CC BY-NC-ND 4.0 · Planta Medica International Open 2020; 07(04): e158-e169
DOI: 10.1055/a-1328-5093
Original Papers

The N-Methyl-(2S, 4R)-trans-4-hydroxy-L-proline-Enriched Methanol Fraction from Sideroxylon obtusifolium Shows an Anticonvulsant Activity Associated with its Anti-inflammatory/Antioxidant Actions

Pedro Everson Alexandre de Aquino
1   Laboratory of Neuropharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
Ítalo Rosal Lustosa
1   Laboratory of Neuropharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
Caren Nádia Soares de Sousa
1   Laboratory of Neuropharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
Adriano José Maia Chaves-Filho
1   Laboratory of Neuropharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
Francisco Arnaldo Viana Lima
1   Laboratory of Neuropharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
Alan Diego da Conceição Santos
2   Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Brazil
Nilce Viana Gramosa
2   Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Brazil
Edilberto Rocha Silveira
2   Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Brazil
Glauce Socorro de Barros Viana
1   Laboratory of Neuropharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
› Author Affiliations
Funding The authors are grateful for the financial support from the Brazilian National Research Council (CNPq), the Coordination for the Improvement of Higher Education Personnel (CAPES), and the Foundation for Support to the Scientific and Technologic Development of the State of Ceará (FUNCAP).


Epilepsy is a neurological disorder characterized by recurrent seizures, resulting from excessive neuronal discharges. Sideroxylon obtusifolium is used in Brazil for its anti-inflammatory/antioxidant properties, known to be involved with epilepsy. The anticonvulsant effects of the methanol fraction from S. obtusifolium leaves, rich in N-methyl-(2S,4R)-trans-4-hydroxy-L-proline, were investigated on pilocarpine- and pentylenetetrazole-induced convulsion models. Mice were pretreated with N-methyl-(2S,4R)-trans-4-hydroxy-L-proline (50, 100, 200 mg/kg, p.o.) and, 1 h later, by pilocarpine (400 mg/kg, i.p.) or pentylenetetrazole (80 mg/kg, i.p.). The animals were observed for latency to the first convulsion and latency to death. Immediately after death, brain areas from the pilocarpine groups were harvested for biochemical measurements. The latency to the first convulsion and latency to death increased after N-methyl-(2S,4R)-trans-4-hydroxy-L-proline treatment compared with the pilocarpine- or pentylenetetrazole-only groups. In both convulsion models, sodium valproate (reference drug) was used as a positive control. Additionally, the decreases in striatal dopamine and 3,4-dihydroxyphenylacetic acid contents observed in the pilocarpine-only group were partially prevented in the N-methyl-(2S,4R)-trans-4-hydroxy-L-proline-treated groups. While brain gamma-aminobutyric acid and glutamate contents decreased and increased, respectively, after pilocarpine only, these changes were also prevented by N-methyl-(2S,4R)-trans-4-hydroxy-L-proline. Similarly, N-methyl-(2S,4R)-trans-4-hydroxy-L-proline reduced the brain oxidative stress by decreasing the levels of nitrite and lipid peroxidation and increasing the glutathione content of the pilocarpine-only group. The increases in hippocampal expressions for interleukin 6, interferon-gamma, and glial fibrillary acidic protein, after pilocarpine only, were decreased to normal levels by N-methyl-(2S,4R)-trans-4-hydroxy-L-proline. In conclusion, the study showed significant anticonvulsant effects for N-methyl-(2S,4R)-trans-4-hydroxy-L-proline, probably related to its anti-inflammatory/antioxidant properties. N-Methyl-(2S,4R)-trans-4-hydroxy-L-proline effects were potentiated by VPA (sodium valproate), thus it may also interact with the GABAergic system, as we had recently shown.

Supplementary Material

Publication History

Received: 04 September 2020
Received: 26 October 2020

Accepted: 30 November 2020

Article published online:
19 January 2021

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