The antiepileptogenic effect of low-frequency stimulation on perforant path kindling involves changes in regulators of G-protein signaling in rat

Namvar, Simin; Fathollahi, Yaghoub; Javan, Mohammad; Zeraati, Maryam; Mohammad-Zadeh, Mohammad; Shojaei, Amir; Mirnajafi‐Zadeh, Javad

doi:10.1016/j.jns.2017.02.047

Cited by 13 publications

(6 citation statements)

References 65 publications

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“…Jensen, 2009; Goldberg and Coulter, 2013;Engel and Pitkanen, 2019) and therapeutic strategies for reducing the impact of epileptogenesis (Rowles and Olsen, 2012;Kaminski et al, 2014;Tchekalarova et al, 2014;Guo et al, 2015;Rensing et al, 2015;Siniscalchi and Mintzer, 2015;Castro et al, 2017;Long et al, 2017;Namvar et al, 2017;Talos et al, 2018;Upadhya et al, 2018Upadhya et al, , 2019, no pharmacological interventions are currently available to reduce or delay the progression of epileptogenesis. In the present study, we developed a rapid hippocampal kindling model to produce stable epileptogenesis ( Figure 1A) and demonstrated a resultant overexpression of GlyT1 and dysregulated DNA methylation in kindled rats.…”

Section: Discussionmentioning

confidence: 99%

“…Prevention of epileptogenesis remains an unmet medical challenge because underlying mechanisms involved in this process remain unclear (Pitkanen and Lukasiuk, 2011;Terrone et al, 2016). No effective treatment is currently available to prevent or delay the epileptogenic process while various therapeutic strategies were explored recently (Rowles and Olsen, 2012;Kaminski et al, 2014;Tchekalarova et al, 2014;Guo et al, 2015;Rensing et al, 2015;Siniscalchi and Mintzer, 2015;Castro et al, 2017;Long et al, 2017;Namvar et al, 2017;Talos et al, 2018;Upadhya et al, 2018Upadhya et al, , 2019. Epigenetic modification may play an important role in epileptogenesis (Hsieh and Gage, 2005;Kobow and Blumcke, 2012) and in particular global hypermethylation was identified in the epileptic hippocampus (Zhu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation

Shen

Weltha

Cook

et al. 2020

Front. Mol. Neurosci.

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Epileptogenesis is a common consequence of brain insults, however, the prevention or delay of the epileptogenic process remains an important unmet medical challenge. Overexpression of glycine transporter 1 (GlyT1) is proposed as a pathological hallmark in the hippocampus of patients with temporal lobe epilepsy (TLE), and we previously demonstrated in rodent epilepsy models that augmentation of glycine suppressed chronic seizures and altered acute seizure thresholds. In the present study we evaluated the effect of the GlyT1 inhibitor, sarcosine (aka N-methylglycine), on epileptogenesis and also investigated possible mechanisms. We developed a modified rapid kindling model of epileptogenesis in rats combined with seizure score monitoring to evaluate the antiepileptogenic effect of sarcosine. We used immunohistochemistry and Western blot analysis for the evaluation of GlyT1 expression and epigenetic changes of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in the epileptogenic hippocampi of rats, and further evaluated expression changes in enzymes involved in the regulation of DNA methylation, ten-eleven translocation methylcytosine dioxygenase 1 (TET1), DNA-methyltransferase 1 (DNMT1), and DNMT3a. Our results demonstrated: (i) experimental evidence that sarcosine (3 g/kg, i.p. daily) suppressed kindling epileptogenesis in rats; (ii) the sarcosine-induced antiepileptogenic effect was accompanied by a suppressed hippocampal GlyT1 expression as well as a reduction of hippocampal 5mC levels and a corresponding increase in 5hmC; and (iii) sarcosine treatment caused differential expression changes of TET1 and DNMTs. Together, these findings suggest that sarcosine has unprecedented disease-modifying properties in a kindling model of epileptogenesis in rats, which was associated with altered hippocampal DNA methylation. Thus, manipulation of the glycine system is a potential therapeutic approach to attenuate the development of epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation

Shen

Weltha

Cook

et al. 2020

Front. Mol. Neurosci.

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“…However, conflicting results have also been reported. Some report that there is an increase in the expression of AC or an increase in the level of cAMP in the epilepsy group [48][49][50]. e difference in these results can perhaps be attributed to the nature of the experimental model used, i.e., acute or chronic [23].…”

Section: Discussionmentioning

confidence: 99%

Effects of Huazhuo Jiedu Shugan Decoction on Cognitive and Emotional Disorders in a Rat Model of Epilepsy: Possible Involvement of AC-cAMP-CREB Signaling and NPY Expression

Xin

Qin

Liu

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Background. Huazhuo Jiedu Shugan decoction (HJSD), a traditional Chinese medicine (TCM), has been used to treat epileptic seizures for many years. Some ingredients in these herbs have been demonstrated to be effective for the treatment of brain damage caused by epilepsy. Aim of the Study. The object of the study is to determine the effects of HJSD on cognitive and emotional disorders in a rat model of epilepsy. Materials and Methods. After a predetermined time period, rats were intraperitoneally injected with pentylenetetrazol and observed in different phases of convulsions. The cognitive and emotional changes in the epileptic rats were assessed using behavioral and immunohistochemical tests. Results. Compared with the epilepsy group, the seizure grade was reduced and seizure latency was prolonged following HJSD-H treatment (P<0.01). Compared with the control group, the epilepsy group displayed marked worse performance on the animal behavior tests (P<0.05) and the HJSD-H group displayed improved behavioral performance (P<0.05). After HJSD-H treatment, the expression of adenylate cyclase (AC), cyclic adenosine monophosphate (cAMP), cAMP-response element binding protein (CREB), and neuropeptide Y (NPY) immunoreactive cells markedly increased in the hippocampus, compared with that of the epilepsy group (P<0.05). Conclusions. The current results demonstrate that HJSD treatment in epileptic rats markedly inhibits epileptic seizures and improves cognitive and emotional disorders, which may be related to the regulation of AC-cAMP-CREB signaling and NPY expression in the hippocampus. The effects of the HJSD treatment may provide a foundation for the use of HJSD as a prescription medicinal herb in the TCM for the treatment of epilepsy.

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“…Decrease and/or desynchronization of neuronal discharges may ensue to decrease neurotransmitter release and summation of excitatory postsynaptic potential, and consequently the relevant neural plasticity ( Shen et al, 2003 ; Kim et al, 2012 ; Guo et al, 2018 ; Chang, 2018 ). Low-frequency stimulation (LFS) (<20 Hz) has also been tested for the possibilities of minimization of tissue damage ( Weiss et al, 1995 ; Goodman et al, 2005 ; Wu et al, 2008 ; Kile et al, 2010 ; Jalilifar et al, 2017 ) and induction of long-lasting hyperpolarization, although the mechanistic rationales are even less clear ( Jahanshahi et al, 2009 ; Rashid et al, 2012 ; Ghotbedin et al, 2013 ; Namvar et al, 2017 ; Paschen et al, 2020 ). In addition to the uncertainties in the mechanism of action, the apparent efficacy of pulsatile DBS (either HFS or LFS) is highly variable as the ideal pulse protocol has remained to be settled ( Rajdev et al, 2011 ; Sobayo and Mogul, 2016 ; Zhang et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Anticonvulsant vs. Proconvulsant Effect of in situ Deep Brain Stimulation at the Epileptogenic Focus

Chou

Kuo

2021

Front. Syst. Neurosci.

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Since deep brain stimulation (DBS) at the epileptogenic focus (in situ) denotes long-term repetitive stimulation of the potentially epileptogenic structures, such as the amygdala, the hippocampus, and the cerebral cortex, a kindling effect and aggravation of seizures may happen and complicate the clinical condition. It is, thus, highly desirable to work out a protocol with an evident quenching (anticonvulsant) effect but free of concomitant proconvulsant side effects. We found that in the basolateral amygdala (BLA), an extremely wide range of pulsatile stimulation protocols eventually leads to the kindling effect. Only protocols with a pulse frequency of ≤1 Hz or a direct current (DC), with all of the other parameters unchanged, could never kindle the animal. On the other hand, the aforementioned DC stimulation (DCS), even a pulse as short as 10 s given 5 min before the kindling stimuli or a pulse given even to the contralateral BLA, is very effective against epileptogenicity and ictogenicity. Behavioral, electrophysiological, and histological findings consistently demonstrate success in seizure quenching or suppression as well as in the safety of the specific DBS protocol (e.g., no apparent brain damage by repeated sessions of stimulation applied to the BLA for 1 month). We conclude that in situ DCS, with a novel and rational design of the stimulation protocol composed of a very low (∼3% or 10 s/5 min) duty cycle and assuredly devoid of the potential of kindling, may make a successful antiepileptic therapy with adequate safety in terms of little epileptogenic adverse events and tissue damage.

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The antiepileptogenic effect of low-frequency stimulation on perforant path kindling involves changes in regulators of G-protein signaling in rat

Cited by 13 publications

References 65 publications

Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation

Sarcosine Suppresses Epileptogenesis in Rats With Effects on Hippocampal DNA Methylation

Effects of Huazhuo Jiedu Shugan Decoction on Cognitive and Emotional Disorders in a Rat Model of Epilepsy: Possible Involvement of AC-cAMP-CREB Signaling and NPY Expression

Anticonvulsant vs. Proconvulsant Effect of in situ Deep Brain Stimulation at the Epileptogenic Focus

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