Tiagabine suppresses pentylenetetrazole-induced seizures in mice and improves behavioral and cognitive parameters by modulating BDNF/TrkB expression and neuroinflammatory markers

  • Biomed Pharmacother. 2023 Apr:160:114406. doi: 10.1016/j.biopha.2023.114406.
Sana Javaid  1 ,  Faleh Alqahtani  2 ,  Waseem Ashraf  3 ,  Syed Muhammad Muneeb Anjum  4 ,  Muhammad Fawad Rasool  5 ,  Tanveer Ahmad  6 ,  Fawaz Alasmari  7 ,  Abdullah F Alasmari  7 ,  Saleh Abdullah Alqarni  7 ,  Imran Imran  8
Affiliations
  • 1. Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan; Department of Pharmacy, The Women University, Multan 60000, Pakistan.
  • 2. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia. Electronic address: [email protected].
  • 3. Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan.
  • 4. The Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore 75270, Pakistan.
  • 5. Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan.
  • 6. Institut pour l'Avancée des Biosciences, Centre de Recherche UGA / INSERM U1209 / CNRS 5309, Université Grenoble Alpes, France.
  • 7. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
  • 8. Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan 60800, Pakistan. Electronic address: [email protected].
PMID: 36791567 DOI: 10.1016/j.biopha.2023.114406
Abstract

Tiagabine (Tia), a new-generation antiseizure drug that mimics the GABAergic signaling by inhibiting GABA transporter type-1, is the least studied molecule in chronic epilepsy models with comorbid neurobehavioral and neuroinflammatory parameters. Therefore, the current study investigated the effects of Tia in a real-time manner on electroencephalographic (EEG) activity, behavioral manifestations and mRNA expression in pentylenetetrazole (PTZ)-kindled mice. Male BALB/c mice were treated with tiagabine (0.5, 1 and 2 mg/kg) for 21 days with simultaneous PTZ (40 mg/kg) injection every Other day for a total of 11 injections and monitored for seizure progression with synchronized validation through EEG recordings from cortical electrodes. The post-kindling protection from anxiety and memory deficit was verified by a battery of behavioral experiments. Isolated brains were evaluated for oxidative alterations and real-time changes in mRNA expression for BDNF/TrkB, GAT-1 and GAT-3 as well as neuroinflammatory markers. Experimental results revealed that Tia at the dose of 2 mg/kg maximally inhibited the development of full bloom seizure and reduced epileptic spike discharges from the cortex. Furthermore, Tia dose-dependently exerted the anxiolytic effects and protected from PTZ-evoked cognitive impairment. Tia reduced lipid peroxidation and increased superoxide dismutase and glutathione levels in the brain via augmentation of GABAergic modulation. PTZ-induced upregulated BDNF/TrkB signaling and pro-inflammatory cytokines were mitigated by Tia with upregulation of GAT-1 and GAT-3 transporters in whole brains. In conclusion, the observed effects of Tia might have resulted from reduced oxidative stress, BDNF/TrkB modulation and mitigated neuroinflammatory markers expression leading to reduced epileptogenesis and improved epilepsy-related neuropsychiatric effects.

Keywords
Anxiety; Electroencephalogram; Epilepsy; Pentylenetetrazole; Real-time PCR; Tiagabine.
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