Current Pharmaceutical Design - Volume 26, Issue 37, 2020

Alzheimer's disease (AD) is a chronic, age-related, and irreversible brain disorder that typically develops slowly and gets worse over time. The potent auspicious drug candidate for the treatment of AD is supposed to perform the simultaneous modulation of several targets linked to AD. The new therapeutic approach involves drug candidates that are designed to act on multiple targets and have various pharmacological properties. This trend has triggered the development of various multimodal drugs including TV-3326 (i.e. ladostigil) and M-30 (i.e. a new multitarget iron chelator). TV-3326 combines the neurorestorative/neuroprotective effects of the cholinesterase (ChE) inhibitory activity of rivastigmine with rasagiline (a selective monoamine oxidase-B inhibitor and novel antiparkinsonian agent) in a single molecule. M-30, the second derivative of rasagiline, was developed by combining the propargyl moiety of rasagiline into the skeleton of VK-28 (i.e. a novel brain permeable neuroprotective iron chelator). It has been revealed that both the compounds possess anti-AD effects and therefore, the clinical development is directed to the treatment of this type of neurodegenerative diseases (NDs). In this article, we have reviewed the neuroprotective molecular mechanisms and multimodal effects of TV-3326 and M-30.

Alzheimer’s disease, categorized by the piling of amyloid-β (Aβ), hyperphosphorylated tau, PHFs, NFTs and mTOR hyperactivity, is a neurodegenerative disorder, affecting people across the globe. Osmolytes are known for osmoprotectants and play a pivotal role in protein folding, function and protein stability, thus, preventing proteins aggregation, and counteracting effects of denaturing solutes on proteins. Osmolytes (viz., sorbitol, inositol, and betaine) perform a pivotal function of maintaining homeostasis during hyperosmotic stress. The selective advantage of utilising osmolytes over inorganic ions by cells is in maintaining cell volume without compromising cell function, which is important for organs such as the brain. Osmolytes have been documented not only as neuroprotectors but they also seem to act as neurodegenerators. Betaine, sucrose and trehalose supplementation has been seen to induce autophagy thereby inhibiting the accumulation of Aβ. In contrast, sucrose has also been associated with mTOR hyperactivity, a hallmark of AD pathology. The neuroprotective action of taurine is revealed when taurine supplementation is seen to inhibit neural damage, apoptosis and oxidative damage. Inositol stereoisomers (viz., scyllo-inositol and myo-inositol) have also been seen to inhibit Aβ production and plaque formation in the brain, inhibiting AD pathogenesis. However, TMAO affects the aging process adversely by deregulating the mTOR signalling pathway and then kindling cognitive dysfunction via degradation of chemical synapses and synaptic plasticity. Thus, it can be concluded that osmolytes may act as a probable therapeutic approach for neurodevelopmental disorders. Here, we have reviewed and focussed upon the impact of osmolytes on mTOR signalling pathway and thereby its role in AD pathogenesis.

Nuts hold prime significance throughout the world as they offer multiple health benefits owing to their highly nutritious profile. A number of scientific studies have demonstrated their actions against inflammation, oxidative damage, the aging process, as well as dementia or memory loss. However, only walnuts, followed by almonds, hazelnuts and pistachios, have shown promising results in empirical studies for memory improvements. So, the current review focuses on presenting hypotheses regarding anti-dementia property of nine different nuts: almond, walnut, pistachio, Brazil nut, peanut, pecans, cashew, hazelnut, and chestnut. The nutritious profile of nuts contains essential fats (mostly mono- and poly-unsaturated fatty acids), proteins (source for arginine, lysine and tryptophan), vitamins (riboflavin, folate, and various tocopherols), fibers, minerals (calcium, sodium, magnesium, phosphorus and potassium) and trace elements (copper, zinc, and selenium). Interestingly, the constituents of natural products, nuts being an excellent example, work synergistically and/or in a side-effect neutralizing manner. These latter properties can make nuts an alternate therapy for humankind to fight against memory loss.

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

Parkinson’s disease is a progressive neurodegenerative disorder of dopaminergic striatal neurons in basal ganglia. Treatment of Parkinson’s disease (PD) through dopamine replacement strategies may provide improvement in early stages and this treatment response is related to dopaminergic neuronal mass which decreases in advanced stages. This treatment failure was revealed by many studies and levodopa treatment became ineffective or toxic in chronic stages of PD. Early diagnosis and neuroprotective agents may be a suitable approach for the treatment of PD. The essentials required for early diagnosis are biomarkers. Characterising the striatal neurons, understanding the status of dopaminergic pathways in different PD stages may reveal the effects of the drugs used in the treatment. This review updates on characterisation of striatal neurons, electrophysiology of dopaminergic pathways in PD, biomarkers of PD, approaches for success of neuroprotective agents in clinical trials. The literature was collected from the articles in database of PubMed, MedLine and other available literature resources.

Despite gigantic advances in medical research and development, chemotherapeutic resistance remains a major challenge in complete remission of CNS tumors. The failure of complete eradication of CNS tumors has been correlated with the existence of several factors including overexpression of transporter proteins. To date, 49 ABC-transporter proteins (ABC-TPs) have been reported in humans, and the evidence of their strong association with chemotherapeutics’ influx, dissemination, and efflux in CNS tumors, is growing. Research studies on CNS tumors are implicating ABC-TPs as diagnostic, prognostic and therapeutic biomarkers that may be utilised in preclinical and clinical studies. With the current advancements in cell biology, molecular analysis of genomic and transcriptomic interplay, and protein homology-based drug-transporters interaction, our research approaches are streamlining the roles of ABC-TPs in cancer and multidrug resistance. Potential inhibitors of ABC-TP for better clinical outcomes in CNS tumors have emerged. Elacridar has shown to enhance the chemo-sensitivity of Dasatanib and Imatinib in various glioma models. Tariquidar has improved the effectiveness of Temozolomide’s in CNS tumors. Although these inhibitors have been effective in preclinical settings, their clinical outcomes have not been as significant in clinical trials. Thus, to have a better understanding of the molecular evaluations of ABC-TPs, as well as drug-interactions, further research is being pursued in research labs. Our lab aims to better comprehend the biological mechanisms involved in drug resistance and to explore novel strategies to increase the clinical effectiveness of anticancer chemotherapeutics, which will ultimately improve clinical outcomes.

Sumoylation is the Post-translational modification gaining most of the research interest recently. Sumoylation is involved in various crucial functions of the cell such as regulation of cell cycle, DNA damage repair, apoptosis, etc. Oncology is advancing in radiotherapy, targeted chemotherapy, various forms of immunotherapy and targeted gene therapy. Researches are being conducted to prove its connotation with a variety of cancers and inhibitors are being developed to obstruct the fatal effect caused by misbalance of the SUMO-catalytic cycle. It has been shown that up-regulation of certain enzymes of Sumoylation correlates with cancer incidence in most of the cases. However, in some cases, down-regulation also associates with cancer invasion such as underexpression of UBC9 in initial stage breast cancer. This can aid in future study, treatment, and diagnosis of a variety of cancers including breast cancer, prostate cancer, lung adenocarcinoma, melanoma, multiple myeloma, etc. Various mechanistic assays are being developed and used to identify potential inhibitors against the dysregulated proteins of Sumoylation. This review summarizes the normal roles of the enzymes involved in the SUMOcatalytic cycle, their misbalanced regulation leading to tumorigenesis and nearly all the potent inhibitors identified to date, while after detailed studied it was observed that ML-792 could be a promising inhibitor in treating cancers by inhibiting Sumoylation enzymes.

As the most popular intrinsic neoplasm throughout the brain, glioblastoma multiforme (GBM) is resistant to existing therapies. Due to its invasive nature, GBM shows a poor prognosis despite aggressive surgery and chemoradiation. Therefore, identifying and understanding the critical molecules of GBM can help develop new therapeutic strategies. Glutamatergic signaling dysfunction has been well documented in neurodegenerative diseases as well as in GBM. Inhibition of glutamate receptor activation or extracellular glutamate release by specific antagonists inhibits cell development, invasion, and migration and contributes to apoptosis and autophagy in GBM cells. This review outlines the current knowledge of glutamate signaling involvement and current therapeutic modalities for the treatment of GBM.

Background: An increasing number of newborn children in numerous nations are enrolled in early childhood education programs, and instructors, in this way, assume a focal job in invigorating language improvement in these youthful kids. Kids with language issues are found to have a higher risk for future scholarly challenges and learning inabilities. Language advancement among kids is an intricate procedure and vital for correspondence. The shortcomings in the utilization of grammatical structures may lessen the useful utilization of language for verbally expressive kids with autism spectrum disorder and exacerbate troubles with academic and social expertise advancement. Results: FOXP2, the single principal gene connected to a speech and language issue, is significant for the right execution of complex motor behaviors used for speech. In any case, changes in FOXP2 lead to a speech/language issue portrayed by childhood apraxia of speech. These days, language learning is fundamentally required for kids who need to move to different nations to pursue the instructive frameworks and be helpful individuals or residents of those nations. Conclusion: The purpose of this study was to explore the role of FOXP2 in language disorder and its management for children’s language and communication development.

Background: Cerebral palsy (CP) is a brain disorder that affects the development, movement and posture leading to limitation of Range of Movement (ROM) in the growing children. CP leads to deformities such as equinus foot deformity. We aim to investigate the efficacy of different botulinum toxin (BTX) products with or without serial casting in reducing the muscle spasticity in equinus foot deformity in patients with CP. Methods: A systematic review of the literature was performed by searching different electronic databases. Pub- Med, Scopus, Web of Science (WOS), and GHL databases were used. We analyzed the extracted data by network meta-analysis method using the R software package (version 3.5.0). Results: Regarding Modified Ashworth score (MAS), BTX-A was superior compared to placebo and BTX-A plus immediate casting (MD = −0.39, 95% CI [−0.60; −0.18]) and (MD = −0.50, 95% CI [−0.98; −0.02]), respectively. Concerning growth motor function movement Classification System (GMFM), Neuronox ranked above at 3 months (MD = −1.60, 95% CI [−2.87; −0.33]) and at six months (MD = −1.90, 95% CI [−3.48; −0.32]) compared to BTX-A. Regarding the Modified Tardieu scale (MTS) with knee flexion, BTX-A was superior to BTX-A plus immediate casting (MD = 8.60, 95% CI [1.76; 15.44]). Concerning passive range of movement (PROM) with Knee flexion or extension at 3 months, BTX-A showed a significant improvement compared to BTX-A plus immediate casting. Conclusion: BTX-A ranked best on a physician rating scale (PRS), MAS, MTS with knee flexion and PROM (Knee flexion and extension) compared to Neuronox and Botulax. BTX-A alone was also better than BTX-A plus immediate casting.

Background: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and non-cognitive functions. Objective: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology. Methods: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using ‘Autodock4.2’. Results: Two phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of -9.02 and -8.89 kcal/mole, respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. Conclusion: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values.

Background: Normal skin pigmentation pattern is an extremely important component of the appearance of a person, as it can be a significant factor in the social context of any person. A condition known as vitiligo is caused by the death of melanocytes leading to pigmentation loss in the skin. This affects all races across the globe and sometimes leads to social avoidance as in some communities, it is stigmatized. Although there are different pathobiological processes suspected because of the different underlying causes of vitiligo, autoimmunity and oxidative stress are suspected to be the most probable ones. Objective: In this review, we present an overview of the underlying mechanisms causing and developing the disease. Also, some of the most successful treatments along with the clinical applications of Mesenchymal Stem Cells (MSCs) as a comprehensive approach for treating this condition will be covered. Results: Autoreactive CD8+ T-cells are the primary suspect considered to be responsible for the destruction of melanocytes. Therefore, topical use of autoimmune inhibitors including those derived from MSCs, thanks to their immune-modulatory properties, have been reported to be successful in the promotion of repigmentation. MSCs can suppress the proliferation of CD8+T via the NKG2D pathway while inducing T-cell apoptosis. The use of pharmacological agents for reducing cellular oxidative stress with the help of topical application of antioxidants and growth factors also have been in use. Intravenous administration of MSCs has been shown to regulate the level of reactive oxidative species (ROS) in a mice model. Growth factors derived from platelet-rich-plasma (PRP) or from MSCs caused rapid tissue regeneration. Conclusions: Finally, MSC therapy also has been shown to stimulate the mobilization of healthy melanocytes, leading to successful repigmentation of skin lesions in vitiligo patients.

Bisphenol A (BPA) is an organic synthetic compound that is ubiquitously present in daily life. It is a typical environmental endocrine disruptor that affects the functions of endogenous hormones. There is a significant negative correlation between BPA and male reproduction. This mini-review describes current research data on the negative effects of BPA on sperm functions in humans and animal models, as well as on its supposed mechanisms of action, such as CATSPER-Ca2+ signaling, cAMP-protein kinase A signaling, and epigenetic changes. The published evidence showed an adverse impact of BPA on sperm tail morphology, counts, motility, and acrosome reaction action. Sperm function related signaling pathways, such as CATSPER-Ca2+ signaling, cAMP-protein kinase A signaling, and phosphorylation signaling, as well as epigenetic changes and sperm aging, are associated with BPA exposure in human and animal models. The clear risks of BPA exposure can provide greater awareness of the potential threat of environmental contaminants on male fertility.