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.

Network-based drug repositioning of linagliptin as a potential agent for uterine fibroids targeting transforming growth factor-beta mediated fibrosis.

Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uterus. Furthermore, linagliptin reduced the gene expression of transforming growth factor-ß (TGF-ß), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids.

Orientin Modulates Nrf2-ARE, PI3K/Akt, JNK-ERK1/2, and TLR4/NF-kB Pathways to Produce Neuroprotective Benefits in Parkinson's Disease.

Parkinson's disease (PD) is characterized by oxidative stress and neuroinflammation as key pathological features. Emerging evidence suggests that nuclear factor erythroid 2 related factor 2-antioxidant response element (Nrf2-ARE), phosphatidylinositol 3­kinase-protein kinase B (PI3K-Akt), c-Jun N-terminal kinase-extracellular signal-regulated kinase 1/2 (JNK-ERK1/2), and toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-kB) pathways play pivotal roles in PD pathogenesis. Orientin, a phenolic phytoconstituent, has demonstrated modulatory potential on these pathways in various experimental conditions other than PD. In this study, we aimed to evaluate the neuroprotective effects of Orientin against rotenone-induced neurodegeneration in SH-SY5Y cell lines and the Swiss albino mice model of PD. Orientin was administered at doses 10 and 20 µM in cell lines and 10 and 20 mg/kg in mice, and its effects on rotenone-induced neurodegeneration were investigated. Oxidative stress markers including mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as inflammatory markers including interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), were measured. The expression levels of genes related to Nrf2-ARE (Nrf2), PI3K/Akt (Akt), JNK-ERK1/2 (TNF-α), and TLR4/NF-kB (TNF-α) pathways were measured to understand the modulatory effect of Orientin on these pathways. Additionally, behavioral studies assessing locomotor activity, muscle coordination, and muscle rigidity were conducted with mice. Our results indicate that Orientin dose-dependently attenuated rotenone-induced changes in oxidative stress markers, inflammatory markers, gene expression levels, and behavioral parameters. Therefore, our study concludes that Orientin exhibits significant neuroprotective benefits against rotenone-induced PD by modulating Nrf2-ARE, PI3K-Akt, JNK-ERK1/2, and TLR4/NF-kB pathways.

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.

The principal molecular mechanisms behind the activation of Keap1/Nrf2/ARE pathway leading to neuroprotective action in Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder. PD is associated with the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Present therapies for PD provide only symptomatic relief by restoring the dopamine (DA) level. However, they are not disease modifying agents and so they do not delay the disease progression. Alpha-synuclein aggregation, oxidative stress, mitochondrial dysfunction and chronic inflammation are considered to be the major pathological mechanisms mediating neurodegeneration in PD. To resist oxidative stress, the human body has an antioxidant defence mechanism consisting of many antioxidants and cytoprotective genes. The expression of those genes are largely controlled by the Kelch-like ECH-associated protein 1/Nuclear factor - erythroid - 2 - related factor 2/Antioxidant response element (Keap1/Nrf2/ARE) signalling pathway. The transcription factor Nrf2 is activated in response to oxidative or electrophilic stress and protects the cells from oxidative stress and inflammation. Nrf2 has been widely considered as a therapeutic target for neurodegeneration and several drugs are now being tested in clinical trials. Regulation of the Keap1/Nrf2/ARE pathway by small molecules which can act as Nrf2 activators could be effective for treating oxidative stress and neuroinflammation in PD. In this review, we had discussed the principal molecular mechanisms behind the neuroprotective effects of Keap1/Nrf2/ARE pathway in PD. Additionally, we also discussed the small molecules and phytochemicals that could activate the Nrf2 mediated anti-oxidant pathway for neuroprotection in PD.