Central nervous system agents in medicinal chemistry最新文献

Background: Cannabis and its extracts are now being explored due to their huge health benefits. Although, the effect they elicit, whether on humans or rodents, may vary based on the age of the animal/subject and or the time in which the extract is administered. However, several debates exist concerning the various medical applications of these compounds. Nonetheless, their applicability as therapeutics should not be clouded based on their perceived negative biological actions.

Methods: Articles from reliable databases such as Science Direct, PubMed, Google Scholar, Scopus, and Ovid were searched. Specific search methods were employed using multiple keywords: ''Medicinal Cannabis; endocannabinoid system; cannabinoids receptors; cannabinoids and cognition; brain disorders; neurodegenerative diseases''. For the inclusion/exclusion criteria, only relevant articles related to medicinal Cannabis and its various compounds were considered.

Results: The current review highlights the role, effects, and involvement of Cannabis, cannabinoids, and endocannabinoids in preventing selected neurodegenerative diseases and possible amelioration of cognitive impairments. Furthermore, it also focuses on Cannabis utilization in many disease conditions such as Alzheimer's and Parkinson's disease among others.

Conclusion: In conclusion, the usage of Cannabis should be further explored as accumulating evidence suggests that it could be effective and somewhat safe, especially when adhered to the recommended dosage. Furthermore, in-depth studies should be conducted in order to unravel the specific mechanism underpinning the involvement of cannabinoids at the cellular level and their therapeutic applications.

Background: Puberty is a developmental transition in which an estrogenic surge occurs, mediating the release of xenoestrogens, like aluminium. Aluminium's effect on anxiety in rodents at the different developmental stages is inconsistent.

Aims: This study aimed at investigating the effect of the metalloestrogenic property of aluminium on anxiety-like behavioral changes in prepubertal and young adult female rats.

Objective: Considering this aim, our objective was to evaluate the anxiety-like behavior by the elevated plus maze in prepubertal and young adult female rats with or without acute exposure to aluminium.

Methods: To address this property of aluminium, 5mg/Kg body weight (Al-5) and 10 mg/Kg body weight (Al-10) of aluminium was administered intraperitoneally to female rats at two developmental stages, prepubertal (PP; n = 8 for each dose) and young adult (YA; n = 6 for each dose) for two weeks. Post-treatment, three days behavioral assessment of the rats was done employing elevated plus maze.

Results: Reduced escape latency was seen in Al-5, Al-10 pre-pubertal rats, and Al-5 young-adult rats on day 3. A significant reduction in open arm time was seen in the Al-5 young-adult rats. Aluminium treatment in the pre-pubertal rats reduced their head dipping and grooming. Reduced sniffing, head dipping, and stretch-attended posture in the treated young-adult female rats showed that they had impaired risk-taking tendency.

Conclusion: Differential effect on the anxiety-like behavior in the pre-pubertal and young-adult female rats might be due to the metalloestrogenic property of aluminium, acting differently on the two age groups.

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.

Aim: The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders.

Background: Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders.

Objectives: The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database.

Methods: Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound.

Results: Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone.

Conclusion: Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.

Background: Existing neuroprotective drugs are not effective enough to treat alcoholic encephalopathy. This makes the development of novel pharmacological approaches to treating patients with ethanol-induced neurodegeneration(EIN) relevant. Therefore, the search for new targets among intracellular signaling molecules of regeneration-competent cells of nervous tissue is promising.

Objective: This study aims to explore the involvement of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the realization of the functions of nervous tissue progenitors and glial cells in EIN.

Methods: Experiments were conducted on mice of C57B1/6. EIN was modeled in vitro and in vivo. The effects of the adenylate cyclase (AC) and PKA inhibitors on the colony-forming capacity of neural stem cells (NSC) and neuronal-committed progenitors (NCP), their proliferative activity, and intensity of specialization were investigated. The secretion of neurotrophins by astrocytes, oligodendrocytes, and microglial cells was also evaluated. Individual fractions of cells were obtained using the immunomagnetic separation method.

Results: The cAMP/PKA signaling is shown to stimulate the proliferation of the NSC and inhibit the mitotic activity of the NCP under the conditions of their optimal vital activity. cAMP reduces the specialization intensity of both types of progenitors. EIN leads to the inversion of the role of the cAMP/PKA-pathway in the regulation of NSC functions. cAMP-pathway has varying influences on the secretion of neurotrophic growth factors by glial cells depending on their living conditions. AC blockage stimulates the realization of the NSC and NCP growth potential and production of neurotrophins by astrocytes and microglial cells in EIN.

Conclusion: These findings show the potential for the use of AC inhibitors as novel effective drugs for the therapy of alcoholic encephalopathy.

Background: Phenytoin (5,5-diphenyl hydantoin) has poor water solubility, which results in incomplete oral availability. Other problems associated with the oral and intramuscular administration of phenytoin are gastric irritation and inflammation at the site of injection.

Objective: The purpose of this study was to synthesize mutual amide prodrugs of phenytoin by using amino acids like glycine, L-tryptophan, L-lysine and taurine.

Methods: These prodrugs were synthesized and characterized by Fourier Transform Infrared (FTIR), Proton nuclear magnetic resonance (1H NMR) and Mass Spectra. Physical and spectral characterization was performed by determination of solubility, maximum wavelength, partition coefficient (log P), ionization constant (pKa), specific (α) and molar rotation (μ), refractive index (n), specific refraction (RS) and molar refraction (RM).

Results: The results obtained from solubility and log P values determination indicated that phenytoin prodrugs can be administered by oral as well as a parenteral route by minimizing the limitations associated with phenytoin. Anticonvulsant activity of prodrugs (4a-4d) was evaluated by using maximal electroshock (MES) and strychnine induced seizure test on albino mice of either sex weighing 25-30 g in which 4b and 4d were found to have significant anticonvulsant activity for MES and strychnine induced seizure test. In vitro enzymatic hydrolysis study of 4b and 4d was performed on liver, intestinal mucosa and plasma sample of male Sprague Dawley rats weighing 280-300 g in which phenytoin was eluted at 10.13 to 10.68 minutes at 220 nm.

Conclusion: The results obtained from the present work showed that amino acid-based mutual prodrug strategy can be a promising method to increase the solubility and anticonvulsant activity of phenytoin for the development of anticonvulsant agents.

Background: The effect of folic acid in mitigating depression has remained pivotal in research.

Objective: To determine the effects of folate supplementation on neurobehaviour oxidative stress and cerebral cortex histomorphology in the dexamethasone mouse model of depression.

Methods: Male mice were assigned to six groups (A-F) of 10 mice each. Animals in groups A and D were fed a standard diet, while those in B and E were fed folic acid supplemented diet (25 mg/kg of feed), while C and F were fed folate supplemented diet at 50 mg/kg of feed for 8 weeks. At the beginning of the sixth 6th week, mice in groups A-C were administered distilled water, while animals in groups D-F were administered dexamethasone (DEX) at 4 mg/kg body weight by gavage. Open-field, forced swim, and tail-suspension tests were conducted at the end of the experimental period, following which animals were euthanised and blood was taken for the estimation of Malondialdehyde (MDA), reduced Glutathione, Glutathione Peroxidase, Catalase activity, and Superoxide Dismutase. Sections of the cerebral cortex were prepared for histological examination.

Results: Folic acid supplementation increased body weight, locomotor, rearing and self-grooming behaviours, and decreased immobility time in the tail suspension and forced swim tests. There was also a reduction of lipid peroxidation and an increase in the antioxidant status. Folic acid supplementation was also found to be protective against the development of dexamethasone-induced changes in body weight, open-field behaviours, behavioural despair, oxidative stress and cerebrocortical morphology.

Conclusion: Folic-acid supplementation improves the behavioral, some antioxidant, and cerebral morphological parameters.

Background: Apart from being an essential heavy metal, Manganese (Mn) serves as an important component of the antioxidant enzyme system in humans. Overexposure to manganese leads to the development of manganism, which is characterized by motor dysfunction along with neurodegeneration. The management of manganism often utilizes chelation therapy. In this regard, Monoisoamyl-2, 3-Dimercaptosuccinic Acid (MiADMSA) has been reported as a novel arsenic chelator, due to the presence of vicinal sulfhydril group. MiADMSA has been reported to reduce the level in divalent ions (like copper) therefore, it may be hypothesized that MiADMSA would be helpful in Mn-induced neurotoxicity.

Objective: This study is envisaged to explore the protective effect of MiADMSA on Mn-induced neurotoxicity.

Methods: Mn exposure was carried out by intraperitoneal administration of Mn (as manganese chloride, 10 mg/kg; i.p.). The animals were treated with MiADMSA (50 mg/kg; p.o.) either alone or in combination with Mn. The effect of different treatments on neurobehavioral functions was observed by assessing spontaneous locomotor activity, motor rotarod test, and depression-like behavior in the forced swim test. After behavioral evaluations, all the animals were sacrificed and the brain and liver were isolated for metal estimations.

Results: Mn exposure leads to loss of motor coordination as observed in spontaneous locomotor activity and rotarod test. However, treatment with MiADMSA significantly improved motor impairments as compared to Mn exposed animals. Accumulation of Mn in the liver and brain has been recorded with Mn exposure; however, MiADMSA treatment significantly reduced the Mn content from the liver and brain.

Conclusion: The outcome of the study suggests that treatment with MiADMSA reversed Mn-induced neurotoxicity by reducing Mn load. Therefore, the use of MiADMSA may be suggested in manganese toxicity, after careful investigation.

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.