Stroke:

โ€‹Stroke is the fifth leading cause of death and a leading cause of disability in the United States. Globally, fifteen million people suffer from a stroke each year and five million stroke patients die with another five million left permanently disabled. Despite decades of research, no clinically effective pharmacotherapies exist to facilitate cellular functional recovery after a stroke. It is still an unmet medical need. None of the treatment options thus far has proven efficacious in clinical studies, despite tremendous outcome in preclinical studies. The failure of many agents in clinical trials could be due to the complex pathology of ischemic stroke and illustrates the sobering challenge ahead for translational stroke therapy. In this scenario, it is very important to target several key molecules simultaneously, which can work by multiple mechanisms to control the early and delayed brain injury in both the ischemic core and the penumbra. The novel approach should adopt preclinical testing, advance the understanding of the pathophysiology of stroke and make it possible to translate it from bench to bedside.

 

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Source:

Figure 1 from Coultrap et al., Acta Pharmacologica Sinica 2011; 32: 861-872

 

Our current research targets both the ischemic core and the penumbra by a combination of two cutting edge approaches; stem cell transplantation and gene silencing, which we believe could significantly improve the microenvironment of ischemic brain as well as neurological recovery after ischemic stroke. To our knowledge, this is for the first time a study has been designed which targets both the ischemic core and the penumbra by a combination of two novel approaches. Our current research could offer a potential therapeutic strategy to treat stroke.

 

 

 

Source:

Figure 6a from Chelluboina et al., Molecular Neurobiology 2014; 49: 50-65

 

 

Source:

Part of Figure 4 from Chelluboina et al., Neurochemical Research 2014; 39: 1511-1521.

 

Our recent findings in a rat model of focal cerebral ischemia provided a large list of upregulated pro-apoptotic molecules and their temporal expression profiles at both the mRNA and protein levels. Protein expression profile of various apoptotic molecules after focal middle cerebral artery occlusion (MCAO) in rats is shown in the figure above. The increased gene expression of anti-apoptotic molecules could be attributed to the activation of the bodys defense mechanism to fight against the increased apoptosis. In our recent study, as shown in the figure above, stem cell treatment 24 h post-MCAO procedure to rats reverted the mRNA expression profile of a majority of the apoptotic molecules to basal levels.

  

Related Publications

  • Chelluboina B, Klopfenstein JD, Pinson DM, Wang DZ, Vemuganti R, Veeravalli KK. Matrix metalloproteinase-12 induces blood-brain barrier damage after focal cerebral ischemia. Stroke 2015; 46: 3523-31.

  • Chelluboina B, Warhekar A, Dillard M, Klopfenstein JD, Pinson DM, Wang DZ, Veeravalli KK. Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage. Scientific Reports 2015; 5: 9504.

  • Chelluboina B, Veeravalli KK. Application of human umbilical cord blood-derived mononuclear cells in animal models of ischemic stroke. Journal of Stem Cell Research and Transplantation 2015; 2: 1014.

  • Chelluboina B, Klopfenstein JD, Gujrati M, Rao JS, Veeravalli KK. Temporal regulation of apoptotic and anti-apoptotic molecules after middle cerebral artery occlusion followed by reperfusion. Molecular Neurobiology 2014; 49: 50-65.

  • Chelluboina B, Klopfenstein JD, Pinson DM, Wang DZ, Veeravalli KK. Stem cell treatment after cerebral ischemia regulates the gene expression of apoptotic molecules. Neurochemical Research 2014; 39: 1511-1521.