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Djajalaksana, Susanthy
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Agriculture, Biological Sciences & Forestry Biochemistry, Genetics & Molecular Biology Chemical Engineering, Chemistry & Bioengineering Chemistry Computer Science & IT Dentistry Earth & Planetary Sciences Education Energy Engineering Environmental Science Health Professions Immunology & microbiology Materials Science & Nanotechnology Mathematics Medicine & Pharmacology Nursing Physics Public Health Other

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Journal : Journal of Multidisciplinary Applied Natural Science

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Furosemide Increases GABAA Receptor Activity via Antagonism to Sodium-Potassium-Chloride Cotransporter 1 In Silico and In Vivo Siregar, Marsintauli Hasudungan; Nurdiana, Nurdiana; Bal’afif, Farhad; Djajalaksana, Susanthy; Setiawansyah, Arif
Journal of Multidisciplinary Applied Natural Science Articles in Press
Publisher : Pandawa Institute

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.47352/jmans.2774-3047.365

Abstract

GABAA receptor dysfunction and altered chloride homeostasis significantly contribute to seizure pathophysiology, with the sodium-potassium-chloride cotransporter 1 (NKCC1) playing a crucial role in regulating neuronal excitability. This study investigated furosemide's capacity to enhance GABAA receptor activity through NKCC1 antagonism and evaluated its therapeutic profile in combination with diazepam for seizure management. Comprehensive molecular docking analyses were conducted to assess binding affinities of furosemide and diazepam to NKCC1, followed by in vivo experiments using pentylenetetrazol-induced seizure models to evaluate GABAA receptor expression, seizure duration, and multiple pathophysiological biomarkers. Molecular analysis revealed that furosemide demonstrated measurable NKCC1 binding capacity (binding energy: -7.09 kcal/mol; Ki: 6.34 µM), though significantly lower affinity compared to diazepam (binding energy: -7.83 kcal/mol; Ki: 1.81 µM). The furosemide-diazepam combination exhibited complex competitive binding interactions, with furosemide substantially reducing diazepam's NKCC1 binding affinity. NKCC1 antagonism by furosemide effectively enhanced GABAA receptor expression by 29.8 ± 1.60% when used alone and 37.60 ± 2.0% in combination with diazepam. However, combination therapies resulted in significantly longer seizure durations (80 ± 3.0 s) compared to diazepam monotherapy (42.5 ± 2.10 s), suggesting antagonistic interactions on acute seizure suppression that may reflect altered chloride gradients or competitive pharmacokinetic effects. Despite reduced efficacy in seizure termination, combination therapy demonstrated selective advantages in other pathophysiological domains, including superior blood-brain barrier protection (reduced albumin level to 90.90 ± 2.70 µg/mL) and reduced excitotoxic damage. These findings indicate that furosemide-diazepam combination therapy presents a complex therapeutic profile characterized by trade-offs between acute seizure control and neuroprotective mechanisms. The data suggest potential utility in maintenance therapy or prevention of seizure-related complications rather than acute seizure termination, warranting further investigation into temporal optimization strategies and dose modifications.
Co-Authors Afif, Zamroni Arif Setiawansyah Arinto Wardoyo Arinto Yudi Ponco Wardoyo Bal’afif, Farhad Bayuadi, Imam Cendani, Wulan Chen, Chung-Yu Chozin, Iin Chozin, Iin Noor Chozin, Iin Nur Christanto, Anthony Damanik, Gracelia Ruth Elisabeth Dani, Adinda Amalia Dewi Santosaningsih Dini, Zata Djajalakasana, Susanthy Djamaludin, Rahma Edwin Widodo Eka Pratiwi Eka Pratiwi Eko Sakti Pramukantoro, Eko Sakti Erawati, Dini Erawati, Dini Rachma Fahmi, Kristia Fajri, Abdul Malik Falyani , Silvy Falyani, Silvy Falyani, Silvy Amalia Febriawati, Juwita Fitri Sari, Fitri Harun Al Rasyid Indah Sari, Fitri Indrastuti Normahayu, Indrastuti Iqbal Muhammad Irfan, Ferdy Syah Isharanto, Artono Kevin Wahyudy Prasetyo Kristiani, Maria Kusuma Wardhana, Koernia Kusworini Handono Listyoko, Aditya Listyoko, Aditya Sri Lyono, Albert Mafisah, Saidah Mahendra, Reza Aditya Matabei, Shannon Conversia Pdabo Michaela, Cleine Muarif, Husnul Nanik Setijowati Nazliah, Fahnida Nggay, Andriana Adolf Nurdiana Nurdiana Okta, Shinta Permana, Deden Permatasari, Adinda Pramitra Prasetya, Fahmi Adhi Prasetyo, Kevin Pratiwi, Suryanti Pratiwi, Suryanti Dwi Priyono, Riski Irawan Putra Putra, Ngakan Putra, Ngakan Putu Parsama Rachma Erawati, Dini Rahman, Perdana Rakhma , Sastia Rakhma, Sastia Ramadhan, Fitratul Retnani, Diah Prabawati Safrina Dewi Ratnaningrum, Safrina Dewi santony, Santony Santosa, Andrew Santosa, I Setyawan, Ungky Setyawan, Ungky Agus Setyo Yudhanto, Hendy Simamora, Hustorio Aliongko Siregar, Marsintauli Hasudungan Sugiri, Yani Jane Sugiri, Yani Jane Rosihaningsih Suprapta, Aloysius Suryaman, Rachmat Susanti, Lia Suwandi, Gede Sasmika Tantular, Rezki Timuda, Caesar Ensang Tjahyadi, Rizal Muldani Tri Wahju Astuti, Tri Wahju triandani, Ni Komang Revina Triwahju Astuti Wahyu Tejakusuma, Wahyu Wardhana, Koernia Yaman, Muli Yudhanto, Hendy Yudhanto, Hendy Setyo Yusdianto, Adrian