoma‐related epilepsy: Review and recommendations for management—Report of the Surgical Task Force of the ILAE Commission on Therapeutic Strategies

Cerebral cavernous malformations (CCMs) are well‐defined, mostly singular lesions present in 0.4–0.9% of the population. Epileptic seizures are the most frequent symptom in patients with CCMs and have a great impact on social function and quality of life. However, patients with CCM‐related epilepsy (CRE) who undergo surgical resection achieve postoperative seizure freedom in only about 75% of cases. This is frequently because insufficient efforts are made to adequately define and resect the epileptogenic zone. The Surgical Task Force of the Commission on Therapeutics of the International League Against Epilepsy (ILAE) and invited experts reviewed the pertinent literature on CRE. Definitions of definitive and probable CRE are suggested, and recommendations regarding the diagnostic evaluation and etiology‐specific management of patients with CRE are made. Prospective trials are needed to determine when and how surgery should be done and to define the relations of the hemosiderin rim to the epileptogenic zone.     

Regional cerebral blood flow and FDG uptake in asymptomatic HIV‐1 men

Despite advances in the treatment of patients with human immunodeficiency virus (HIV), HIV‐associated neurocognitive disorder occurs in 15–50% of HIV‐infected individuals, and may become more apparent as ageing advances. In the present study we investigated regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose uptake (rCMRglc) in medically and psychiatrically stable HIV‐1‐infected participants in two age‐groups. Positron emission tomography (PET) and magnetic resonance imaging (MRI)‐based arterial spin labeling (ASL) were used to measure rCMRglc and rCBF, respectively, in 35 HIV‐infected participants and 37 HIV‐negative matched controls. All participants were currently asymptomatic with undetectable HIV‐1 viral loads, without medical or psychiatric comorbidity, alcohol or substance misuse, stable on medication for at least 6 months before enrolment in the study. We found significant age effects on both ASL and PET with reduced rCBF and rCMRglc in related frontal brain regions, and consistent, although small, reductions in rCBF and rCMRglc in the anterior cingulate cortex (ACC) in HIV, a finding of potential clinical significance. There was no significant interaction between HIV status and the ageing process, and no significant HIV‐related changes elsewhere in the brain on PET or ASL. This is the first paper to combine evidence from ASL and PET method in HIV participants. These finding provide evidence of crossvalidity between the two techniques, both in ageing and a clinical condition (HIV). Hum Brain Mapp 34:2484–2493, 2013. © 2012 Wiley Periodicals, Inc.     

Effects of dopamine and dobutamine on skeletal muscle oxygenation in normoxemic rats

The effects of two vasoactive drugs, dopamine and dobutamine, on skeletal muscle tissue oxygenation were studied in a normoxemic rat model. It is usually claimed that drugs may increase or decrease oxygen delivery to tissues. However, this claim is only valid on the global level. Our interest is directed towards individual organs. Two groups of rats (n = 7 each) were studied. One group received dopamine, the other dobutamine. Blood gases, hematocrits, and mean arterial blood pressures were measured in addition to tissue pO2. Infusion of dopamine 2.5 micrograms/kg/min resulted in a statistically significant decrease in skeletal muscle pO2. Higher doses of dopamine, and all doses of dobutamine, did not influence pO2 at all. The results raise the question of whether blood flow to vital organs may be negatively affected by dopamine 2.5 micrograms/kg/min. Direct measurements of tissue oxygenation are warranted in, e.g., the liver and gut.     

Epileptogenesis in Experimental Models

Summary:  Epileptogenesis refers to a phenomenon in which the brain undergoes molecular and cellular alterations after a brain-damaging insult, which increase its excitability and eventually lead to the occurrence of recurrent spontaneous seizures. Common epileptogenic factors include traumatic brain injury (TBI), stroke, and cerebral infections. Only a subpopulation of patients with any of these brain insults, however, will develop epilepsy. Thus, there are two great challenges: (1) identifying patients at risk, and (2) preventing and/or modifying the epileptogenic process. Target identification for antiepileptogenic treatments is difficult in humans because patients undergoing epileptogenesis cannot currently be identified. Animal models of epileptogenesis are therefore necessary for scientific progress. Recent advances in the development of experimental models of epileptogenesis have provided tools to investigate the molecular and cellular alterations and their temporal appearance, as well as the epilepsy phenotype after various clinically relevant epileptogenic etiologies, including TBI and stroke. Studying these models will lead to answers to critical questions such as: Do the molecular mechanisms of epileptogenesis depend on the etiology? Is the spectrum of network alterations during epileptogenesis the same after various clinically relevant etiologies? Is the temporal progression of epileptogenesis similar? Work is ongoing, and answers to these questions will facilitate the identification of molecular targets for antiepileptogenic treatments, the design of treatment paradigms, and the determination of whether data from one etiology can be extrapolated to another.