Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 21, Issue 1, 2021

Threats, challenging events, adverse experiences, predictable or unpredictable, namely stressors, characterize life, being unavoidable for humans. The hypothalamus-pituitary-adrenal axis (HPA) and the sympathetic nervous system (SNS) are well-known to underlie adaptation to psychosocial stress in the context of other interacting systems, signals and mediators. However, much more effort is necessary to elucidate these modulatory cues for a better understanding of how and why the "brain-body axis" acts for resilience or, on the contrary, cannot cope with stress from a biochemical and biological point of view. Indeed, failure to adapt increases the risk of developing and/or relapsing mental illnesses such as burnout, post-traumatic stress disorder (PTSD), and at least some types of depression, even favoring/worsening neurodegenerative and somatic comorbidities, especially in the elderly. We will review here the current knowledge on this area, focusing on works presenting the main brain centers responsible for stressor interpretation and processing, together with those underscoring the physiology/biochemistry of endogenous stress responses. Autonomic and HPA patterns, inflammatory cascades and energy/redox metabolic arrays will be presented as allostasis promoters, leading towards adaptation to psychosocial stress and homeostasis, but also as possible vulnerability factors for allostatic overload and non-adaptive reactions. Besides, the existence of allostasis buffering systems will be treated. Finally, we will suggest promising lines of future research, particularly the use of animal and cell culture models together with human studies by means of high-throughput multi-omics technologies, which could entangle the biochemical signature of resilience or stress-related illness, a considerably helpful facet for improving patients’ treatment and monitoring.

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: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is the most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi-factorial etiology of Alzheimer’s disease, novel ligands strategy appears as an up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds, Molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction, PASS software was used, while the toxicity profile of compounds was analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better druglikeness, LD50 value, better anti-Alzheimer’s, and nootropic activities. However, these compounds had poor blood-brain barrier (BBB) permeability. Compounds 4 and 9 were predicted with a better docking score for the AChE enzyme. Conclusion: The outcome of in silico studies has suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 has shown promising drug-likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one of the major limitations of all these compounds. Further studies are required to confirm its biological activities.

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.