Current Pharmaceutical Design - Volume 27, Issue 3, 2021

Combination therapy involving different therapeutic strategies mostly provides more rapid and effective results as compared to monotherapy in diverse areas of clinical practice. The most worldwide famous acetylcholinesterase inhibitor (AChEIs) donepezil for its dominant role in Alzheimer’s disease (AD) has also attracted the attention of many pharmaceuticals due to its promising pharmacological potencies such as neuroprotective, muscle relaxant, and sleep inducer. Recently, a combination of donepezil with other agents has displayed better desirable results in managing several disorders, including the most common Alzheimer’s disease (AD). This study involves all the data regarding the therapeutic effect of donepezil in its combination with other agents and explains its therapeutic targets and mode of action. Furthermore, this review also puts light on the current status of donepezil with other agents in clinical trials. The combination therapy of donepezil with symptomatic relief drugs and disease-modifying agents opens a new road for treating multiple pathological disorders. To the best of our knowledge, this is the first report encircling all the pharmacologic effects of donepezil in its combination therapy with other agents and their current status in clinical trials.

Aging is a normal human cycle and the most important risk factor for neurodegenerative diseases. Alternations in cells due to aging contribute to loss of the nutrient-sensing, cell function, increased oxidative stress, loss of the homeostasis cell, genomic instability, the build-up of malfunctioning proteins, weakened cellular defenses, and a telomere split. Disturbance of these essential cellular processes in neuronal cells can lead to life threats including Alzheimer's disease (AD), Huntington's disease (HD), Lewy's disease, etc. The most common cause of death in the elderly population is AD. Specific therapeutic molecules were created to alleviate AD’s social, economic, and health burden. In clinical practice, almost every chemical compound was found to relieve symptoms only in palliative treatment. The reason behind these perfect medicines is that the current medicines are not effective in targeting the cause of this disease. In this paper, we explored the potential role of flavonoid and polyphenolic compounds, which could be the most effective preventative anti-Alzheimer 's strategy.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is marked by cognitive dysfunctions and the existence of neuropathological hallmarks such as amyloid plaques, and neurofibrillary tangles. It has been observed that a persistent immune response in the brain has appeared as another neuropathological hallmark in AD. The sustained activation of the microglia, the brain’s resident macrophages, and other immune cells has been shown to aggravate both tau and amyloid pathology and may consider as a connection in the AD pathogenesis. However, the basic mechanisms that link immune responses in the pathogenesis of AD are unclear until now since the process of neuroinflammation can have either a harmful or favorable effect on AD, according to the phase of the disease. Numerous researches recommend that nutritional fruits, as well as vegetables, possess neurodefensive properties against the detrimental effects of neuroinflammation and aging. Moreover, these effects are controlled by diverse phytochemical compounds that are found in plants and demonstrate anti-inflammatory, neuroprotective, as well as other beneficial actions. In this review, we focus on the link of neuroinflammation in AD as well as highlight the probable mechanisms of alkaloidal phytochemicals to combat the neuroinflammatory aspect of AD.

Mental disorders comprise diverse human pathologies, including depression, bipolar affective disorder, schizophrenia, and dementia that affect millions of people around the world. The causes of mental disorders are unclear, but growing evidence suggests that oxidative stress and the purine/adenosine system play a key role in their development and progression. Xanthine oxidase (XO) is a flavoprotein enzyme essential for the catalysis of the oxidative hydroxylation of purines -hypoxanthine and xanthine- to generate uric acid. As a consequence of the oxidative reaction of XO, reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are produced and, further, contribute to the pathogenesis of mental disorders. Altered XO activity has been associated with free radical-mediated neurotoxicity inducing cell damage and inflammation. Diverse studies reported a direct association between an increased activity of XO and diverse mental diseases including depression or schizophrenia. Small-molecule inhibitors, such as the well-known allopurinol, and dietary flavonoids, can modulate the XO activity and subsequent ROS production. In the present work, we review the available literature on XO inhibition by small molecules and their potential therapeutic application in mental disorders. In addition, we discuss the chemistry and molecular mechanism of XO inhibitors, as well as the use of structure-based and computational methods to design specific inhibitors with the capability of modulating XO activity.

Plant-derived sterols, phytosterols, are well known for their cholesterol-lowering activity in serum and their anti-inflammatory activities. Recently, phytosterols have received considerable attention due to their beneficial effects on various non-communicable diseases, and recommended use as daily dietary components. The signaling pathways mediated in the brain by phytosterols have been evaluated, but little is known about their effects on neuroinflammation, and no clinical studies have been undertaken on phytosterols of interest. In this review, we discuss the beneficial roles of phytosterols, including their attenuating effects on inflammation, blood cholesterol levels, and hallmarks of the disease, and their regulatory effects on neuroinflammatory disease pathways. Despite recent advancements made in phytosterol pharmacology, some critical questions remain unanswered. Therefore, we have tried to highlight the potential of phytosterols as viable therapeutics against neuroinflammation and to direct future research with respect to clinical applications.

Alzheimer's disease (AD) is an irrevocable chronic brain disorder featured by neuronal loss, microglial accumulation, and progressive cognitive impairment. The proper pathophysiology of this life-threatening disorder is not completely understood and no exact remedies have been found yet. Over the last few decades, research on AD has mainly highlighted pathomechanisms linked to a couple of the major pathological hallmarks, including extracellular senile plaques made of amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs) made of tau proteins. Aβ can induce apoptosis, trigger an inflammatory response, and inhibit the synaptic plasticity of the hippocampus, which ultimately contributes to reducing cognitive functions and memory impairment. Recently, a third disease hallmark, the neuroinflammatory reaction that is mediated by cerebral innate immune cells, has become a spotlight in the current research area, assured by pre-clinical, clinical, and genetic investigations. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ΚB), a cytokine producer, is significantly associated with physiological inflammatory proceedings and thus shows a promising candidate for inflammation- based AD therapy. Recent data reveal that phytochemicals, mainly polyphenol compounds, exhibit potential neuroprotective functions and these may be considered as a vital resource for discovering several drug candidates against AD. Interestingly, phytochemicals can easily interfere with the signaling pathway of NF-ΚB. This review represents the anti-neuroinflammatory potential of polyphenols as inhibitors of NF-ΚB to combat AD pathogenesis.

MicroRNA (miRNA/miR) is a class of small evolutionarily conserved non-coding RNA, which can inhibit the target gene expression at the post-transcriptional level and serve as significant roles in cell differentiation, proliferation, migration and apoptosis. Of note, the aberrant miR-21 has been involved in the generation and development of multiple lung diseases, and identified as a candidate of biomarker, therapeutic target, or indicator of prognosis. MiR-21 relieves acute lung injury via depressing the PTEN/Foxo1-TLR4/NF-ΚB signaling cascade, whereas promotes lung cancer cell growth, metastasis, and chemo/radio-resistance by decreasing the expression of PTEN and PDCD4 and promoting the PI3K/AKT transduction. The purpose of this review is to elucidate the potential mechanisms of miR-21 associated lung diseases, with an emphasis on its dual regulating effects, which will trigger novel paradigms in molecular therapy.

Background: Protecting intellectual property rights are important and particularly pertinent for inventions that are an outcome of rigorous research and development. While the grant of patents is subject to establishing novelty and inventive step, it further indicates the technological development and is helpful for researchers working in the same technical domain. The aim of the present research work is to map the existing work through an analysis of patent literature in the field of Coronaviruses (CoV), particularly COVID-19 (2019-nCoV). CoV is a large family of viruses known to cause illness in humans and animals, particularly known for causing respiratory infections, as evidenced in earlier times, such as in MERS i.e., Middle East Respiratory Syndrome; and SRS i.e., Severe Acute Respiratory Syndrome. A recently identified novel-coronavirus, known as COVID-19, has caused pandemic situations across the globe. Objective: To expand the analysis of patents related to CoV and 2019-nCoV, an evaluation has been conducted by patenting trends of particular strains of identified CoV diseases by present legal status, main concerned countries via the earliest priority years and its assignee types and inventors of identified relevant patents. The global patent documents were analyzed to check the scope of claims along with focuses and trends of the published patent documents for the entire CoV family, including 2019-nCoV through the present landscape. Methods: To extract the results, the Derwent Innovation database was used by a combination of different keystrings. Approximately 3800 patents were obtained and further scrutinized and analyzed. The present write-up also discusses the recent progress of patent applications in a period of the year 2010 to 2020 (present) along with the recent developments in India for the treatment options for CoV and 2019-nCoV. Results: Present analysis showed that key areas of the inventions were the vaccines and diagnostic kits apart from the composition for the treatment of CoV. It was also observed that no specific vaccine treatments are available for the treatment of 2019-nCov; however, developing novel chemical or biological drugs and kits for early diagnosis, prevention, and disease management is the primary governing topic among the patented inventions. The present study also indicates potential research opportunities for the future, particularly to combat 2019-nCoV. Conclusion: The present paper analyzes the existing patents in the field of Coronaviruses and 2019-nCoV and suggests a way forward for the effective contribution in this upcoming research area. From the trend analysis, an increase in the filing of the overall trend of patent families was observed for a period of 2010 to the current year. This multifaceted analysis of identified patent literature provides an understanding of the focuses on present ongoing research and a grey area in terms of the trends of technological innovations in disease management in patients with CoV and 2019-nCoV. Furthermore, the findings and outcome of the present study offer insights for the proposed research and innovation opportunities and provide actionable information in order to facilitate policymakers, academia, research-driven institutes and also investors to make better decisions regarding programmed steps for research and development for the diagnosis, treatment and taking preventive measures for CoV and 2019-nCoV. The present article also emphasizes the need for future development and the role of academia and collaboration with industry for speedy research with a rationale.

Background and aim: Anxiety is one of the most common psychiatric disorders that lead to the disruption of daily life and also the quality of life. Routine medications have many side effects and cause physical dependence and psychosocial addiction. Diosgenin is a phytosteroid found in a number of herbs. The present study aimed to investigate the anxiolytic-like effect of diosgenin in the maternal separation model in male mice focusing on the role of NMDA receptors. Materials and Methods: Maternal separation (MS) paradigm was performed daily (3 h) from postnatal day (PND) 2-14. Male mice were treated with different doses of diosgenin to find effective and sub-effective doses. In the next step, mice were treated with an effective dose of diosgenin plus NMDA and or a sub-effective dose of diosgenin plus ketamine (NMDA antagonist). Valid behavioral tests for the evaluation of anxiety-like behavior were performed. Then, mice were euthanized, the hippocampus was dissected out and gene expression of NMDA receptors (NR2a and NR2b subunits) was assessed. Results: MS provokes anxiety-like behaviors in the open field test (OFT) and elevated plus maze (EPM) test. Diosgenin significantly mitigated the negative effects of MS. Co-administration of NMDA attenuated anxiolyticlike effect of the effective dose of diosgenin, while ketamine potentiated the anxiolytic effect of sub-effective dose of diosgenin. Furthermore, MS increased the expression of the NMDA receptor in the hippocampus which to some extent modulated with diosgenin. Conclusion: Diosignin has an anxiolytic-like effect on MS mice which at least, in part, mediated through NMDA receptors.

Background: The aging of hippocampal neurons leads to a substantial decline in memory formation, storage and processing. The neuroprotective effect of melatonin has been confirmed, however, its protective mechanism remains unclear. Objective: In this study, mouse hippocampus-derived neuronal HT22 cells were used to investigate whether melatonin protects the hippocampus from hydrogen peroxide (H2O2)-induced injury by regulating autophagy. Methods: Rapamycin (an activator of autophagy) and 3-methyladenine (3MA, an inhibitor of autophagy) were used to induce or inhibit autophagy, respectively. HT22 cells were treated with 200 μM H2O2 in the presence or absence of 50 μM melatonin. Cell counting kit 8 (CCK-8), β-galactosidase and Hoechst staining were used to measure the viability, aging and apoptosis of cells, respectively. Western blot analysis was used to detect the levels of autophagy-related proteins. Results: The activation of autophagy by rapamycin alleviated H2O2-induced oxidative injury, as evidenced by morphological changes and decreased viability, while the inhibition of autophagy by 3MA exacerbated H2O2- induced injury. The inhibitory effect of melatonin on H2O2-induced injury was similar to that of rapamycin. Melatonin also alleviated H2O2-induced aging and apoptosis. Melatonin activated autophagy in the presence or absence of H2O2, as evidenced by an increased Lc3b 14/16 kd ratio and a decreased P62 level. In addition, H2O2 decreased the levels of Beclin1 and Atg5/12/16, which were reversed by rapamycin or melatonin. The effects of melatonin on H2O2-induced injury, autophagy and protein expressions were effectively reversed by 3MA. Conclusion: In conclusion, these results demonstrate that melatonin protects HT22 hippocampal neurons from H2O2-induced injury by increasing the levels of the Beclin1 and Atg proteins to activate autophagy.