Pharmacological upregulation of GLT-1 alleviates the cognitive impairments in the animal model of temporal lobe epilepsy

It is known that hippocampal epileptogenesis is accompanied by hyperexcitability, glutamate-related neuronal dysfunctions and consequently cognitive deficits. However, the neuroprotective role of astrocytic glutamate uptake through the Glutamate Transporter-1 (GLT-1) remains to be unknown in these processes. Therefore, to assess the effect of glutamate uptake, pharmacological upregulation of GLT-1 using ceftriaxone administration (200 mg/kg/day, i.p, 5 days) was utilized in Li-PIL animal models of temporal lobe epilepsy (TLE). Glutamate concentration and glutamine synthetase activity were analyzed using biochemical assays. In addition, GLT-1 gene expression was assessed by RT-qPCR. Finally, cognitive function was studied using Morris water maze (MWM) test and novel object recognition task (NORT). Our results demonstrated that the acute phase of epileptogenesis (first 72 hours after Status Epilepticus) was accompanied by an increase in the hippocampal glutamate and downregulation of GLT-1 mRNA expression compared to controls. Ceftriaxone administration in epileptic animals led to a reduction of glutamate along with elevation of the level of glutamine synthetase activity and GLT-1 expression in the acute phase. In the chronic phase of epileptogenesis (4 weeks after Status Epilepticus), glutamate levels and GLT-1 expression were decreased compared to controls. Ceftriaxone treatment increased the levels of GLT-1 expression. Furthermore, impaired learning and memory ability in the chronic phase of epileptogenesis was rescued by Ceftriaxone administration. This study shows that astrocytic glutamate uptake can profoundly impact the processes of hippocampal epileptogenesis through the reduction of glutamate-induced excitotoxicity and consequently rescuing of cognitive deficits caused by epilepsy.

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Manganese-enhanced magnetic resonance imaging in the acute phase of the pilocarpine-induced model of epilepsy

Einstein (São Paulo) ◽

10.1590/s1679-45082012000200023 ◽

2012 ◽

Vol 10 (2) ◽

pp. 247-252 ◽

Cited By ~ 4

Author(s):

Jackeline Moraes Malheiros ◽

Beatriz Monteiro Longo ◽

Alberto Tannús ◽

Luciene Covolan

Keyword(s):

Status Epilepticus ◽

Magnetic Resonance ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Acute Phase ◽

Cell Activation ◽

Experimental Models ◽

Magnetic Resonance Images ◽

Control Group ◽

Experimental Conditions

Magnetic resonance images are useful in the study of experimental models of temporal lobe epilepsy. The manganese-enhanced MRI (MEMRI) technique is of interest since it combines the effects caused by manganese on the increased contrast in activated cell populations, when competing with calcium in synaptic transmission. Thus, the purpose of this study was to investigate the temporal evolution of the contrast related to manganese in the acute phase of temporal lobe epilepsy induced by systemic pilocarpine and compare it to the expression of the c-Fos protein. During this phase, the intensity of the MEMRI signal was analyzed at three different time points (5, 15 or 30 minutes) after the onset of status epilepticus (SE). The group that was maintained in status epilepticus for 30 minutes showed a decrease in intensity of the signal in CA1 and the dentate gyrus (DG). There were no differences between the control group and the other groups treated with pilocarpine. The expression of the protein, c-Fos, in the same animals showed that even in the short-duration status epilepticus (5 minutes), there was already maximal cellular activation in subregions of the hippocampus (DG, CA1 and CA3). Under the experimental conditions tested, our data suggest that the MEMRI signal was not sensitive for the identification of detectable variations of cell activation in the acute phase of the pilocarpine model. Our findings are not consistent with the idea that manganese contrast reflects primarily alterations in cellular activity during SE when other signal-modifying elements can act.

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Caloric restriction increases hippocampal glutamate uptake and glutamine synthetase activity in Wistar rats

Neuroscience Research ◽

10.1016/j.neures.2009.04.004 ◽

2009 ◽

Vol 64 (3) ◽

pp. 330-334 ◽

Cited By ~ 15

Author(s):

Letícia Carina Ribeiro ◽

André Quincozes-Santos ◽

Marina Concli Leite ◽

Renata Torres Abib ◽

Juliana Kleinkauf-Rocha ◽

...

Keyword(s):

Glutamine Synthetase ◽

Caloric Restriction ◽

Wistar Rats ◽

Glutamate Uptake ◽

Synthetase Activity ◽

Glutamine Synthetase Activity

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Low grade inflammation in the epileptic hippocampus contrasts with explosive inflammation occurring in the acute phase following status epilepticus in rats: translation to patients with epilepsy

10.1101/2021.03.25.436701 ◽

2021 ◽

Author(s):

Nadia Gasmi ◽

Fabrice P. Navarro ◽

Michaël Ogier ◽

Amor Belmeguenaï ◽

Thomas Lieutaud ◽

...

Keyword(s):

Status Epilepticus ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Chronic Phase ◽

Mesial Temporal Lobe Epilepsy ◽

Low Grade ◽

Gene Transcript ◽

Transcript Levels ◽

Inflammatory Status ◽

Mesial Temporal Lobe

ABSTRACTThere is still a lack of robust data, acquired identically and reliably from tissues either surgically resected from patients with mesial temporal lobe epilepsy (mTLE) or collected in animal models, to answer the question of whether the degree of inflammation of the hippocampus differs between mTLE patients, and between epilepsy and epileptogenesis. Here, using highly calibrated RTqPCR, we show that neuroinflammatory marker expression was highly variable in the hippocampus and the amygdala of mTLE patients. This variability was not associated with gender, age, duration of epilepsy, seizure frequency, and anti-seizure drug treatments. In addition, it did not correlate between the two structures and was reduced when the inflammatory status was averaged between the two structures. We also show that brain tissue not frozen within minutes after resection had significantly decreased housekeeping gene transcript levels, precluding the possibility of using post-mortem tissues to assess physiological baseline transcript levels in the hippocampus. We thus used rat models of mTLE, induced by status epilepticus (SE), that have the advantage of providing access to physiological baseline values. They indisputably indicated that inflammation measured during the chronic phase of epilepsy was much lower than the explosive inflammation occurring after SE, and was only detected when epilepsy was associated with massive neurodegeneration and gliosis. Comparison between the inter-individual variability measured in patients and that established in all epileptic and control rats suggests that some mTLE patients may have very low inflammation in the hippocampus, close to control values. However, the observation of elevated inflammation in the amygdala of some patients indicates that inflammation should be studied not only at the epileptic hippocampus, but also in the associated brain structures in order to have a more integrated view of the degree of inflammation present in brain networks involved in mesial temporal lobe epilepsy.

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