Changes in synaptic proteins of the complex PSD-95/NMDA receptor/nNOS and mitochondrial dysfunction after levocabastine treatment

• Published in: Neurochemistry international Vol. 148; p. 105100
• Main Authors: Lores-Arnaiz, Silvia, Karadayian, Analía G., Gutnisky, Alicia, Miranda, Jennifer, Rodríguez de Lores Arnaiz, Georgina
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2021
• Subjects: Adenosine Triphosphate - biosynthesis; Animals; Disks Large Homolog 4 Protein - metabolism; Histamine H1 Antagonists - pharmacology; Levocabastine; Male; Membrane Potential, Mitochondrial - drug effects; Mitochondrial function; Mitochondrial Membranes - drug effects; Neurotensin receptor NTS2; Nitric Oxide Synthase Type II - drug effects; Nitric Oxide Synthase Type II - metabolism; NMDA receptor; Oxygen Consumption - drug effects; Piperidines - pharmacology; PSD-95; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Synapses - drug effects; Synapses - metabolism; Synaptosomal membranes; Synaptosomes - drug effects; Neurotensin receptor NTS2; Synaptosomal membranes; Levocabastine; PSD-95; NMDA receptor; Mitochondrial function
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2021.105100

Nitric oxide generation is related to the activity of certain proteins located at synaptic sites. Previous findings show that NOS activity, nNOS protein expression, respiratory parameters and mitochondrial complex activities are altered in rat cerebral cortex by administration of levocabastine, an antagonist of histamine H1 and neurotensin NTS2 receptors. ATP provision by mitochondria may play an important role in the functional interaction between synaptic proteins NMDA receptor and PSD-95 with NO synthesis. In this context, our purpose was to evaluate the effect of levocabastine administration on protein expression of PSD-95, GluN2B and iNOS, as well as on mitochondrial ATP production. Male Wistar rats received a single (i.p.) dose of levocabastine (50 μg/kg) or saline solution (controls) and were decapitated 18 h later. Mitochondrial and synaptosomal membrane fractions were isolated from cerebral cortex by differential and sucrose gradient centrifugation. Expression of synaptic proteins was evaluated by Western blot assays in synaptosomal membrane fractions. Oxygen consumption, mitochondrial membrane potential and ATP production rate were determined in fresh crude mitochondrial fractions. After levocabastine treatment, protein expression of PSD-95, GluN2B and β-actin decreased 97, 45 and 55%, respectively, whereas that of iNOS enhanced 3.5-fold versus controls. In crude mitochondrial fractions levocabastine administration reduced roughly 15% respiratory control rate as assayed with malate-glutamate or succinate as substrates, decreased mitochondrial membrane potential (21%), and ATP production rates (57%). Results suggested that levocabastine administration induces alterations in synaptic proteins of the protein complex PSD-95/NMDA receptor/nNOS and in neuron cytoskeleton. Mitochondrial bioenergetics impairment may play a role in the functional link between synaptic proteins and NO synthesis.
•Levocabastine alters synaptic proteins and mitochondrial function.•Protein expression of PSD-95, GluN2B and β-actin are decreased by levocabastine.•Levocabastine affects mitochondrial membrane potential and ATP production.•Mitochondrial function is altered by levocabastine both ex vivo and in vitro•Mitochondrial bioenergetics impairment may be associated with decreased NO synthesis.