Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 21, Issue 2, 2021

Suicides on railway tracks are one of the most drastic ones. No research concerning this phenomenon has been conducted to this date in Poland. This article focuses on the connection between suicidal behaviors on Polish railway tracks and sociodemographic traits and presents risk factors. Background: The Incidence of suicide is spread across many European countries. Of these, Poland ranks 22nd in terms of suicide attempts. This study aims to highlight the suicide attempts rates on Polish railways lines and their main risk factors. Limited available of statistical data before 2013. Methods: Statistical review of the available Central Police headquarters database and analyses of the influence of the risk factors on people’s awareness during the suicide attempts and their geographical distribution in Poland during the years 2013-2016. The prevalence of railway suicides in individual voivodeships (provinces) in Poland has been indicated in a 3D map. Results: There were 834 cases of railway suicide fatalities across the entire country. Of the total suicide statistics by any means, 3.75% are railway related. The average known age of those committing railway suicides were: 37.9 years for men (n = 627) and 34.6 for women (n = 155). In most cases, suicides were committed by bachelors (54.3%). The largest group of people who committed suicide had a primary level of education (42.0%). Among the suicides, a significant group are unemployed (45.2%). Alcohol intoxication was found established responsible for a person’s low awareness of his actions in 70.9% of cases. Almost 63.3% of people had a higher propensity for suicidal ideation and behavior, resulting in their being treated for mental health issues. Conclusion: Alcohol intoxication, illegal narcotics and psychotropic medication are responsible for a person’s lower awareness of his or her actions, in most of the cases of suicide on Polish railway lines.

Background: Motion sickness occurs worldwide in healthy individuals regardless of age, ethnicity, or gender. It is an acute disorder; it can also present as a chronic disorder in some individuals. Motion sickness not only includes vomiting and nausea, but also includes other features such as pallor of varying degrees, cold sweating, headache, drowsiness, increased salivation, and cranial pain, which are severe. Some of the other assessment scales can interpret sickness on exposure to virtual or visual stimulation and while travelling in different types of transport. Aim: The aim of our research is to study the effect of the drug on the level of blood flow and vascular reactivity of cerebral vessels when simulating changes in the cerebral circulation in terrestrial conditions characteristic of hypogravity. Methods: Chronic experiments were performed on non-anesthetized rabbits with large hemispheres, thalamus and hypothalamus were implanted with the needle-platinum electrodes 150 mm in diameter in the cortex, and local blood flow and vascular reactivity were recorded accordingly. Cerebrovascular disturbances were modeled using an MSAOP (motion sickness of animals in the anti-orthostatic position) with an inclined angle of 45° for 2 hours. Local blood flow (BF) was measured in ml/min/100g of tissue by the method of registration of hydrogen clearance. The vasodilator coefficient of reactivity (CrCO2) was calculated by the ratio of BF against the background of inhalation of a mixture of 7% CO2 with air to the initial BF; vasoconstrictor - in relation to BF on the background of inhalation of 100% O2 to the initial BF (CrO2). A series of experiments were carried out with different routes of drug administration: First, inosine was administered intravenously at a dose of 5 mg/kg immediately before the start of SMS modeling, same dose was administered 30 minutes before the start of exposure. As a control, we used the results of experimental animals under similar conditions without the administration of the drugs. Results: Inosine has pronounced protective properties in cerebrovascular disorders on the background of space motion sickness (SMS) modeling, which is manifested by normalization of BF and restoration of compensatory reactions of cerebral vessels. In the mechanism of cerebroprotective action of inosine, it is able to correct the metabolic processes, which play an important role and help increase the compensatory capabilities and functional stability of the cerebrovascular system under gravitational influences. Conclusion: When using inosine orally, the effects are more pronounced than when administered intravenously, which should be taken into account when using it for the prevention of cerebrovascular disorders in extreme conditions.

Background: Ascorbic acid (AA) is a water-soluble vitamin that is concentrated in the brain in large quantities. There have been reports that it is essential for proper brain functioning. However, there is insufficient information on the possible effects of dietary fortification with AA on the health of the brain. Objective: This study examined the effects of dietary fortification of rodent chow with AA on neurobehaviour, antioxidant status, lipid peroxidation, and inflammatory/apoptotic markers in the brain of healthy mice. Methods: Mice were randomly assigned into four groups of ten animals each. Groups were normal control [fed rodent chow], and three groups were fed AA-fortified chow at 100, 200, and 300 mg/kg of feed, respectively, for eight weeks. Behavioural tests {Open field, Y-maze, radial-arm maze, and elevated plus maze (EPM)} were carried out on day 57. Twenty-four hours after the last behavioural test, animals were euthanised, and the brains were excised and homogenised for assessment of brain acetylcholinesterase activity, lipid peroxidation, antioxidant status, inflammatory and apoptotic markers. Results: Ascorbic acid fortified diet was associated with concentration-dependent changes in body weight, open-field behaviours, working-memory, and anxiety indices. Also, brain levels of malondialdehyde, caspase-3, and TNF-α decreased, while superoxide dismutase activity, total antioxidant capacity, and IL-10 level increased. Conclusion: Dietary AA fortification with concentrations up to 300 mg/kg of feed was associated with sustained improvement in neurobehavioural and biochemical parameters in the brain of healthy mice, reiterating additional health benefits of AA fortification beyond the prevention of nutritional deficiencies.

Background: The ethnopharmacological relevance suggests that the ethnic minorities of India use leaves of Cissampelos pareira L. as a traditional medicine for curing various psychopharmacological disorders. Objective: To evaluate anti-depressant, anxiolytic, and muscle relaxant activity of hydro-alcoholic extract of Cissampelos pareira. Methods: Leaves of Cissampelos pareira were extracted using a hydro-alcoholic solvent. The safety of hydro-alcoholic extract of Cissampelos pareira was assessed by acute oral toxicity (OECD 423). The anti-depressant activity was measured using open field test, locomotor test, despair swim test, tail suspension test. The anxiolytic activity was assessed using elevated plus maze and hole board test, and skeletal muscle relaxant activity was assessed using rotarod, grip strength, chimney, and inclined plane test. Results: No moribund status or mortality was observed in experimental mice up to 2000 mg/kg dose of Cissampelos pareira hydro-alcoholic extract (CPHE). In the open field and actophotometer tests, CPHE 200 and 400 mg/kg treated mice significantly abridged ambulation, number of central squares crossed, total locomotion, and depicted less coordinated movements, and in despair swim and tail suspension tests, CPHE 400 mg/kg treated mice significantly decreased duration of immobility and increased number of climbing, confirming its anti-depressant effect. In an elevated plus-maze test, CPHE 200 and 400 mg/kg increased the open arm exploration, while in the hole board test, CPHE 400 mg/kg treated rats augmented the number of head dips, depicting its anxiolytic effect. In rotarod, grip strength, and inclined plane test, CPHE 400 mg/kg treated mice decreased the fall-off time on a rotating rod, suspended wire, or inclined plane. Furthermore, in the chimney test, treatment with CPHE 400 depicted less coordinated movements in mice; the mice of this group took more time to leave the cylinder, depicting its skeletal muscle relaxant effect. Conclusion: Based on the results, of this study, it can be concluded that CPHE 400 mg/kg exhibits strong anti-depressant, anxiolytic, and muscle relaxant effects, justifying its traditional uses.

Background: Epilepsy, the second most frequent neurological disease, is a chronic disorder with a high lifetime prevalence. Therefore, various studies are needed to find new effective therapeutic agents to treat seizures or prevent their complications. In this study, we investigated the effects of thiamine, melatonin and their combination on pentylenetetrazol (PTZ)-induced tonic-clonic seizures in mice. Methods: Male mice were randomly divided into six groups, including control, seizure control, diazepam, melatonin, thiamine and melatonin, and thiamine combination groups. Drugs were given orally in drinking water for 14 days. On the 15th day, the seizure was induced (except the control group) by intraperitoneal injection of PTZ. In all groups, the time between the injection and the start of the seizure (latency), and also the length of the seizure attack (duration), were measured in a 30-minute period. After measuring the latency and duration in all groups, mice were killed by CO2 Box and their brains were dissected to be analyzed for malondialdehyde (MDA) level as a marker of oxidative stress. Results: The seizure duration was significantly lower in the groups of melatonin, thiamine and thiamine and melatonin combination compared to the seizure control group. The latency times in these groups were significantly greater than in the seizure control group. Moreover, MDA concentrations were lower in these groups compared to the seizure control group. Conclusion: Thiamine, melatonin and their combination can decrease the duration time of seizure and increase the latency period, which may result from inhibition of oxidative stress in the brain.

Background: Benzothiazole is an organosulfur heterocyclic compound that has a considerable place in drug discovery due to significant pharmacological actions. Objective: The main objective of the present study was to synthesize some novel 2-(5-substituted 1,3,4-oxadiazole-2-yl)-1,3-benzothiazole derivatives and evaluate them for their anticonvulsant activity using in silico and in vivo methods. Methods: A set of sixteen 2-(5-substituted 1, 3, 4-oxadiazole-2-yl)-1, 3-benzothiazole derivatives were prepared using multi-step reactions starting from o-amino-thiophenol and characterized by suitable spectral techniques. The synthesized compounds were evaluated for anticonvulsant activity using in silico and in vivo methods. In silico molecular docking study was performed using Molegro Virtual Docker software to analyze binding modes of compounds with the internal ligand of PDB ID: 1OHY and 1OHV; and in vivo pharmacological activities were tested for both generalized tonic-clonic seizures and generalized absence (petit mal) seizures using Maximal Electrical Shock and PTZ-induced seizure models, respectively. Results: Some new 2-(5-substituted-1,3,4-oxadiazole-2-yl)-1,3- benzothiazole (5a-5p) were successfully synthesized by finally refluxing 1, 3-benzothiazole-2-carboxyhydrazide with different aromatic acids in phosphoryl chloride. Docking results showed that compounds 5c, 5j, and 5m were found to have the highest number of H-bond interactions; i.e. 4, 4, and 7 respectively with target proteins 1OHY and 6, 3, and 4 respectively with target protein 1OHV, whereas phenytoin showed only two H-bonding with both proteins. In the Maximal electroshock seizure method, the synthesized compounds 5h, 5k and 5o demonstrated potent anticonvulsant activity against the tonic seizure with a significant decrease in tonic hind leg extension period with a mean duration of 7.9, 7.4, and 7.0 sec respectively, as compared to the other synthesized compounds. In contrast, in the PTZ-induced seizure model, compounds 5c, 5h, and 5m showed protection against clonic convulsion with significant elevation in the onset time of clonic convulsion at 311.2, 308.0, and 333.11 sec, respectively. Conclusion: Thus, from the results, it can be concluded that compound 5h, a benzothiazole derivative endowed with an oxadiazole ring, can be developed as a potential anticonvulsant agent.

Background: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity. Aim: This study assessed the changes in the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20 mg/Kg/i.p.). Objective: To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats. Methods: Ten adult rats were randomly assigned into 2 groups: Control or CBD (20 mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure. Results: CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD- treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2. Conclusion: The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.

Background: Ischemic stroke is a serious public health problem. Despite extensive researches focusing on the area, little is known about novel treatments. Objective: In this study, we aimed to investigate the effects of Capparis spinosa (C. spinosa) extract in the middle cerebral artery occlusion (MCAO) model of ischemic stroke. Methods: Wistar rats underwent 30-min MCAO-induced brain ischemia followed by 24 h of reperfusion. C. spinose was administrated orally once a day for 7 days before the induction of MCAO. The neurologic outcome, infarct volume (TTC staining), histological examination, and markers of oxidative stress, including total thiol content, and malondialdehyde (MDA) levels, were measured 24hr. after the termination of MCAO. Results: Pretreatment with C. spinosa reduced neurological deficit score, histopathological alterations, and infarct volume in treated groups compared to the stroke group. Furthermore, pretreatment with C. spinosa extract significantly reduced the level of MDA with concomitant increases in the levels of thiol in the brain tissues compared to the stroke group. Conclusion: Our study demonstrates that C. spinosa extract effectively protects MCAO injury through the attenuation or the suppression of the oxidative stress.