Ameliorative Potential of (-) Pseudosemiglabrin in Mice with Pilocarpine-Induced Epilepsy: Antioxidant, Anti-Inflammatory, Anti-Apoptotic, and Neurotransmission Modulation

• Published in: International journal of molecular sciences 2023-06, Vol.24 (13), p.10773
• Main Authors: Balaha, Mohamed F, Alamer, Ahmed A, Abdel-Kader, Maged S, Alharthy, Khalid M
• Format: Article
• Language: English
• Subjects: (-) pseudosemiglabrin; 1-Phosphatidylinositol 3-kinase; 4-Aminobutyrate transaminase; AKT protein; Anesthesia; Animals; Anti-Inflammatory Agents - adverse effects; Anti-inflammatory drugs; Antioxidants; Antioxidants - adverse effects; Apoptosis; B cells; Bcl-2 protein; bcl-2-Associated X Protein; Benzodiazepines; Caspase-3; Convulsions; Convulsions & seizures; Cytokines; Diazepam; Drug dosages; Epilepsy; Epilepsy - chemically induced; Epilepsy - drug therapy; GABA; GABAergic and glutamatergic neurotransmission; Gene expression; Glutamate; Glutamate decarboxylase; Glutamatergic transmission; Health aspects; Inflammation; Kinases; Mice; Mortality; Neuromodulation; Neurotransmission; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-κB protein; Nrf2/HO-1 pathway; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt pathway; Pilocarpine; Pilocarpine - adverse effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA; RNA, Messenger; Synaptic Transmission; TLR-4/NF-κB pathway; Toll-Like Receptor 4 - genetics; Transaminase; Tumor necrosis factor-TNF; Tumor necrosis factor-α; γ-Aminobutyric acid
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241310773

One prevalent neurological disorder is epilepsy. Modulating GABAergic/glutamatergic neurotransmission, Nrf2/HO-1, PI3K/Akt, and TLR-4/NF-B pathways might be a therapeutic strategy for epilepsy. Eight-week-old BALB/c mice were administered 12.5, 25, or 50 mg/kg (-) pseudosemiglabrin orally one hour before inducing epilepsy with an i.p. injection of 360 mg/kg pilocarpine. (-) Pseudosemiglabrin dose-dependently alleviated pilocarpine-induced epilepsy, as revealed by the complete repression of pilocarpine-induced convulsions and 100% survival rate in mice. Furthermore, (-) pseudosemiglabrin significantly enhanced mice's locomotor activities, brain GABA, SLC1A2, GABARα1 levels, glutamate decarboxylase activity, and SLC1A2 and GABARα1mRNA expression while decreasing brain glutamate, SLC6A1, GRIN1 levels, GABA transaminase activity, and SLC6A1 and GRIN1 mRNA expression. These potentials can be due to the suppression of the TLR-4/NF-κB and the enhancement of the Nrf2/HO-1 and PI3K/Akt pathways, as demonstrated by the reduction in TLR-4, NF-κB, IL-1β, TNF-α mRNA expression, MDA, NO, caspase-3, Bax levels, and Bax/Bcl-2 ratio, and the enhancement of Nrf2, HO-1, PI3K, Akt mRNA expression, GSH, Bcl-2 levels, and SOD activity. Additionally, (-) pseudosemiglabrin abrogated the pilocarpine-induced histopathological changes. Interestingly, the (-) pseudosemiglabrin intervention showed a comparable effect to the standard medication, diazepam. Therefore, (-) pseudosemiglabrin can be a promising medication for the management of epilepsy.