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Combined Therapeutics: Future Opportunities for Co-therapy with Thrombectomy.

ABSTRACT: Stroke is an urgent public health issue with millions of patients worldwide living with its devastating effects. The advent of thrombolysis and endovascular thrombectomy has transformed the hyperacute care of these patients. However, a significant proportion of patients receiving these therapies still goes on to have unfavorable outcomes and many more remain ineligible for these therapies based on our current guidelines. The future of stroke care will depend on an expansion of the scope of thrombolysis and endovascular thrombectomy to patients outside traditional time windows, more distal occlusions, and large vessel occlusions with mild clinical deficits, for whom clinical trial results have not proven therapeutic efficacy. Novel cytoprotective therapies targeting the ischemic cascade and reperfusion injury therapy, in combination with our existing treatment modalities, should be explored to further improve outcomes for these patients with acute ischemic stroke. In this review, we will review the current status of thrombolysis and thrombectomy, suggest additional data that is needed to enhance these therapies, and discuss how cytoprotection might be combined with thrombectomy.

SUBMITTER: Rajendram P

PROVIDER: S-EPMC10275848 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Combined Therapeutics: Future Opportunities for Co-therapy with Thrombectomy.

Rajendram Phavalan P Ikram Asad A Fisher Marc M

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20230321 3

Stroke is an urgent public health issue with millions of patients worldwide living with its devastating effects. The advent of thrombolysis and endovascular thrombectomy has transformed the hyperacute care of these patients. However, a significant proportion of patients receiving these therapies still goes on to have unfavorable outcomes and many more remain ineligible for these therapies based on our current guidelines. The future of stroke care will depend on an expansion of the scope of throm ...[more]

PMID: 36943636

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Project description:Peroxisome proliferator-activated receptor gamma (PPAR?) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism, endothelial function and inflammation. Rosiglitazone (RGZ) and other thiazolidinedione (TZD) synthetic ligands of PPAR? are insulin sensitizers that have been used for the treatment of type 2 diabetes. However, undesirable side effects including weight gain, fluid retention, bone loss, congestive heart failure, and a possible increased risk of myocardial infarction and bladder cancer, have limited the use of TZDs. Therefore, there is a need to better understand PPAR? signaling and to develop safer and more effective PPAR?-directed therapeutics. In addition to PPAR? itself, many PPAR? ligands including TZDs bind to and activate G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor 1. GPR40 signaling activates stress kinase pathways that ultimately regulate downstream PPAR? responses. Recent studies in human endothelial cells have demonstrated that RGZ activation of GPR40 is essential to the optimal propagation of PPAR? genomic signaling. RGZ/GPR40/p38 MAPK signaling induces and activates PPAR? co-activator-1?, and recruits E1A binding protein p300 to the promoters of target genes, markedly enhancing PPAR?-dependent transcription. Therefore in endothelium, GPR40 and PPAR? function as an integrated signaling pathway. However, GPR40 can also activate ERK1/2, a proinflammatory kinase that directly phosphorylates and inactivates PPAR?. Thus the role of GPR40 in PPAR? signaling may have important implications for drug development. Ligands that strongly activate PPAR?, but do not bind to or activate GPR40 may be safer than currently approved PPAR? agonists. Alternatively, biased GPR40 agonists might be sought that activate both p38 MAPK and PPAR?, but not ERK1/2, avoiding its harmful effects on PPAR? signaling, insulin resistance and inflammation. Such next generation drugs might be useful in treating not only type 2 diabetes, but also diverse chronic and acute forms of vascular inflammation such as atherosclerosis and septic shock.

Dataset Information

Combined Therapeutics: Future Opportunities for Co-therapy with Thrombectomy.

Publications

Combined Therapeutics: Future Opportunities for Co-therapy with Thrombectomy.

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