intra-arterial-delivery-neural-stem-cells-to-rat-mouse-brain

Intra-Arterial Delivery of Neural Stem Cells to the Rat and Mouse Brain: Application to Cerebral Ischemia

Neural stem cell (NSC) therapy is an emerging innovative treatment for stroke, traumatic brain injury and neurodegenerative disorders. As compared to ...

University of Kentucky

Skin cancer is one of the most commonly diagnosed cancers in the United States. Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, is present in various vegetables and fruits especially in edible berries, and displays potent antioxidant and anticarcinogenic properties. In this study, we have assessed the in vivo effects of C3G on UVB irradiation induced chronic inflammatory responses in SKH-1 hairless mice, a well-established model for UVB-induced skin carcinogenesis. Here, we show that C3G inhibited UVB-induced skin damage and inflammation in SKH-1 hairless mice. Our results indicate that C3G inhibited glutathione depletion, lipid peroxidation and myeloperoxidation in mouse skin by chronic UVB exposure. C3G significantly decreased the production of UVB-induced pro-inflammatory cytokines, such as IL-6 and TNF-α, associated with cutaneous inflammation. Likewise, UVB-induced inflammatory responses were diminished by C3G as observed by a remarkable reduction in the levels of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Furthermore, C3G also decreased UVB-induced cyclooxygenase-2 (COX-2), PGE2 and iNOS levels, which are well-known key mediators of inflammation and cancer. Treatment with C3G inhibited UVB-induced nuclear translocation of NF-κB and degradation of IκBα in mice skin. Immunofluorescence assay revealed that topical application of C3G inhibited the expression of 8-hydroxy-2'-deoxyguanosine, proliferating cell nuclear antigen, and cyclin D1 in chronic UVB exposed mouse skin. Collectively, these data indicates that C3G can provide substantial protection against the adverse effects of UVB radiation by modulating UVB-induced MAP kinase and NF-κB signaling pathways. 

Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin.

Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at 48h intervals, or five sham injuries at 24h intervals were evaluated across a 10 week period after injury. Animals with repeated CHI exhibited motor coordination and memory deficits, but not gait abnormalities when compared to sham animals. At 10wks post-injury, no notable neuron loss or glial reactivity was observed in the cortex, hippocampus, or corpus callosum. Argyrophilic axons were found in the pyramidal tract of some injured animals, but neither silver stain accumulation nor inflammatory responses in the injury groups were statistically different from the sham group in this region. However, argyrophilic axons, microgliosis and astrogliosis were significantly increased within the optic tract of injured animals. Repeated mild CHI also resulted in microgliosis and a loss of neurofilament protein 200 in the optic nerve. Lengthening the inter-injury interval from 24h to 48h did not effectively reduce these behavioral or cellular responses. These results suggest that repeated mild CHI results in persistent behavioral dysfunction and chronic pathological changes within the visual system, neither of which was significantly attenuated by lengthening the inter-injury interval from 24h to 48h. 

Repeated Closed Head Injury in Mice Results in Sustained Motor and Memory Deficits and Chronic Cellular Changes.

Traumatic brain injury can result in lasting cognitive dysfunction due to degeneration of mature hippocampal neurons as well as the loss of immature neurons within the dentate gyrus. While endogenous neurogenesis affords a partial recovery of the immature neuron population, hippocampal neurogenesis may be enhanced through therapeutic intervention. Insulin-like growth factor-1 (IGF-1) has the potential to improve cognitive function and promote neurogenesis after TBI, but its short half-life in the systemic circulation makes it difficult to maintain a therapeutic concentration. IGF-1 modified with a polyethylene glycol moiety (PEG-IGF-1) exhibits improved stability and half-life while retaining its ability to enter the brain from the periphery, increasing its viability as a translational approach.

Assessment of systemic administration of PEGylated IGF-1 in a mouse model of traumatic brain injury.

Mild traumatic brain injuries (mTBI), accounting for more than 80% of TBIs, can cause cognitive and behavioral impairments, the severity and duration of which increase after additional mTBIs. While mTBI does not cause widespread neuronal death, the mechanisms underlying increased cellular susceptibility to subsequent head impacts remain unknown. To investigate the hypothesis that altered mitochondrial bioenergetics underlie cellular vulnerability to repeated insults, we employed a mouse model of mild closed head injury (CHI) to examine mitochondrial function and oxidative stress, because these mechanisms are often intertwined. Mitochondrial respiration was assayed (Seahorse XFe24 Flux Analyzer) from cortex and hippocampus collected at 6 h, 24 h, 48 h, and 96 h post-injury. State III (adenosine diphosphate [ADP]-mediated) respiration was significantly decreased in the hippocampal mitochondria of the CHI group compared with sham at 48 h post-injury. Further, cortex-derived mitochondria exhibited a decrease in State III respiration at 24 h and 48 h post-injury. No significant differences were observed at 6 h or 96 h post-injury in either region of interest. A second CHI repeated either 48 h or 96 h after the first did not worsen State III respiration at 48 h after the final injury compared with a single CHI, but CHI repeated at a 48 h interval prolonged cortical mitochondrial dysfunction to 96 h after the final injury. Markers of oxidative stress were significantly elevated after two CHIs delivered 48 h apart, but not after single CHI or two CHI delivered 96 h apart. This study establishes that mTBI results in early mitochondrial dysfunction, which may be a determinant for cellular vulnerability to repeated head impacts. Thus, therapies targeting mitochondrial impairment could improve outcomes after repeated mTBI.

Binoy Joseph

Spinal Cord and Brain Injury Research Center,
Department of Physiology,
Spinal Cord and Brain Injury Research Center, Department of Physiology

University of Kentucky

Intra-Arterial Delivery of Neural Stem Cells to the Rat and Mouse Brain: Application to Cerebral Ischemia

Binoy Joseph

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Spinal Cord and Brain Injury Research Center,Department of Physiology,Spinal Cord and Brain Injury Research Center, Department of Physiology

University of Kentucky

Intra-Arterial Delivery of Neural Stem Cells to the Rat and Mouse Brain: Application to Cerebral Ischemia

Spinal Cord and Brain Injury Research Center,
Department of Physiology,
Spinal Cord and Brain Injury Research Center, Department of Physiology