New small molecule powerfully attenuates neuroinflammation in brain and glial cells – sciencedaily

Neuroinflammation can worsen the consequences of stroke, traumatic brain injury or spinal cord injury, as well as accelerate neurodegenerative diseases like ALS, Parkinson’s disease or Alzheimer’s disease. This suggests that limiting neuroinflammation may represent a promising new approach for treating neurological diseases and neuropathic pain that are induced by neuroinflammation.

In a preclinical study published in the journal Glia, Peter King, MD, and Burt Nabors, MD, show that their small molecule drug, SRI-42127, can strongly attenuate triggers for neuroinflammation. These experiments on glial cell cultures and mice now open the door to testing SRI-42127 in models of acute and chronic neurological injury.

Glial cells are the non-neuronal cells in the central nervous system, or CNS, that help support and protect neurons. One of the types, microglia, are brain macrophages that respond to injury or infection. “Microglia and astroglia are key cells in the central nervous system that, when activated, cause neuroinflammation by secreting toxic inflammatory mediators, including cytokines and chemokines,” King and Nabors said.

King and Nabors, both professors at the University of Alabama in the Birmingham Department of Neurology, have collaborated for 25 years to study the mechanisms that trigger neuroinflammation and the role of neuroinflammation in neurological damage, degenerative diseases and the cancer. They say this current study builds on their earlier findings that microglia and astroglia cells rely on a key RNA-binding protein called HuR that protects messenger RNAs encoding inflammatory mediators of the cell. degradation and promotes their translation into proteins.

Neuroinflammation occurs when microglia and activated astrocytes in the brain or spine secrete cytokines and chemokines like IL1β, IL-6, TNF-α, iNOS, CXCL1, and CCL2. The messenger RNAs of these pro-inflammatory signaling proteins contain elements rich in adenine and uridine, or ARE, which govern their expression.

Colleagues from King, Nabors and UAB have already shown that HuR, an RNA regulatory protein that binds to AREs, plays a major positive role in regulating the production of inflammatory cytokines, making it a major checkpoint. in neuroinflammation.

HuR normally concentrates in the nuclei of glial cells. However, when glial cells are activated, HuR travels out of the nucleus and into the cell cytoplasm, where it can stimulate the production of neuroinflammatory cytokines and chemokines.

In previous work, UAB researchers have shown that HuR exits the nucleus of astrocytes in acute CNS disease, spinal injury and stroke. They have also shown that it travels out of the nucleus into the microglia in ALS, a chronic CNS disease, or amyotrophic lateral sclerosis.

It is important to note that the HuR monomer cannot cross the nuclear envelope which acts as a regulatory membrane barrier between the nucleus and the cytoplasm. Only the HuR dimers – formed by the coupling of two unique HuR molecules – are able to move from the nucleus to the cytoplasm. This knowledge enabled collaborative research by Southern Research, of Birmingham, Alabama and UAB, using high throughput screening, to identify the small molecule drug SRI-42127 which inhibits the dimerization of HuR.

In the present study, King, Nabors, Natalia Filippova, Ph.D., and their colleagues at UAB tested the biological relevance of SRI-42127, using lipopolysaccharide, or LPS, to activate glial cells in order to initiate the inflammatory cascade. UAB researchers found that treatment with SRI-42127 suppressed the HuR translocation from the nucleus to the cytoplasm in LPS-activated glial cells, both in tissue culture and in mice. SRI-42127 also significantly attenuated the production of pro-inflammatory mediators, including the cytokines IL1β, IL-6, TNF-α and iNOS, and the chemokines CXCL1 and CCL2.

In addition, SRI-42127 suppressed microglial activation in the brain of mice and attenuated the recruitment of neutrophils and monocytes of immune cells into the CNS from outside the blood-brain barrier. Such entry of neutrophils and monocytes can exacerbate inflammation in the brain or spinal cord. In summary, SRI-42127 penetrated the blood brain barrier and rapidly suppressed neuroinflammatory responses.

“Our results,” said King and Nabors, “underscore the essential role of HuR in promoting glial activation and the potential of SRI-42127 and other HuR inhibitors to treat neurological diseases induced by this activation. “

In unpublished work in collaboration with Robert Sorge, Ph.D., associate professor in the Department of Psychology, UAB College of Arts and Sciences, King and Nabors discovered potential beneficial effects of SRI-42127 in reducing neuropathic pain, a condition that is triggered by microglia-induced neuroinflammation. “It would be a non-opioid approach to treating pain,” they said.

Any potential future clinical treatment will require finesse.

“Therapeutic targeting of glia in CNS disease is a balancing act since these cells also exert neuroprotective and neuroplastic effects, depending on the stage of recovery from a CNS injury or the stage of the neurodegenerative disease” King and Nabors said. “In the initial stages after spinal cord injury, head trauma, or stroke, pro-inflammatory activation of the glia worsens secondary tissue damage and triggers chronic neuropathic pain pathways, unlike more severe stages. chronic conditions where the glia becomes protective. In neurodegenerative processes such as ALS and Alzheimer’s disease, the glia also plays changing roles during the disease. “

The coauthors with King, Nabors and Filippova in the present study, “SRI-42127, a novel small inhibitor of RNA regulator molecules HuR, potently attenuates glial activation in a model of lipopolysaccharide-induced neuroinflammation”, are Rajeshwari Chellappan, Abhishek Guha, Ying Si, Thaddaeus Kwan, Xiuhua Yang, Anish S. Myneni, Shriya Meesala and Ashley S. Harms, Department of Neurology at UAB.

Support came from National Institutes of Health grants NS092651 and NS111275-01, and US Department of Veterans Affairs grant BX001148.

In their long collaboration, King and Nabors have used glioblastoma, a primary brain cancer, as a disease model to study HuR, because many factors that lead to neuroinflammation also promote the growth of glioblastoma. Nabors focused on the tumor suppressive properties of SRI-42127 and its potential use in the treatment of glioblastoma and other cancers.


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