Ramping up post-stroke neurogenesis

Neurogenesis increases after stroke, but is largely unsuccessful at repairing injury. In part this is due to the low survival of newly generated neurons. We have focused on identifying the vulnerabilities of immature neurons, and ways to increase survival in the post-stroke brain. We have discovered that immature neurons are especially sensitive to mitochondrial inhibition, dying rapidly with even mild levels of mitochondrial inhibition. We then found several ways to support mitochondrial function and improve neuronal survival. These include direct provision of mitochondrial substrates, reduction of inflammation which impairs mitochondrial function, and altering miRNAs that influence mitochondrial function. As mitochondrial function is also a central determinant of inflammatory activation patterns of immune cells, mitochondrial protective strategies improve immature neuronal survival by at least two distinct mechanisms, reduction of inflammation, which inhibits neurogenesis, and directly increasing survival of immature neurons.

  1. Voloboueva LA, Lee SW, Emery JF, Palmer TD, Giffard RG. Mitochondrial Protection Attenuates Inflammation-Induced Impairment of Neurogenesis. In Vitro and In Vivo. Journal of Neuroscience:30:12242-51, 2010.
  2. Voloboueva LA, Giffard RG. Inflammation, mitochondria, and the inhibition of adult neurogenesis. Journal of Neuroscience Research 89: 1989-1996, 2011.
  3. Voloboueva LA, Emery JF, Sun X, Giffard RG. Inflammatory response of microglial BV2 cells includes a glycolytic shift and is modulated by mitochondrial glucose regulated protein 75/mortalin. FEBS Letters, 587(6):756-62, 2013.
  4. Ouyang YB, Stary CM, White RE, Giffard RG. The Use of microRNAs to Modulate Redox and Immune Response to Stroke. Antioxidants & Redox Signaling. 22(2): 187-202, 2015.

MicroRNAs to treat stroke

Translation of treatments for stroke from preclinical models to the clinic have been largely unsuccessful. We have been studying the effects of microRNAs (miR) in stroke, and their ability to regulate levels of cell survival proteins. miRNAs are short non-coding RNAs that regulate expression of messenger RNAs (mRNA) by base pairing over short recognition sequences of 5-7 bp, so they can regulate multiple mRNAs, suppressing protein synthesis. We have focused on the ability of miR-181 to alter outcome from both stroke, or focal cerebral ischemia, and forebrain ischemia, the pattern of neurodegeneration seen after cardiac arrest and resuscitation. miR-181 targets both chaperone proteins and antiapoptotic proteins, both of which are beneficial in protecting brain from injury. We found that inhibiting miR-181, which allows the mRNAs to which it binds to express proteins, is protective in both these models. We then tested the ability to improve stroke outcome when the miRNA inhibitor was given after the stroke, and found that this was still effective. This raises the exciting possibility that miRNA treatments can be developed to influence neurodegeneration, as clinical trials are already underway for miRNA drugs in other diseases.

  1. Xu LJ, Ouyang YB, Xiong X, Stary CM, Giffard RG. Post-stroke treatment with miR-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia. Experimental Neurology.264:1-7 S0014-4886(14)00367-7, 2014.
  2. Moon JM, Xu L, Giffard RG. Inhibition of microRNA-181 reduces forebrain ischemia induced neuronal loss. Journal of Cerebral Blood Flow and Metabolism, 33(12): 1976-82, 2013.
  3. Ouyang YB, Lu Y, Yue S, Xu L, Xiong X, White RE, Sun X, Giffard RG. miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo. Neurobiology of Disease 45: 555–563, 2012.
  4. Ouyang YB, Lu Y, Yue S, Giffard RG. miR-181 targets multiple Bcl-2 family members and influences apoptosis and mitochondrial function in astrocytes. Mitochondrion, 12: 213-219, 2012.

Classification of chronic pelvic pain based on brain biomarkers:

First study to use objective brain based biomarkers to detect and classify chronic pelvic pain. Using Neuroimaging data we collected as part of an NIH multicenter project to characterize chronic pelvic pain, we used machine learning approaches to a known dataset of women with pelvic pain. We then developed a brain “signature” to characterize the presence or absence of chronic pain. Using this signature, we were able to classify with 73% accuracy. This builds on our prior work of classifying chronic back pain (Ung, et al, Cerebral Cortex, 2012).

  1. Bagarinao, E, Johnson, K, Martucci, K, Ichesco, E, Labus, J, Ness, TJ, Farmer, M, Maravilla, K, Harris, RE, Deutsch, G, Apkarian, AV, Mayer, EA, Clauw, DJ, and Mackey, S, Preliminary structural MRI based brain classification of chronic pelvic pain: A MAPP Network Study Pain, 2014

CHOIR (Collaborative Health Outcomes Information Registry)
In response to the Institute of Medicine Report Relieving Pain in America, and in partnership with the National Institutes of Health, we have developed and implemented an open source, open standard, and free national Collaborative Health Outcomes Information Registry (CHOIR) system. CHOIR is being used to collect data from larger numbers of patients for: (1) point of care decision making, (2) longitudinal assessment, (3) comparative effectiveness research, and (4) large simple trial designs. CHOIR has now expanded into other academic pain centers and other medical specialties.