Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 23, Issue 2, 2023

Introduction: Depression is one of the most frequently occurring psychiatric disorders worldwide, affecting 121 million worldwide. World Health Organization (WHO) estimates that it is the leading cause of disability and the fourth leading contributor to the "global burden of diseases". Objective: Investigating and developing a drug with a novel benefit-risk profile is critical. Marine sources have been explored for their benefits as an alternative therapy for depression treatment. Numerous studies have shown that natural compounds containing peptides, alkaloids, polyphenols, diterpenes, glycosides, vitamins, and minerals from marine sources can potentially treat a wide range of disorders, including depression. Such phytoconstituents are known to reduce oxidative stress and neuroinflammation, regulate the synthesis or function of neurotransmitters such as glutamate and acetylcholinesterase, and aid in enhancing serotonin levels and nerve development. Methods: In this review study, a literature search was conducted using terms often used, including animal models of depression and their precise phases, marine sources, algae, sponges, and indole alkaloids. Additionally, databases were examined, including Scopus, Wiley, Elsevier, Google Scholar, and Web of Science. The Snowball technique was used to identify several articles about depression but correlated to marine sources in addition to database searches. Results: Current antidepressant medications have several negative side effects on the human body, including dry mouth, cardiovascular interference, gastrointestinal symptoms, genitourinary symptoms, hepatotoxicity, convulsions, and obesity. As a result, researchers can identify a wide range of potential targets for medications derived from marine sources. A combination of marinederived drugs and available treatments can be estimated to minimize the negative effects. So that these resources can be used as efficiently as possible, and various marine-derived substances can be studied for therapeutic efficacy. Conclusion: This review focuses on the preclinical and clinical findings of marine-derived compounds with antidepressant properties that alter behavioural parameters and biochemical abnormalities, as well as their mechanism of action and in-vivo potential.

Background: Depression and anxiety are the most common mental disorders worldwide. Objective: We aimed to review silymarin and silibinin effects and underlying mechanisms in the central nervous system (CNS) for depression and anxiety treatment. Methods: The research protocol was prepared based on following the PRISMA statement. An extensive search was done in essential databases such as PubMed, Cochrane Library, Web of Science (ISI), Embase, and Scopus. Considering the study inclusion and exclusion criteria, 17 studies were finally included. The desired information was extracted from the studies and recorded in Excel, and the consequences and mechanisms were reviewed. Results: Silymarin and silibinin upregulated brain-derived neurotrophic factor (BDNF) and improved neural stem cells (NSCs) proliferation in the cortex and hippocampus. They also increased neurochemical serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. Silymarin and silibinin reduced malondialdehyde (MDA) formation and increased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. In addition, silymarin and silibinin reduced interleukin (IL)-6, IL-1β, and IL-12β, reducing tumor necrosis factor α (TNF-α) induced neuroinflammation. Conclusion: Silymarin and silibinin exert anti-depression and anxiolytic effects by regulating neurotransmitters, endocrine, neurogenesis, and immunologic systems. Therefore, as natural and complementary medicines, they can be used to reduce the symptoms of depression and anxiety; However, more clinical studies are needed in this field.

Background: In Alzheimer’s Disease (AD), chemokines recruit pro-inflammatory mediators and increase the aggregation of both Aβ (amyloid-β) plaque and neurofibrillary tangles (NFTs). Chemokine receptor 5 (CCR5) has been demonstrated to be involved in neuroinflammation and neuroimmunology, where its inhibition was shown to enhance memory, plasticity and learning. Objective: In this study, compounds that inhibit CCR5 obtained from the ChEMBL database were analysed, specifically for whether specific substructures and physicochemical properties are correlated to biological activity. Methods: Clustering was first performed to group 1,237 compounds into 10 clusters based on the similarities of their structure. Then, molecular docking was performed on 10 compounds representative of each cluster. Lastly, the Spearman correlation was computed between physicochemical properties and biological activity. Results: Results showed that potent CCR5 inhibitors tend to: (i) be larger in size (molecular weight of more than 500 g/mol), (ii) bind at the deep hydrophobic pocket, mostly through π-π stacking and (iii) have more than 1 aromatic ring. The larger size may aid in reaching the deep hydrophobic pocket. However, these requirements may lead to the violation of more than 1 Lipinski’s Rule of 5. Conclusion: Future studies should include analyses of the analogues or derivatives of the representative compounds to further expand on the findings here and establish the structure-activity relationship for CCR5 inhibition. This would aid in the development of new AD drugs since drug discovery and development of AD drugs are suffering from high attrition.

Background: Alzheimer's disease (AD) is a major neurodegenerative disorder with multiple manifestations, including oxidative stress, brain-derived neurotrophic factor (BDNF) depletion, and cholinergic dysfunction. Capparis spinosa (C. spinosa) is identified as a potential source of nutrition for alleviating various ailments. The current study assessed the ameliorating properties of C. spinosa hydroethanolic extract on memory dysfunction and the possible roles of oxidative stress and BDNF in the scopolamine (Scop)-treated rats. Methods: Forty male Wistar rats were divided into the following four groups: Control, Scop (2 mg/kg, intraperitoneal injection (i.p.)), Scop + C. spinosa 150, and Scop + C. spinosa 300 groups. The rats were given C. spinosa extract (150 or 300 mg/kg, oral) for 3 weeks. During the third week, Passive Avoidance (PA) and Morris Water Maze (MWM) tests were done to assess memory and learning performance. Finally, oxidative stress markers and BDNF in the brain tissue were evaluated. Results: Scop injection was associated with a significant increase in the time latency and travelled distance to reach the platform during the learning phase of MWM In the probe test, the Scoptreated rats showed a lower time and distance in the target area. Furthermore, Scop injection significantly decreased the latency to enter the dark while increasing the dark time and the frequency of entries to the dark zone of the PA task. C. spinosa extract effectively reversed the behavioural changes induced by Scop. Treatment with the extract also significantly increased the levels of superoxide dismutase, catalase, thiols, and BDNF, while decreasing malondialdehyde production in the brains of the Scop-injured rats. Conclusion: C. spinosa hydroethanolic extract successfully ameliorated Scop-induced memory impairment by modifying BDNF and oxidative stress markers in the brain of amnesic rats.

Background: NMDA receptors have a significant role in the development of opioid physical dependence. Evidence demonstrated that a drug of abuse enhances neuronal excitability in the Paraventricular Nucleus (PVT). The current research studied whether blocking NMDA receptors through the administration of MK801 in the PVT nucleus could affect the development of Morphine (Mor) dependence and hence the behavioral indices induced by morphine withdrawal in rats. Methods: Male Wistar rats weighing 250-300 g were used. For induction of drug dependence, we injected Mor subcutaneously (s.c.) (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two groups in which the NMDA receptor antagonist, MK801 (20 mM in 0.1 ml), or its vehicle were applied into the PVT nucleus for 7 days before each Mor administration. On day 8, after injection of naloxone (Nal, 2.5 mg/kg, i.p.), withdrawal behaviors were checked for 25 min. Results: The current results demonstrated that the blockade of the NMDA receptor in the PVT nucleus significantly increased withdrawal behaviors provoked by the application of Nal in morphinedependent (Mor-d) rats. Conclusion: We concluded that the NMDA receptor in the PVT nucleus changes the development of Mor dependence.

Background: The primary phytoconstituents reported to have neuroprotective effects are flavonoids and phenolic compounds. Aerva persica roots are reported to be rich in flavonoids and phenolic compounds. Therefore, this study aimed to explore the nootropic potential of Aerva persica roots. Objective: The objective of this study was to evaluate the nootropic potential of Aerva persica roots against D-galactose-induced memory impairment. Methods: In this study, the roots of Aerva persica were extracted with 70% ethanol. The obtained extract was evaluated for total phenolic content using the Folin-Ciocalteu method and total flavonoid content using the aluminium chloride colorimetric assay. Afterward, the acute oral toxicity of the extract was determined following the Organisation for Economic Co-operation and Development (OECD) guideline 423. Additionally, two doses of Aerva persica (100 and 200 mg/kg body weight (BW)) were evaluated for their nootropic potential against D-galactose-induced memory impairment. The nootropic potential of the crude extract was assessed through a behavioural study and brain neurochemical analysis. Behavioural studies involved the evaluation of spatial reference- working memory using the radial arm maze test and the Y-maze test. Neurochemical analysis was performed to determine the brain’s acetylcholine, acetylcholinesterase, glutathione (GSH), and malondialdehyde (MDA) levels. Results: The total phenolic content and total flavonoid content were found to be 179.14 ± 2.08 μg GAE/mg and 273.72 ± 3.94 μg QE/mg, respectively. The Aerva persica extract was found to be safe up to 2000 mg/kg BW. Following the safety assessment, the experimental mice received various treatments for 14 days. The behavioural analysis using the radial maze test showed that the extract at both doses significantly improved spatial reference-working memory and reduced the number of total errors compared to disease control groups. Similarly, in the Y-maze test, both doses significantly increased the alteration percentage and the percentage of novel arm entry (both indicative of intact spatial memory) compared to disease control. In neurochemical analysis, Aerva persica at 200 mg/kg significantly normalised the acetylcholine level (p<0.0001) and GSH level (p<0.01) compared to disease control. However, the same effect was not observed with Aerva persica at 100 mg/kg. Additionally, Aerva persica at 200mg/kg BW significantly decreased the acetylcholinesterase level (p<0.0001) and decreased the brain’s MDA level (p<0.01) compared to the disease control, whereas the effect of Aerva persica at 100 mg/kg BW in reducing acetylcholinesterase was non-significant. Conclusion: Based on the results, it can be concluded that the nootropic potential of Aerva persica was comparable to that of the standard drug, Donepezil, and the effect might be attributed to the higher content of flavonoids and phenolic compounds.

Objective: Insomnia is a condition that causes sleep problems, and many people suffer from it. Patients with this disorder have difficulty with beginning or continuation of sleep, so they are exhausted all day long, and their performance reduces. This study was designed to assess the efficacy of capsules that contain tomato extract in patients with primary insomnia. Methods: In this study, 70 patients with primary insomnia were assigned to 2 groups randomly: intervention and control. The intervention group used to take tomato capsules every night for 2 weeks, and the placebo one used to take placebo capsules every night for 2 weeks. All patients used to fill out Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after the intervention. ISI and PSQI results were analyzed separately on SPSS software. Results: A total of 70 patients (35 in the intervention group and 35 in the control group), including 50 females and 20 males, were studied. Female to male ratio and the rate of unemployment were significantly higher in the intervention group (in both cases P < 0.001), but there was no significant difference between the intervention and control groups in other characteristics (Age, marital status, weight, height, education; in all cases P > 0.05). At the end of the study, the amount of actual sleep had increased, and the delay in falling asleep decreased in both groups; the two groups at the end of the study were not significantly different in terms of these two variables (P > 0.05). The ISI score in both groups decreased significantly at the end of the study, and the PSQI score in both groups decreased significantly at the end of the study (In both cases, P < 0.05). The absolute value of ISI score change in the intervention group was significantly higher than the control group (P < 0.001); But the absolute value of PSQI score change was not significantly different between the two groups (P = 0.102). Most importantly, the improvement of both ISI and PSQI scores in the intervention group was significantly better than the control group (P > 0.05). Conclusion: This study showed that tomato capsules have sleep-inducing effects, although there was no significant difference in the amount of actual sleep, and the delay in falling sleep in the intervention group compared to the control group.