Neuroprotective action of Cortexin, Cerebrolysin and Actovegin in acute or chronic brain ischemia in rats

• Published in: PloS one Vol. 16; no. 7; p. e0254493
• Main Authors: Kurkin, Denis V, Bakulin, Dmitry A, Morkovin, Evgeny I, Kalatanova, Anna V, Makarenko, Igor E, Dorotenko, Artem R, Kovalev, Nikolay S, Dubrovina, Marina A, Verkholyak, Dmitry V, Abrosimova, Elizaveta E, Smirnov, Alexey V, Shmidt, Maksim V, Tyurenkov, Ivan N
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.07.2021; Public Library of Science (PLoS)
• Subjects: Acute Disease; Amino Acids - pharmacology; Animal cognition; Animal models; Animals; Antioxidants; Binding; Biology and Life Sciences; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain damage; Brain injury; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Carotid artery; Cerebral blood flow; Cerebral ischemia; Chronic Disease; Cognitive ability; Complications and side effects; Conflicts of interest; Damage assessment; Disease Models, Animal; Drug therapy; Field tests; Glutamatergic transmission; Glutamic acid receptors; Glutamic acid receptors (metabotropic); Health aspects; Heme - analogs & derivatives; In vivo methods and tests; Infarction, Middle Cerebral Artery - drug therapy; Ischemia; Isoflavones - pharmacology; Isoflavones - therapeutic use; Kainic acid receptors; Lysine - analogs & derivatives; Lysine - pharmacology; Male; Medicine and Health Sciences; Membrane permeability; Mice; Necrosis; Neuroprotection; Neuroprotective agents; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Occlusion; Open-field behavior; Patient outcomes; Performance tests; Physical Sciences; Rats; Rats, Wistar; Rattus; Receptors; Sensorimotor system; Stenosis; Traumatic brain injury; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; γ-Aminobutyric acid; Russia
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0254493

This study was the first to compare the neuroprotective activity of Cerebrolysin®, Actovegin® and Cortexin® in rodent models of acute and chronic brain ischemia. The neuroprotective action was evaluated in animals with acute (middle cerebral artery occlusion) or chronic (common carotid artery stenosis) brain ischemia models in male rats. Cortexin® (1 or 3 mg/kg/day), Cerebrolysin® (538 or 1614 mg/kg/day) and Actovegin® (200 mg/kg/day) were administered for 10 days. To assess the neurological and motor impairments, open field test, adhesive removal test, rotarod performance test and Morris water maze test were performed. Brain damage was assessed macro- and microscopically, and antioxidant system activity was measured in brain homogenates. In separate experiments in vitro binding of Cortexin® to a wide panel of receptors was assessed, and blood-brain barrier permeability of Cortexin® was assessed in mice in vivo. Cortexin® or Cerebrolysin® and, to a lesser extent, Actovegin® improved the recovery of neurological functions, reduced the severity of sensorimotor and cognitive impairments in rats. Cortexin® reduced the size of necrosis of brain tissue in acute ischemia, improved functioning of the antioxidant system and prevented the development of severe neurodegenerative changes in chronic ischemia model. Radioactively labeled Cortexin® crossed the blood-brain barrier in mice in vivo with concentrations equal to 6-8% of concentrations found in whole blood. During in vitro binding assay Cortexin® (10 μg/ml) demonstrated high or moderate binding to AMPA-receptors (80.1%), kainate receptors (73.5%), mGluR1 (49.0%), GABAA1 (44.0%) and mGluR5 (39.7%), which means that effects observed in vivo could be related on the glutamatergic and GABAergic actions of Cortexin®. Thus, Cortexin, 1 or 3 mg/kg, or Cerebrolysin®, 538 or 1614 mg/kg, were effective in models acute and chronic brain ischemia in rats. Cortexin® contains compounds acting on AMPA, kainate, mGluR1, GABAA1 and mGluR5 receptors in vitro, and readily crosses the blood-brain barrier in mice.