A Proline Derivative-Enriched Fraction from <i>Sideroxylon obtusifolium</i> Protects the Hippocampus from Intracerebroventricular Pilocarpine-Induced Injury Associated with <i>Status Epilepticus</i> in Mice

Abstract

The N-methyl-(2S,4R)-trans-4-hydroxy-l-proline-enriched fraction (NMP) from Sideroxylon obtusifolium was evaluated as a neuroprotective agent in the intracerebroventricular (icv) pilocarpine (Pilo) model. To this aim, male mice were subdivided into sham (SO, vehicle), Pilo (300 µg/1 µL icv, followed by the vehicle per os, po) and NMP-treated groups (Pilo 300 µg/1 µL icv, followed by 100 or 200 mg/kg po). The treatments started one day after the Pilo injection and continued for 15 days. The effects of NMP were assessed by characterizing the preservation of cognitive function in both the Y-maze and object recognition tests. The hippocampal cell viability was evaluated by Nissl staining. Additional markers of damage were studied—the glial fibrillary acidic protein (GFAP) and the ionized calcium-binding adaptor molecule 1 (Iba-1) expression using, respectively, immunofluorescence and western blot analyses. We also performed molecular docking experiments revealing that NMP binds to the γ-aminobutyric acid (GABA) transporter 1 (GAT1). GAT1 expression in the hippocampus was also characterized. Pilo induced cognitive deficits, cell damage, increased GFAP, Iba-1, and GAT1 expression in the hippocampus. These alterations were prevented, especially by the higher NMP dose. These data highlight NMP as a promising candidate for the protection of the hippocampus, as shown by the icv Pilo model.

Keywords

• mesial temporal lobe epilepsy
• pilocarpine
• GABA transporter 1
• glial fibrillary acidic protein
• ionized calcium-binding adaptor molecule 1
• l-proline%22%2C%22default_operator%22%3A%22AND%22%7D%7D%7D"> <i>N</i>-methyl-(2S,4R)-trans-4-hydroxy-<span style="font-variant: small-caps">l</span>-proline