Molecular insights into the potential effects of selective estrogen receptor ß agonists in Alzheimer's and Parkinson's diseases.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders. Pathologically, AD and PD are characterized by the accumulation of misfolded proteins. Hence, they are also called as proteinopathy diseases. Gender is considered as one of the risk factors in both diseases. Estrogens are widely accepted to be neuroprotective in several neurodegenerative disorders. Estrogens can be produced in the central nervous system, where they are called as neurosteroids. Estrogens mediate their neuroprotective action mainly through their actions on estrogen receptor alpha (ERα) and estrogen receptor beta (ERß). However, ERα is mainly involved in the growth and development of the primary and secondary sexual organs in females. Hence, the activation of ERα is associated with undesired side effects such as gynecomastia and increase in the risk of breast cancer, thromboembolism, and feminization. Therefore, selective activation of ERß is often considered to be safer. In this review, we explore the role of ERß in regulating the expression and functions of AD- and PD-associated genes. Additionally, we discuss the association of these genes with the amyloid-beta peptide (Aß) and α-synuclein mediated toxicity. Ultimately, we established a correlation between the importance of ERß activation and the process underlying ERß's neuroprotective mechanisms in AD and PD.

The identification of c-Abl inhibitors as potential agents for Parkinson's disease: a preliminary in silico approach.

Parkinson's disease (PD) is the most common movement disorder worldwide. PD is primarily associated with the mutation, overexpression, and phosphorylation of α-synuclein. At the molecular level, the upstream protein c-Abl, a tyrosine kinase, has been shown to regulate α-synuclein activation and expression patterns. This study aimed to identify potential c-Abl inhibitors through in silico approaches. Molecular docking was performed using PyRx software, followed by Prime MM-GBSA studies. BBB permeability and toxicity were predicted using CBligand and ProTox-II, respectively. ADME was assessed using QikProp. Molecular dynamics were carried out using Desmond (Academic version). DFT calculations were performed using the Gaussian 16 suite program. The binding scores of the top hits, norimatinib, DB07326, and entinostat were - 11.8 kcal/mol, - 11.8 kcal/mol, and - 10.8 kcal/mol, respectively. These hits displayed drug-likeness with acceptable ADME properties, except for the standard, nilotinib, which violated Lipinski's rule of five. Similarly, the molecular dynamics showed that the top hits remained stable during the 100 ns simulation. DFT results indicate DB04739 as a potent reactive hit. While based on toxicity prediction, entinostat may be a potential candidate for preclinical and clinical testing in PD. Further studies are warranted to confirm the activity and efficacy of these ligands for PD.

The identification of cianidanol as a selective estrogen receptor beta agonist and evaluation of its neuroprotective effects on Parkinson's disease models.

AIM: The present study aims to identify selective estrogen receptor beta (ERß) agonists and to evaluate the neuroprotective mechanism in Parkinson's disease (PD) models. MAIN METHODS: In-silico studies were carried out using Maestro and GROMACS. Neuroprotective activity and apoptosis were evaluated using cytotoxicity assay and flow cytometry respectively. Gene expression studies were carried out by reverse transcription polymerase chain reaction. Motor and cognitive functions were assessed by actophotometer, rotarod, catalepsy, and elevated plus maze. The neuronal population in the substantia nigra and striatum of rats was assessed by hematoxylin and eosin staining. KEY FINDINGS: Cianidanol was identified as a selective ERß agonist through virtual screening. The cianidanol-ERß complex is stable during the 200 ns simulation and was able to retain the interactions with key amino acid residues. Cianidanol (25 µM) prevents neuronal toxicity and apoptosis induced by rotenone in differentiated SH-SY5Y cells. Additionally, cianidanol (25 µM) increases the expression of ERß, cathepsin D, and Nrf2 transcripts. The neuroprotective effects of cianidanol (25 µM) were reversed in the presence of a selective ERß antagonist. In this study, we found that selective activation of ERß could decrease the transcription of α-synuclein gene. Additionally, cianidanol (10, 20, 30 mg/kg, oral) improves the motor and cognitive deficit in rats induced by rotenone. SIGNIFICANCE: Cianidanol shows neuroprotective action in PD models and has the potential to serve as a novel therapeutic agent for the treatment of PD.

Side effects based network construction and drug repositioning of ropinirole as a potential molecule for Alzheimer's disease: an in-silico, in-vitro, and in-vivo study.

Alzheimer's disease (AD) is the leading cause of dementia in older adults. Drug repositioning is a process of finding new therapeutic applications for existing drugs. One of the methods in drug repositioning is to use the side-effect profile of a drug to identify a new therapeutic indication. The drugs with similar side-effects may act on similar biological targets and could affect the same biochemical process. In this study, we explored the Food and Drug Administration-approved drugs using PROMISCUOUS database to find those that have adverse effects profile comparable with the ligands being studied or used to treat AD. Here, we found that the ropinirole, a dopamine receptor agonist, shared a maximum number of side-effects with the drugs proven beneficial for treating AD. Furthermore, molecular modelling demonstrated that ropinirole exhibited strong binding affinity (-9.313 kcal/mol) and best ligand efficiency (0.49) with sigma-1 receptor. Here, we observed that the quaternary amino group of ropinirole is essential for binding with sigma-1 receptor. Molecular dynamic simulation indicated that the movement of the carboxy-terminal helices (α4/α5) could play a major role in the receptor's physiological functions. The neurotoxicity induced by Aß25-35 in SH-SY5Y cells was reduced by ropinirole at concentrations 10, 30, and 50 µM. The effect on spatial learning and memory was examined in mice with Aß25-35 induced memory deficit using the radial arm maze. Ropinirole (10 and 20 mg/kg) significantly improved the short and long-term memories in the radial arm maze test. Our results suggest that ropinirole has the potential to be repositioned for AD treatment.Communicated by Ramaswamy H. Sarma.

Phosphodiesterase-4 Inhibition in Parkinson's Disease: Molecular Insights and Therapeutic Potential.

Clinicians and researchers are exploring safer and novel treatment strategies for treating the ever-prevalent Parkinson's disease (PD) across the globe. Several therapeutic strategies are used clinically for PD, including dopamine replacement therapy, DA agonists, MAO-B blockers, COMT blockers, and anticholinergics. Surgical interventions such as pallidotomy, particularly deep brain stimulation (DBS), are also employed. However, they only provide temporal and symptomatic relief. Cyclic adenosine monophosphate (cAMP) is one of the secondary messengers involved in dopaminergic neurotransmission. Phosphodiesterase (PDE) regulates cAMP and cGMP intracellular levels. PDE enzymes are subdivided into families and subtypes which are expressed throughout the human body. PDE4 isoenzyme- PDE4B subtype is overexpressed in the substantia nigra of the brain. Various studies have implicated multiple cAMP-mediated signaling cascades in PD, and PDE4 is a common link that can emerge as a neuroprotective and/or disease-modifying target. Furthermore, a mechanistic understanding of the PDE4 subtypes has provided perceptivity into the molecular mechanisms underlying the adverse effects of phosphodiesterase-4 inhibitors (PDE4Is). The repositioning and development of efficacious PDE4Is for PD have gained much attention. This review critically assesses the existing literature on PDE4 and its expression. Specifically, this review provides insights into the interrelated neurological cAMP-mediated signaling cascades involving PDE4s and the potential role of PDE4Is in PD. In addition, we discuss existing challenges and possible strategies for overcoming them.

A preliminary study to identify existing drugs for potential repurposing in breast cancer based on side effect profile.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death in women after lung cancer. The present study aims to identify potential drug candidates using the PROMISCUOUS database for breast cancer based on side effect profile and then proceed with in silico and in vitro studies. PROMISCUOUS database was used to construct a group of drugs that share maximum side effects with letrozole. Based on the existing literature, ropinirole, risperidone, pregabalin, and gabapentin were selected for in silico and in vitro studies. The molecular docking was carried out using AUTODOCK 4.2.6. MCF-7 cell line was used to evaluate the anti-cancer activity of the selected drugs. PROMISCUOUS database revealed that as many as 23 existing drugs shared between 62 and 79 side-effects with letrozole. From docking result, we found that, ropinirole showed a good binding affinity (-7.7 kcal/mol) against aromatase compared to letrozole (-7.1 kcal/mol) which was followed by gabapentin (-6.4 kcal/mol), pregabalin (-5.7 kcal/mol) and risperidone (-5.1 kcal/mol). From the in vitro results, ropinirole and risperidone showed good anti-cancer activity of IC50 with 40.85±11.02 µg/ml and 43.10±9.58 µg/ml cell viability. Based on this study results and existing literature we conclude that risperidone, pregabalin, and gabapentin are not ideal candidates for repurposing in breast cancer but ropinirole could be an excellent choice for repurposing in breast cancer after further studies.

Importance of Fibrosis in the Pathogenesis of Uterine Leiomyoma and the Promising Anti-fibrotic Effects of Dipeptidyl Peptidase-4 and Fibroblast Activation Protein Inhibitors in the Treatment of Uterine Leiomyoma.

Uterine fibroid or leiomyoma is the most common benign uterus tumor. The tumor is primarily composed of smooth muscle (fibroid) cells, myofibroblast, and a significant amount of extracellular matrix components. It mainly affects women of reproductive age. They are uncommon before menarche and usually disappear after menopause. The fibroids have excessive extracellular matrix components secreted by activated fibroblast cells (myofibroblast). Myofibroblast has the characteristics of fibroblast and smooth muscle cells. These cells possess contractile capability due to the expression of contractile proteins which are normally found only in muscle tissues. The rigid nature of the tumor is responsible for many side effects associated with uterine fibroids. The current drug treatment strategies are primarily hormone-driven and not anti-fibrotic. This paper emphasizes the fibrotic background of uterine fibroids and the mechanisms behind the deposition of excessive extracellular matrix components. The transforming growth factor-ß, hippo, and focal adhesion kinase-mediated signaling pathways activate the fibroblast cells and deposit excessive extracellular matrix materials. We also exemplify how dipeptidyl peptidase-4 and fibroblast activation protein inhibitors could be beneficial in reducing the fibrotic process in leiomyoma. Dipeptidyl peptidase-4 and fibroblast activation protein inhibitors prevent the fibrotic process in organs such as the kidneys, lungs, liver, and heart. These inhibitors are proven to inhibit the signaling pathways mentioned above at various stages of their activation. Based on literature evidence, we constructed a narrative review on the mechanisms that support the beneficial effects of dipeptidyl peptidase-4 and fibroblast activation protein inhibitors for treating uterine fibroids.

Evaluation of anti-inflammatory and anti-arthritic property of ethanolic extract of Clitoria ternatea.

Objective: Clitoria ternatea is a well-known bioactive plant used to treat several inflammatory ailments in Ayurvedic system of medicine in India. The present investigation aimed to determine the anti-inflammatory and anti-arthritic activity of ethanolic extract of Clitoria ternatea roots (EECT) in animal models. Methods: The anti-inflammatory activity of the EECT was evaluated by carrageenan and histamine-induced paw edema. Results: EECT showed a significant reduction in mean paw edema volume in both carrageenan and histamine-induced inflammation. The efficacy of EECT in rheumatoid arthritis was tested against Freund's complete adjuvant (CFA) induced arthritic model in Wistar rats. The anti-arthritic effect of EECT was determined by systematic scoring of arthritis symptoms and measuring paw edema. A considerable decrease in paw diameter was observed in the EECT (200 and 400 mg/kg) and diclofenac (10 mg/kg) treated groups after day 7. Diclofenac (10 mg/kg) and EECT (400 mg/kg) showed a significant reduction in paw diameter from day 14 compared with CFA control (P < 0.001). The anti-arthritic activity was also confirmed from the altered biochemical, haematological (Hb, RBC and WBC) and anti-oxidant parameters (SOD, MDA, CAT, and GSH). EECT (400 and 200 mg/kg) also showed a marked inhibition of joint destruction. Conclusion: This study provides a pharmacological rationale for the traditional use of C. ternatea against inflammation and rheumatoid arthritis in India.

Ropinirole, a potential drug for systematic repositioning based on side effect profile for management and treatment of breast cancer.

Drug repositioning offers two main advantages in drug discovery - the process is less tedious and less costly. In the past, many drugs like thalidomide and sildenafil were successfully repositioned but the process was entirely serendipitous. These days drug repositioning is widely accepted as an alternate method of drug discovery and the process is based on building a strong hypothesis guided by systematic computational and experimental methods. One of the methods used in drug repositioning is based on shared side effects by drugs of different pharmacological categories. This method rests on the principle that drugs that share side effects might also share common biological targets and therefore same pharmacological indications. Old drugs can be repositioned for new uses by identifying the shared side effects of existing drugs and by modulating their chemical structure if required. Breast cancer is the most common type of cancer in women and the second leading cause of death worldwide after lung cancer in both men and women. Letrozole, an aromatase inhibitor, is used in the treatment of advanced, recurrent and metastatic breast cancer in post-menopausal women. Identification of drugs that share side effects with letrozole might help us to identify a potential drug for repositioning in the treatment of breast cancer. Ropinirole, a dopaminergic agonist was found to share the maximum number of side effects with letrozole. Studies have proposed that dopaminergic agonists induce apoptosis in breast, colon, ovarian cancer cells and leukemia neuroblastoma. This is consistent with our hypothesis that ropinirole that shares the maximum number of side effects with letrozole might be effective in the management of breast cancer. This hypothesis was further validated by preliminary molecular docking and in-vitro cell-line studies.