Animals deficient in NOX4 are strongly protected from ischemic stroke ( Kleinschnitz et al., 2010 Radermacher et al., 2013). As a result of these findings NOX4, is thought to be responsible for the majority of oxidative stress observed in acute traumatic brain injury ( Cooney et al., 2013). NOX4 has been in neurons, astrocytes, and microglia, while NOX3 has been identified only in neurons, and NOX2 is expressed in microglia and neurons. During ischemic stroke NOX2, NOX3, and NOX4 isotypes modulates their expression depending on cell type and time post-injury.
The NOX enzymes are the primary source of reactive oxygen species (ROS) and are expressed by microglia after ischemic stroke ( Li et al., 2009 Cooney et al., 2013). Ischemic stroke results in acute and chronic inflammation, as a result of activation and polarization towards pro-inflammatory (M1) microglia and subsequent activation of the NADPH oxidase (NOX) enzyme. The interruption of oxygenation and metabolites results in neuronal death. It is caused by the impairment of cerebral blood flow (ischemic stroke) or the rupture of blood vessels in the brain (haemorrhagic stroke). Stroke is one of the leading causes of death in North America ( Xu et al., 2018 Statistics Canada, 2018 Rios, 2019). This study is the first to conclusively demonstrate both siRNA-carrier delivery and therapeutic efficacy in any CNS disease model where the BBB remains intact and thus offers new avenues for potential treatments of oxidative stress underlying neuroinflammation in a variety of neuropathologies that are currently refractory to existing therapies.Ī common denominator in neurodegenerative disorders such as stroke, traumatic brain injury, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, is the induction of oxidative stress triggering neuroinflammation ( Guo et al., 2013 Kowal et al., 2013 Murray et al., 2013 Bennett et al., 2014 Rubiano et al., 2015 Whiteford et al., 2015 Chiurchiù et al., 2016 Global Burden of Disease Cancer Collabration et al., 2017 Ma et al., 2017). The data demonstrates that the MTfp can act as a nanomule to facilitate BBB transcytosis of siRNAs where the NOX-4 specific siRNA moiety can elicit effective therapeutic knockdown of a gene responsible for oxidative stress in the central nervous system. Following induction of ischemic stroke, animals pretreated with the POC exhibited significantly smaller infarcts accompanied by increased protection against neurological deterioration and improved recovery. The MTfp-NOX4 POC has the ability to cross the intact BBB and knockdown NOX4 expression in the brain. A twelve-amino acid peptide that transcytoses the BBB, termed MTfp, was chemically conjugated to siRNA to create a novel peptide-oligonucleotide conjugate (POC), directed to downregulate NOX4, a gene thought responsible for oxidative stress in ischemic stroke. The blood-brain barrier (BBB) hinders the distribution of therapeutics intended for treatment of neuroinflammation (NI) of the central nervous system. 13Department of Zoology, University of British Columbia, Vancouver, BC, Canada.12Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.11Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
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