Abstract
Epilepsy is a condition marked by sudden, self-sustained, and recurring brain events, showcasing unique electro-clinical and neuropathological phenomena that can alter the structure and functioning of the brain, resulting in diverse manifestations. Antiepileptic drugs (AEDs) can be very effective in 30% of patients in controlling seizures. Several factors contribute to this: drug resistance, individual variability, side effects, complexity of epilepsy, incomplete understanding, comorbidities, drug interactions, and no adherence to treatment. Therefore, research into new AEDs is important for several reasons such as improved efficacy, reduced side effects, expanded treatment options, treatment for drug-resistant epilepsy, improved safety profiles, targeted therapies, and innovation and progress. Animal models serve as crucial biological tools for comprehending neuronal damage and aiding in the discovery of more effective new AEDs. The utilization of antioxidant agents that act on the central nervous system may serve as a supplementary approach in the secondary prevention of epilepsy, both in laboratory animals and potentially in humans. Chlorogenic acid (CGA) is a significant compound, widely prevalent in numerous medicinal and food plants, exhibiting an extensive spectrum of biological activities such as neuroprotection, antioxidant, anti-inflammatory, and analgesic effects, among others. In this research, we assessed the neuroprotective effects of commercially available CGA in Wistar rats submitted to lithium-pilocarpine-induced status epilepticus (SE) model. After 72-h induction of SE, rats received thiopental and were treated for three consecutive days (1st, 2nd, and 3rd doses). Next, brains were collected and studied histologically for viable cells in the hippocampus with staining for cresyl-violet (Nissl staining) and for degenerating cells with Fluoro-Jade C (FJC) staining. Moreover, to evaluate oxidative stress, the presence of malondialdehyde (MDA) and superoxide dismutase (SOD) was quantified. Rats administered with CGA (30 mg/kg) demonstrated a significant decrease of 59% in the number of hippocampal cell loss in the CA3, and of 48% in the hilus layers after SE. A significant reduction of 75% in the cell loss in the CA3, shown by FJC+ staining, was also observed with the administration of CGA (30 mg/kg). Furthermore, significant decreases of 49% in MDA production and 72% in the activity of SOD were seen, when compared to animals subjected to SE that received vehicle. This study introduces a novel finding: the administration of CGA at a dosage of 30 mg/kg effectively reduced oxidative stress induced by lithium-pilocarpine, with its effects lasting until the peak of neural damage 72 h following the onset of SE. Overall, the research and development of new AEDs are essential for advancing epilepsy treatment, improving patient outcomes, and ultimately enhancing the quality of life for individuals living with epilepsy.
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Data availability
The data that supports the findings of this study are available upon request.
Abbreviations
- 6-OHDA:
-
6-Hydroxydopamine
- ANOVA:
-
Analysis of variance
- CGA:
-
Chlorogenic acid
- CQA:
-
4,5-di-O-[E]-Caffeoylquinic acid
- FJC:
-
Fluoro-Jade C
- FJC+:
-
Fluoro-Jade C positive
- ER:
-
Endoplasmic reticulum
- Li-Pilo:
-
Lithium-pilocarpine
- MDA:
-
Malondialdehyde
- NO:
-
Nitric oxide
- ROS:
-
Reactive oxygen species
- SE:
-
Status epilepticus
- SOD:
-
Superoxide dismutase
- SRS:
-
Spontaneous recurrent seizures
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Acknowledgements
We would like to acknowledge Dr. Javier Marín-Prida (Center for Research and Biological Evaluations (CEIEB), Institute of Pharmacy and Food, University of Havana Havana, Cuba) for his help with the oxidative stress protocols.
Funding
This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES–PROEX) to AJCG and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), both from Brazil.
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AJC-G wrote, and edited the first step of the manuscript, also contributed to data analysis tools; these data were part of his master’s thesis. JLL wrote, reviewed, and edited the manuscript, also contributed to data analysis tools. MVC contributed by doing the experiments and to data analysis tools. NPL conceived and designed the analysis, wrote the paper, and acquired funding. JLCL conceived and designed the analysis, and wrote the manuscript. LGN collected the data, and performed the analysis. ACKF conceived and designed the analysis, and wrote, reviewed, and edited the manuscript. WFS conceived and designed the analysis; wrote, reviewed, and edited the manuscript; and acquired funding. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.
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The experimental protocol was in accordance with and approved by the local Animal Care Committee (protocol number 08.1.834.53.9 CEUA–Campus University of São Paulo, Ribeirão Preto, Brazil).
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Carreño-González, A.J., Liberato, J.L., Celani, M.V.B. et al. Neuroprotective effects of chlorogenic acid against oxidative stress in rats subjected to lithium-pilocarpine-induced status epilepticus. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03080-0
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DOI: https://doi.org/10.1007/s00210-024-03080-0