sm-346 and Disease-Models--Animal

Anti-ischemic activity of fabomotizole hydrochloride was studied on the model of subendocardial ischemia in rats with endothelial dysfunction. Endothelial dysfunction was modeled by intragastric administration of methionine (3 g/kg, once a day for 7 days). Acute subendocardial ischemia was induced in narcotized rats by intraperitoneal injection of isoproterenol (20 μg/kg/min over 5 min). Fabomotizole hydrochloride (intraperitoneally, 15 mg/kg) significantly reduced isoproterenol-induced ST segment depression in animals with endothelial dysfunction and with intact vasculature.

Topics: Animals; Animals, Outbred Strains; Benzimidazoles; Cardiotonic Agents; Disease Models, Animal; Endocardium; Endothelium, Vascular; Isoproterenol; Male; Methionine; Morpholines; Myocardial Ischemia; Rats; Treatment Outcome

Parkinson's disease (PD) is a progressive neurodegenerative disease with limited treatment options. Therefore, the identification of therapeutic targets is urgently needed. Previous studies have shown that the ligand activation of the sigma-1 chaperone (Sigma1R) promotes neuroprotection. The multitarget drug afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was shown to interact with Sigma1Rs and prevent decreases in striatal dopamine in the 6-hydroxydopamine (6-OHDA)-induced parkinsonism model. The aim of the present study was to elucidate the role of Sigma1Rs in afobazole pharmacological activity. Using ICR mice we found that administration of afobazole (2.5 mg/kg, i.p.) or selective agonist of Sigma1R PRE-084 (1.0 mg/kg, i.p.) over 14 days normalizes motor disfunction and prevents decreases in dopamine in the 6-OHDA-lesioned striatum. Afobazole administration also prevents the loss of TH + neurons in the substantia nigra. The pre-administration of selective Sigma1R antagonist BD-1047 (3.0 mg/kg, i.p.) abolishes the activity of either afobazole or PRE-084, as determined using the rotarod test and the analysis of striatal dopamine content. The current study demonstrates the contribution of Sigma1Rs in the neuroprotective effect of afobazole in the 6-OHDA model of Parkinson's disease and defines the therapeutic perspective of Sigma1R agonists in the clinic.

Topics: Animals; Benzimidazoles; Corpus Striatum; Disease Models, Animal; Dopamine; Ethylenediamines; Male; Mice; Mice, Inbred ICR; Morpholines; Neurons; Neuroprotection; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Receptors, sigma; Rotarod Performance Test; Sigma-1 Receptor; Substantia Nigra

Afobazole (10 mg/kg) alleviated cognitive rigidity in BALB/c mice, a phenotypic model of autism spectrum disorders. It improved spatial memory and retraining in T-maze with drinking reinforcement and restored the retrieval of acquired skill during reversal learning in Morris water maze.

Topics: Adaptation, Psychological; Animals; Anti-Anxiety Agents; Autism Spectrum Disorder; Benzimidazoles; Cognition; Disease Models, Animal; Male; Maze Learning; Mice; Mice, Inbred BALB C; Morpholines; Psychological Distress; Spatial Memory

The study of novel selective anxiolytic afobazol on rats with experimental intracerebral post-traumatic hematoma (cerebral hemorrhage) demonstrated its efficiency in a dose of 5 mg/kg applied by a single or repeated administration for 2 weeks. The preparation significantly decreased the incidence of neurological disturbances in most rats (pareses, paralyses, convulsive movements, lateral posture). The therapeutic course of afobazol improved survival rate. Afobazol improved learning and memory in rats with cerebral hemorrhage in the conditioned passive avoidance test and positively affected motor activity in the open field test, which was documented by significant increase in total motor activity indices. The effects of afobazol were more pronounced after course treatment.

Topics: Animals; Benzimidazoles; Cerebral Hemorrhage; Disease Models, Animal; Hematoma; Learning; Male; Memory; Morpholines; Neuroprotective Agents; Rats; Time Factors

Topics: Adult; Animals; Anti-Anxiety Agents; Benzimidazoles; Benzodiazepines; Dipeptides; Disease Models, Animal; Drug Therapy, Combination; Humans; Hypnotics and Sedatives; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Morpholines; Personality; Rats; Rats, Inbred Strains; Stress, Psychological; Tranquilizing Agents