Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 22, Issue 3, 2022

The nervous system regulates the visual system through neurotransmitters that play an important role in visual and ocular functions. One of those neurotransmitters is acetylcholine, a key molecule that plays a variety of biological functions. Moreover, acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine, is implicated in cholinergic function. However, several studies have demonstrated that in addition to their enzymatic functions, acetylcholinesterase exerts non-catalytic functions. In recent years, the importance of evaluating all possible functions of acetylcholine-acetylcholinesterase has been shown. Nevertheless, there is evidence suggesting that cholinesterase activity in the eye can regulate some biological events both in structures of the anterior and posterior segment of the eye and, therefore, in the visual information that is processed in the visual cortex. Hence, the evaluation of cholinesterase activity could be a possible marker of alterations in cholinergic activity in both ocular and systemic diseases.

Background: Neuroinflammation is a key component in the etiopathogenesis of neurological diseases and brain aging. This process involves the brain immune system that modulates synaptic functions and protects neurons from infection or damage. Hence, the knowledge of neuroinflammation related pathways and modulation by drugs or natural compounds is functional to developing therapeutic strategies aimed at preserving, maintaining and restoring brain health. Objective: This review article summarizes the basics of neuroinflammation and related signaling pathways, the success of the dietary intervention in clinical practice and the possible development of RNA-based strategies for treating neurological diseases. Methods: Pubmed search from 2012 to 2022 with the keywords neuroinflammation and molecular mechanisms in combination with diet, miRNA and non-coding RNA. Results: Glial cells-play a crucial role in neuroinflammation, but several pathways can be activated in response to different inflammatory stimuli, inducing cell death by apoptosis, pyroptosis or necroptosis. The dietary intervention has immunomodulatory effects and could limit the inflammatory process induced by microglia and astrocytes. Thus by inhibiting neuroinflammation and improving the symptoms of a variety of neurological diseases, diet exerts pleiotropic neuroprotective effects independently from the spectrum of pathophysiological mechanisms underlying the specific disorder. Furthermore, data from animal models revealed that altered expression of specific noncoding RNAs, in particular microRNAs, contributes to neuroinflammatory diseases; consequently, RNA-based strategies may be promising to alleviate the consequences of neuroinflammation. Conclusion: Further studies are needed to identify the molecular pathways and the new pharmacological targets in neuroinflammation to lay the basis for more effective and selective therapies to be applied, in parallel to dietary intervention, in the treatment of neuroinflammation-based diseases.

Introduction: Ischemic stroke remains the leading cause of death worldwide and is the primary cause of disability globally. Numerous studies have shown that plant-origin medicines are promising and can influence the treatment of neurological disorders. Phyllanthus embilica L. (P. emblica or Amla) is one of the herbal plants whose medicinal properties are widely studied. The objective of the present study is to determine the neuroprotective effects of an aqueous extract of the fruit of P. emblica (hereinafter referred to as just P. emblica) on cerebral ischemia-reperfusion injury and explore if it can regulate BDNF/PI3K pathway to modulate glutathione for mitoprotection and neuroprotection. Methods: In vivo studies were conducted on male Sprague Dawley rats, where rats were prophylactically administered 100 mg/kg P. emblica for 30 days. In the treatment group, rats were given 100 mg/kg P. emblica, 1 h post middle cerebral artery occlusion (MCAo). Rats were evaluated for neuro deficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, protein expression studies, and mitochondrial studies. Results: Prophylaxis and treatment with P. emblica demonstrated significant improvement in functional outcome with a reduction in infarct size. Normalization of glutathione, nitrite, and malondialdehyde levels was also observed. Improvement in mitochondrial complex I and IV activities was also reported. Expressions of BDNF, PI3K, SDF1 and VEGF increased while that of ROCK2 decreased following P. emblica administration. Conclusion: P. emblica regulates BDNF/PI3K pathway to modulate glutathione in ischemic stroke to confer mitoprotection and neuroprotection.

Background: Most studies of the prevalence of cannabis use among patients with schizophrenia used a self-report as declared by the patient himself. We hypothesize that patients with schizophrenia did not tell the truth and might underreport their use for many reasons to be discussed later. Indeed, the under-report of cannabis use among these patients can affect the effectiveness of their treatment. Aims: To assess the degree of agreement between the prevalence values obtained from patients’ reports and the results of the toxicological tests. Methods: A cross-sectional study was carried out on 403 patients with schizophrenia. A sociodemographic, psychiatric history and illicit drug use profile was performed for each patient. We assessed the patients with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression score (CDSS), Barratt Impulsiveness Score (BIS-10) and Medication Adherence Rating Scale (MARS). The consumption of cannabis used was confirmed with MINI International Neuropsychiatric Interview (MINI-DSM IV) and using toxicological analysis. Results: Among the 403 patients who consented to give their urine samples, 49.1% (198/403) tested positive for cannabis, and 41.41% (82/198) underreported their use. The sensitivity and specificity of the questionnaire were 0.58 and 0.74. Based on the comparison between sociodemographic and psychiatric history data of patients who self-report and underreport their cannabis use, no significant difference was observed except for the duration of cannabis use and the score on the medication adherence scale. Moreover, it was found that impulsivity, PANSS score, CDSS score, and the type of schizophrenia are not involved in predicting the underreporting of cannabis use. Conclusion: The rate of patients who under-report cannabis use is important. Therefore, toxicological analysis is becoming relevant for identifying drug use among schizophrenic patients and in the addictive comorbidity research field.

Background: Escitalopram, a selective serotonin reuptake inhibitor (SSRI), acts by increasing the serotonin level in the brain and is used widely for the management of depression and anxiety disorders. However, the poor dissolution rate of escitalopram due to less water solubility is a consequential problem confronting the pharmaceutical industry in developing pharmaceutical dosage forms for oral delivery systems. Objective: The present work aims to deliver a novel formulation for improving the dissolution profile and, thus, the bioavailability of escitalopram. Methods: Fast Dissolving Tablets (FDT) are expected to enable quick drug release, which will improve the drug's dissolving profile, allowing for the initial increase in plasma concentration mandatory in an acute depression attack. The use of co-processed excipients in tablets has been shown to increase the compressibility and disintegration properties of the tablets, resulting in improved in-vitro drug release and bioavailability. As co-processed excipients, a mixture of banana powder (a natural super disintegrant with nutritional value) and microcrystalline cellulose (a highly compressible substance with good wicking and absorption capacity) was used. Results: The tablets were made using a response surface, randomised central composite design, and a direct compression technique. The manufactured tablets were found to be released more than 95% of the drug within 10 minutes and showed an improved drug release profile than the available marketed formulation. Conclusion: After confirming in-vivo potential, the fast release formulation exhibited impressive in-vitro findings and may prove to be a boon in treating acute depression attacks.

Background: Ellagic acid (EA) has various pharmacological effects such as antiinflammatory and anti-oxidant effects. Objective: This study aimed to investigate the effects of EA on learning and memory dysfunction as well as oxidative stress in scopolamine-induced amnesic rats. Methods: The studied rats were treated according to the following protocol: Control (group 1) and scopolamine (group 2) groups received saline (intraperitoneal injection (i.p.)) while the treatment groups (group 3-5) were given EA (25, 50, and 100 mg/kg, i.p.) for 3 weeks. Thereafter, their behavioral performance was evaluated using Morris water maze (MWM) and passive avoidance (PA) tasks. Notably, scopolamine was injected (into groups II-V at a dose of 2 mg/kg, i.p.) before conducting the tasks. Finally, the oxidative stress indicators in the brain were measured. Results: EA reduced the escape latencies and distances during the learning phase of MWM. The results of probe trials also indicated that EA improved memory retrieval and helped animals recall the platform. Moreover, EA increased delay and light time, while decreasing the frequency of entries to the dark area of PA. In the EA-treated groups, the level of malondialdehyde was decreased, while the levels of total thiol groups, superoxide dismutase, and catalase were increased. Conclusion: EA prevented the negative effects of scopolamine on learning and memory which is probably mediated via modulating oxidative stress. Hence, EA could be considered as a potential alternative therapy for dementia.