Agomelatine protects against neuronal damage without preventing epileptogenesis in the kainate model of temporal lobe epilepsy

Tchekalarova, Jana; Atanasova, Dimitrinka; Nenchovska, Zlatina; Atanasova, Milena; Kortenska, Lidia; Gesheva, R; Lazarov, Nikolai

doi:10.1016/j.nbd.2017.04.017

Cited by 34 publications

(21 citation statements)

References 61 publications

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“…Rodents are spontaneously thigmotaxic and prefer the safer and darker periphery of the arena over the central and bright part of the apparatus. In accordance with previous studies, 21 , 22 we found that epileptic animals spent a progressively increasing amount of time in the aversive central part of the field, indicating a hyperactive and disinhibited state. In contrast, rats implanted with BDNF devices had a behavior indistinguishable from that of naive rats.…”

Section: Discussionsupporting

confidence: 93%

Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

Falcicchia

Paolone

Emerich

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Brain-derived neurotrophic factor (BDNF) may represent a therapeutic for chronic epilepsy, but evaluating its potential is complicated by difficulties in its delivery to the brain. Here, we describe the effects on epileptic seizures of encapsulated cell biodelivery (ECB) devices filled with genetically modified human cells engineered to release BDNF. These devices, implanted into the hippocampus of pilocarpine-treated rats, highly decreased the frequency of spontaneous seizures by more than 80%. These benefits were associated with improved cognitive performance, as epileptic rats treated with BDNF performed significantly better on a novel object recognition test. Importantly, long-term BDNF delivery did not alter normal behaviors such as general activity or sleep/wake patterns. Detailed immunohistochemical analyses revealed that the neurological benefits of BDNF were associated with several anatomical changes, including reduction in degenerating cells and normalization of hippocampal volume, neuronal counts (including parvalbumin-positive interneurons), and neurogenesis. In conclusion, the present data suggest that BDNF, when continuously released in the epileptic hippocampus, reduces the frequency of generalized seizures, improves cognitive performance, and reverts many histological alterations associated with chronic epilepsy. Thus, ECB device-mediated long-term supplementation of BDNF in the epileptic tissue may represent a valid therapeutic strategy against epilepsy and some of its co-morbidities.

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Section: Discussionsupporting

confidence: 93%

Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

Falcicchia

Paolone

Emerich

et al. 2018

Molecular Therapy - Methods & Clinical Development

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“…These findings indicated that different mechanisms are involved in neuronal loss after different seizure activity. In epilepsy patients or in animal models of seizure, neuronal damage could also be investigated in the cerebral cortex [ 19 ]. Johnson et al found that the inhibition of efflux transporters induced hippocampal seizures in 100% of pregnant rats; the hippocampal seizures in non-pregnant rats were considerably less prevalent.…”

Section: Resultsmentioning

confidence: 99%

Changes in the Expression of AQP4 and AQP9 in the Hippocampus Following Eclampsia-Like Seizure

Han

Huang

Liu

et al. 2018

IJMS

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Eclampsia is a hypertensive disorder of pregnancy that is defined by the new onset of grand mal seizures on the basis of pre-eclampsia. Until now, the mechanisms underlying eclampsia were poorly understood. Brain edema is considered a leading cause of eclamptic seizures; aquaporins (AQP4 and AQP9), the glial water channel proteins mainly expressed in the nervous system, play an important role in brain edema. We studied AQP4 and AQP9 expression in the hippocampus of pre-eclamptic and eclamptic rats in order to explore the molecular mechanisms involved in brain edema. Using our previous animal models, we found several neuronal deaths in the hippocampal CA1 and CA3 regions after pre-eclampsia and that eclampsia induced more neuronal deaths in both areas by Nissl staining. In the current study, RT-PCR and Western blotting data showed significant upregulation of AQP4 and AQP9 mRNA and protein levels after eclamptic seizures in comparison to pre-eclampsia and at the same time AQP4 and AQP9 immunoreactivity also increased after eclampsia. These findings showed that eclamptic seizures induced cell death and that upregulation of AQP4 and AQP9 may play an important role in this pathophysiological process.

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“…The complex interplay of chronic and dynamic underlying mechanisms has made it difficult to develop therapies capable of treating the broad spectrum of behavioral deficits in epilepsy, and the data provided here suggest that direct CNS delivery of trophic molecules such as GDNF can, at least in part, fulfill this requirement. In fact, pilocarpine SE induces a progressive increase in seizure frequency as well as significant impairments in the normal exploratory behavior (Brandt et al, 2006;Tchekalarova et al, 2017; avoidance of open space) and in the ability of the rat to use learning and recognition memory capabilities (Ainge et al, 2007;Wood et al, 2000), and all these signs of disease are strongly attenuated by GDNF.…”

Section: Discussionmentioning

confidence: 99%

Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy

et al. 2019

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Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the desired brain region. We have developed an encapsulated cell technology that overcomes these obstacles by providing a targeted, continuous, de novo synthesized source of high levels of neurotrophic molecules from human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Here we illustrate the potential of this approach for delivering glial cell line-derived neurotrophic factor (GDNF) directly to the hippocampus of epileptic rats. In vivo studies demonstrated that bilateral intrahippocampal implants continued to secrete GDNF that produced high hippocampal GDNF tissue levels in a long-term manner. Identical implants robustly reduced seizure frequency in the pilocarpine model. Seizures were reduced rapidly, and this effect increased in magnitude over 3 months, ultimately leading to a reduction of seizures by 93%. This effect persisted even after device removal, suggesting potential disease-modifying benefits. Importantly, seizure reduction was associated with normalized changes in anxiety and improved cognitive performance. Immunohistochemical analyses revealed that the neurological benefits of GDNF were associated with the normalization of anatomical alterations accompanying chronic epilepsy, including hippocampal atrophy, cell degeneration, loss of parvalbumin-positive interneurons, and abnormal neurogenesis. These effects were associated with the activation of GDNF receptors. All in all, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner, paving the way for continuing preclinical evaluation and eventual clinical translation of this approach for epilepsy.Epilepsy is one of the most common neurological conditions, affecting millions of individuals of all ages. These patients experience debilitating seizures that frequently increase over time and can associate with significant cognitive decline and psychiatric disorders that are generally poorly controlled by pharmacotherapy. We have developed a clinically validated, implantable cell encapsulation system that delivers high and consistent levels of GDNF directly to the brain. In epileptic animals, this system produced a progressive and permanent reduction (Ͼ90%) in seizure frequency. These benefits were accompanied by improvements in cognitive and anxiolytic behavior and the normalization of changes in CNS anatomy that underlie chronic epilepsy. Together, these data suggest a novel means of tackling the frequently intractable neurological consequences of this devastating disorder.

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Agomelatine protects against neuronal damage without preventing epileptogenesis in the kainate model of temporal lobe epilepsy

Cited by 34 publications

References 61 publications

Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

Changes in the Expression of AQP4 and AQP9 in the Hippocampus Following Eclampsia-Like Seizure

Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy

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