Effects of a compound from the group of substituted thiadiazines with hypothermia inducing properties on brain metabolism in rats, a study in vivo and in vitro

Abstract

The aim of the present study was to examine how administration of a compound of 1,3,4- thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17) with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/kg and 760 mg/kg). Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 μM, 30 min). Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5°C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism.

Immunomodulatory Action of Substituted 1,3,4-Thiadiazines on the Course of Myocardial Infarction

“…Thus, it was found that several chemical compounds of the group of substituted thiadiazines possessed the attributes of atypical antipsychotics, having a significant effect on the behavior of animals and the course of the stress reaction [ 54 , 88 ]. Concurrently, this class of compounds had an exceptional breadth on the biological activity spectrum [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. Such pleiotropic actions served as the basis for the search for a single mechanism capable of influencing both the course of the inflammatory process and the stress reaction.…”

“…Some of the compounds are able to inhibit the non-enzymatic glycosylation of proteins in experiments in vitro [ 51 ] and to cause hypothermia in experiments in vivo [ 52 ]. Several substituted 1,3,4-thiadiazines were provided as anaesthetic, cardiovascular and hypometabolic agents [ 53 ].…”

“…In the PubMed and ScienceDirect search engines, no publications were published on the activity of 1,3,4-thiadiazines in myocardial infarction, other than those referenced in this review [ 48 , 49 , 50 , 51 , 52 , 53 , 54 ] (search query “thiadiazine myocardial infarction”).…”

“…Promising activities were those for which the calculated probability of having activity Pa was ≥0.1 and the likelihood ratio between Pa/Pi was ≥1.0, where Pi was the calculated probability of lack of activity. Taking into account the high ability of compound L-17 to penetrate the BBB and the results of its pharmacological evaluation [ 52 ], the following activities were identified for further targeted analysis: general anesthetic (Pa = 0.413, Pa/Pi = 304.33), anesthetic (Pa = 0.464, Pa/Pi = 35.69), cognition disorders treatment (Pa = 0.489, Pa/Pi = 27.17), anti-inflammatory (Pa = 0.625, Pa/Pi = 23.15), phobic disorders treatment (Pa = 0.703, Pa/Pi = 9.37), psychotropic (Pa = 0.258, P /Pi = 1.74), immunostimulant (Pa = 0.191, Pa/Pi = 1.39), antinociceptive (Pa = 0.271, Pa/Pi = 1.32), cardiovascular analeptic (Pa = 0.170, Pa/Pi = 1.21), antidepressant (Pa = 0.162, Pa/Pi = 1.14).…”

“…The prediction of the presence/absence of the linked target activities was performed during the third stage of the in silico study, for the aforementioned target systemic types of pharmacological activity, using the PharmaExpert 10.1 program [ 57 ]. According to joint predictive evaluations in PASS, PharmaExpert and experimental data [ 52 ], the most likely targeted activities corresponding to the systemic pharmacological effects of compound L-17 were found: 5-hydroxytryptamine 3 receptor antagonist (Pa = 0.139, Pa/Pi = 1.17), 5-hydroxytryptamine release inhibitor (Pa = 0.225, Pa/Pi = 1.01), acetylcholine agonist (Pa = 0.154, Pa/Pi = 7.00), benzodiazepine agonist (Pa = 0.141, Pa/Pi = 5.64), benzodiazepine omega receptor agonist (Pa = 0.385, Pa/Pi = 2.89), calpain inhibitor (Pa = 0.375, Pa/Pi = 19.74), cholinergic (Pa = 0.153, Pa/Pi = 3.26), complement factor D inhibitor (Pa = 0.430, Pa/Pi = 4.06), GABA B receptor agonist (Pa = 0.163, Pa/Pi = 1.46), GABA receptor agonist (Pa = 0.257, Pa/Pi = 6.27), glutamate release inhibitor (Pa = 0.113, Pa/Pi = 1.53), Janus tyrosine kinase inhibitor (Pa = 0.193, Pa/Pi = 6.43), Neurotransmitter uptake inhibitor (Pa = 0.470, Pa/Pi = 6.35). A separate analysis in the PASS program revealed that the L-17 compound practically did not act on the glutamatergic system (for glutamate, AMPA, NMDA and kainate receptors).…”