Diosgenin (DG) is a saponin glycoside and an active constituent generally present in medicinal plants like Rhizoma polgonita, Trigonella foenum, Dioscorea villosa and Dioscorea rhizome. It is also the starting material for the biosynthesis of steroidal hormones. DG has also been reported as a multipurpose drug aiding in the treatment of various cardiovascular, neurological diseases as well as as malignancies, osteoporosis, diabetes, and atherosclerosis. The underlying mechanisms of DG contributing towards potential therapeutic ability is to suppress the expression of oncogenic genes, preventing the formation of free radicals and thereby resulting in neuroprotection etc. However, the use of DG is restricted due to its limited pharmacokinetic properties such as poor aqueous solubility, poor bioavailability, and quicker biotransformation into its metabolites. Hence, in this study we have briefed the current therapeutic approaches of DG and its derivatives alongside to its medicinal chemistry and its physicochemical, pharmacological & toxicological properties.
Excitotoxicity, depletion of energy metabolites, and ionic imbalance are the major factors involved in neurodegeneration mediated through excitatory amino acid transporter-2 (EAAT-2) dysfunction in ischemic insult. Recent studies have revealed that ceftriaxone expresses EAAT-2 via nuclear transcription factor kappa-B (NF-kB) signaling pathway, stimulation of EAAT-2 expression in the ischemic, and excitotoxic conditions that could provide potential benefits to control neurodegeneration. In this study, we have predicted the in silico model for interaction between NF-kB and EAAT-2 promoter region to rule out the conformational changes for the expression of EAAT-2 protein. Using homology-built model of NF-kB, we identified ceftriaxone-induced conformational changes in gene locus −272 of DNA where NF-kB binding with EAAT-2 promoter region through protein−DNA docking calculation. The interaction profile and conformational dynamics occurred between ceftriaxone predocked and postdocked conformations of NF-kB with DNA employing HADDOCK 2.2 web server followed by 250 ns long all atom explicit solvent molecular dynamics simulations. Both the protein and DNA exhibited modest conformational changes with respect to HADDOCK score, energy terms (desolvation energy [E desolv ]), van der waal energy (E vdw ), electrostatic energy (E elec ), restraints energy (E air ), buried surface area, root mean square deviation, RMSF, radius of gyration, total hydrogen bonds when ceftriaxone pre-and postdocked NF-kB conformations were bound to DNA. Hence, the conformational changes in the C-terminal domain could be the reason for EAAT-2 expression through ceftriaxone specific binding pocket of −272 of DNA.
Multiple sclerosis (MS) is one of the most affecting autoimmune neurodegenerative disease characterized by chronic neuroinflammation, demyelination and impaired neuronal conduction. The oligodendrocytes toxicity by inflammatory cytokines and oxy-radicals are considered to be the most important factor in demyelination of motor neurons. The dysfunction of neuronal A1 adenosine receptor (A1AR) contributes to the demyelination of neurons by triggering the pro-inflammatory cytokines, oxy-radicals and neuroinflammatory cascades. In MS pathogenesis, Antigen presenting cells, MHC protein, CD4+T-cells, GM-CSF along with effector cells enhance the activation of macrophages in adenosinergic declined conditions, where it shows cumulative effects which leads to oligodendrocytes toxicity and demyelination of motor neurons. In general, A1AR is mainly expressed in macrophage lineage cells in central nervous system which could control the macrophage activation upon stimulation by its agonists. In this review, we have mainly emphasized on the pathogenesis of MS and highlighted the importance of adenosinergic system in reversing the molecular events in MS. In addition, we have discussed about the beneficial role of A1AR agonists in MS management.
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