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4-Phenylbutyric Acid Plus Valproic Acid Exhibits the Therapeutic and Neuroprotective Effects in Acute Seizures Induced by Pentylenetetrazole

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Abstract

Endoplasmic reticulum (ER) stress and apoptosis are implicated in the pathogenesis of epilepsy. Here we examine the effects of valproic acid (VA) plus 4-phenylbutyric acid (4-PBA) on abnormal electrical brain activity, ER stress and apoptosis in acute seizures induced by pentylenetetrazole (PTZ). Forty male rats were randomly divided into five groups, each consisting of 8 rats as follows: Sham, PTZ, VA+PTZ, 4-PBA+PTZ, and VA plus 4-PBA+PTZ. The treated groups received VA, 4-PBA and VA plus 4-PBA by intraperitoneal application for 7 days prior to PTZ-induced seizure. On the 8th day, acute epileptic seizures were induced by PTZ (50 mg/kg, i.p.) injection, except for the sham group. Then, the seizure stage was observed and ECoG activities were recorded during the 30 min. At 24th post seizures, the hippocampus and blood samples were collected for biochemical and histopathological examinations. Administration of VA plus 4-PBA prior to PTZ-induced seizures significantly decreased seizure stage, the duration of generalized tonic–clonic seizure and the total number of spikes as increased the latency to the first myoclonic jerk when compared to the PTZ group. 4-PBA suppressed the increased levels of ER stress markers GRP78 and CHOP in the hippocampus. VA plus 4-PBA treatment before seizures significantly inhibited PTZ-induced elevations of apoptosis-related indicators caspase-3 and caspase-12, and significantly reduced the number of histopathological lesions of the hippocampus region at 24th post seizures. These findings suggest that administration of VA plus 4-PBA prior to PTZ-induced seizures may be involved in the neuroprotective potential of these agents for seizures.

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Acknowledgements

We are grateful to PYO office of Ondokuz Mayıs University for the financial support.

Funding

The research project was supported by Ondokuz Mayıs University, the project code: pyo.tip.1904.19.019.

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Authors and Affiliations

  1. Department of Medical Biochemistry, Faculty of Medicine, Ondokuz Mayıs University, Atakum, 55139, Samsun, Turkey

    Emil Rzayev & Ramazan Amanvermez

  2. Department of Medical Pathology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey

    Seda Gün

  3. Department of Physiology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey

    Emre S. Tiryaki & Gökhan Arslan

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  1. Emil Rzayev
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All authors contributed equally to data preparation, reviewing, editing and revision of the manuscript.

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Correspondence to Ramazan Amanvermez.

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Research with animals was approved by the local ethics committees of the Ondokuz Mayıs University, ethics code: 47/2018.

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Rzayev, E., Amanvermez, R., Gün, S. et al. 4-Phenylbutyric Acid Plus Valproic Acid Exhibits the Therapeutic and Neuroprotective Effects in Acute Seizures Induced by Pentylenetetrazole. Neurochem Res 47, 3104–3113 (2022). https://doi.org/10.1007/s11064-022-03662-5

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