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A Ketogenic Diet may Improve Cognitive Function in Rats with Temporal Lobe Epilepsy by Regulating Endoplasmic Reticulum Stress and Synaptic Plasticity

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Abstract

A ketogenic diet (KD) is often used in the treatment of refractory epilepsy. Many studies have found that it also has a positive impact on cognitive comorbidities, but the specific mechanism remains unclear. In many disease models, endoplasmic reticulum stress (ERS) and synaptic plasticity is considered a new therapeutic target for improving cognitive impairment, and it has become a research focus in recent years. Recently, studies have found that a KD has a certain regulatory effect on both ERS and synaptic plasticity, but this result has not been confirmed in epilepsy. To investigate the effect of a KD on ERS and synaptic plasticity. In this study, a rat model of temporal lobe epilepsy (TLE) induced by lithium chloride–pilocarpine was used. After the model was successfully established, the rats in each group were fed a normal diet or a KD for 28 days, and the effect of a KD on the latency and seizure frequency of spontaneous recurrent seizures (SRSs) was observed via video monitoring. Subsequently, a Morris water maze was used to evaluate the spatial learning and memory abilities of the rats in each group; the ultrastructure of the ER and the synapses of the hippocampus were observed by transmission electron microscopy, and the dendritic spine density of the hippocampus was analysed by Golgi staining. Long-term potentiation (LTP) was used to detect the synaptic plasticity of the rats’ hippocampi, and the expression of ERS-related proteins and synapse-related proteins was detected by Western blotting. A KD effectively reduced the frequency of SRSs in rats with TLE and improved their learning and memory impairment. Further investigations found that a KD inhibited the up-regulation of glucose-regulated protein 78, phospho-protein kinase-like ER kinase, phosphorylated α subunit of eukaryotic initiation factor 2, activating transcription factor 4 and C/EBP homologous protein expression in the hippocampi of rats with TLE and protected the ultrastructure of the neuronal ER, suggesting that a KD suppressed excessive ERS induced by epilepsy. Concurrently, we also found that a KD not only improved the synaptic ultrastructure and increased the density of dendritic spines in rats with TLE but also reversed the epilepsy-induced LTP deficit to some extent. More importantly, the expression of postsynaptic density protein 95, synaptotagmin-1 and synaptosomal-associated protein 25 in the hippocampi of rats with epilepsy was significantly increased after KD intervention. The study findings indicate that a KD improves learning and memory impairment in rats with epilepsy, possibly by regulating ERS and synaptic plasticity.

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Data Availability

All data generated or analyzed during this study are included in this published article.

The data that support the findings of this study are available from the corresponding author, [Weiping Wang], upon reasonable request.

Abbreviations

Syp:

Synaptophysin

Syt 1:

Synaptotagmin 1

SNAP-25:

Synaptosome associated protein 25

PSD-95:

Postsynaptic density 95

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This work was supported by Project of Hebei Provincial Department of Health (20180310) and Natural Science Foundation of Hebei Province (H2018206435).

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  1. Key Laboratory of Neurology of Hebei Province, Department of Neurology, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, China

    Qi Qiao, Liqin Che, Qing Li, Zhenzhen Qu & Weiping Wang

  2. Department of Neurology, Shijiazhuang People’s Hospital, Shijiazhuang, 050000, China

    Shuang Tian

  3. Department of Neurology, Hebei General Hospital, Shijiazhuang, 050000, China

    Yuan Zhang

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All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

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Qiao, Q., Tian, S., Zhang, Y. et al. A Ketogenic Diet may Improve Cognitive Function in Rats with Temporal Lobe Epilepsy by Regulating Endoplasmic Reticulum Stress and Synaptic Plasticity. Mol Neurobiol 61, 2249–2264 (2024). https://doi.org/10.1007/s12035-023-03659-3

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