Deciphering neuroprotective mechanism of nitroxoline in cerebral ischemia: network pharmacology and molecular modeling-based investigations.

Cerebral ischemia is one of the major causes of death and disability worldwide. Currently, existing approved therapies are based on reperfusion and there is an unmet need to search for drugs with neuroprotective effects. The present study aims to investigate the neuroprotective mechanisms of nitroxoline, a nitro derivative of 8-Hydroxyquinoline, against cerebral ischemia using integrated network pharmacology and molecular docking approaches. Critical analytical tools used were SwissTarget, PharmMapper, BindingDB, DisGeNet, Cytoscape, GeneMANIA, ShinyGo, Metascape, GeneCodis, and Schrodinger GLIDE. Thirty-six overlapping drug and disease targets were identified and used for further analysis. Gene Ontology results showed that nitroxoline enriched the genes involved in biological processes of oxidative stress and apoptotic cell death that are highly implicated in hypoxic injury. KEGG enrichment analysis showed nitroxoline influenced a total of 159 biological pathways, out of which, top pathways involved in cerebral ischemia included longevity regulating pathway, VEGF signaling, EGFR tyrosine kinase inhibitor resistance, IL-17 and HIF-1 pathways, FoxO signaling, and AGE-RAGE pathway. Protein-protein interaction analysis using string database showed PARP1, EGFR, PTEN, BRD4, RAC1, NOS2, MTOR, MAPK3, BCL2, MAPK1, APP, METAP2, MAPK14, SIRT1, PRKAA1, and MCL1 as highly interactive proteins involved in pathogenesis of ischemic stroke regulated by nitroxoline. The highly interactive protein targets were validated by molecular docking studies and molecular dynamic simulations. Amongst all these targets, nitroxoline showed the highest binding affinity towards BRD4 followed by PARP1 and PTEN. Nitroxoline, through network pharmacology analysis, showed a role in regulating proteins, biological processes, and pathways crucial in cerebral ischemia. The current study thus provides a preliminary insight that nitroxoline might be used as a neuroprotectant against cerebral ischemia via modulating the epigenetic reader BRD4 and transcription factors such as RELA, NF-κß1, and SP1. However, further in-vitro and preclinical studies need to be performed for concrete evidence.

Cardiolipin-Mediated Alleviation of Mitochondrial Dysfunction Is a Neuroprotective Effect of Statin in Animal Model of Ischemic Stroke.

In clinical settings, the benefit of statin for stroke is debatable as regular statin users may suffer from myalgia, statin-associated myopathy (SAM), and rarely rhabdomyolysis. Studies suggest that patients on statin therapy show lesser vulnerability toward ischemic stroke and post-stroke frailty. Both pre- and post-treatment benefits of statin have been reported as evident by its neuroprotective effects in both cases. As mitochondrial dysfunction following stroke is the fulcrum for neuronal death, we hereby explore the role of statin in alleviating mitochondrial dysfunction by regulating the mitochondrial dynamics. In the present study, we intend to evaluate the role of statin in modulating cardiolipin-mediated mitochondrial functionality and further providing a therapeutic rationale for repurposing statins either as preventive or an adjunctive therapy for stroke.

Advancement in CRISPR/Cas9 Technology to Better Understand and Treat Neurological Disorders.

Neurological disorders have complicated pathophysiology that may involve several genetic mutations. Conventional treatment has limitations as they only treat apparent symptoms. Although, personalized medicine is emerging as a promising neuro-intervention, lack of precision is the major pitfall. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is evolving as a technological platform that may overcome the therapeutic limitations towards precision medicine. In the future, targeting genes in neurological disorders may be the mainstay of modern therapy. The present review on CRISPR/Cas9 and its application in various neurological disorders may provide a platform for its future clinical relevance towards developing precise and personalized medicine.

Phyllanthus emblica L. Regulates BDNF/PI3K Pathway to Modulate Glutathione for Mitoprotection and Neuroprotection in a Rodent Model of Ischemic Stroke.

INTRODUCTION: Ischemic stroke remains the leading cause of death worldwide and is the primary cause of disability globally. Numerous studies have shown that plant-origin medicines are promising and can influence the treatment of neurological disorders. Phyllanthus embilica L. (P. emblica or Amla) is one of the herbal plants whose medicinal properties are widely studied. The objective of the present study is to determine the neuroprotective effects of an aqueous extract of the fruit of P. emblica (hereinafter referred to as just P. emblica) on cerebral ischemia-reperfusion injury and explore if it can regulate BDNF/PI3K pathway to modulate glutathione for mitoprotection and neuroprotection. METHODS: In vivo studies were conducted on male Sprague Dawley rats, where rats were prophylactically administered 100 mg/kg P. emblica for 30 days. In the treatment group, rats were given 100 mg/kg P. emblica, 1 h post middle cerebral artery occlusion (MCAo). Rats were evaluated for neuro deficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, protein expression studies, and mitochondrial studies. RESULTS: Prophylaxis and treatment with P. emblica demonstrated significant improvement in functional outcome with a reduction in infarct size. Normalization of glutathione, nitrite, and malondialdehyde levels was also observed. Improvement in mitochondrial complex I and IV activities was also reported. Expressions of BDNF, PI3K, SDF1 and VEGF increased while that of ROCK2 decreased following P. emblica administration. CONCLUSION: P. emblica regulates BDNF/PI3K pathway to modulate glutathione in ischemic stroke to confer mitoprotection and neuroprotection.