TY - JOUR
T1 - Targeting vascular inflammation in ischemic stroke
T2 - Recent developments on novel immunomodulatory approaches
AU - Shekhar, Shashank
AU - Cunningham, Mark W.
AU - Pabbidi, Mallikarjuna R.
AU - Wang, Shaoxun
AU - Booz, George W.
AU - Fan, Fan
N1 - Funding Information:
The authors acknowledge support from the following Grants R21AG050049 , P20GM104357 , R01HL36279 , R01DK104184 , R01HL102042 , F32HL78147 , F32HL51971 , and R01HD067541 , T32HL105324 , and R01HL138685 from the National Institutes of Health and 16GRNT31200036 from the American Heart Association .
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/8/15
Y1 - 2018/8/15
N2 - Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.
AB - Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.
KW - Biologics
KW - Blood brain barrier
KW - IL-17
KW - Immune system
KW - Nanomedicine
KW - Tissue plasminogen activator
UR - http://www.scopus.com/inward/record.url?scp=85049805445&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2018.06.028
DO - 10.1016/j.ejphar.2018.06.028
M3 - Article
C2 - 29935175
AN - SCOPUS:85049805445
SN - 0014-2999
VL - 833
SP - 531
EP - 544
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -