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New small molecule strongly reduces neuroinflammation in brain and glial cells-ScienceDaily

Neuroinflammation not only exacerbates the consequences of stroke, traumatic brain injury, or spinal cord injury, but can also accelerate neurodegenerative diseases such as ALS, Parkinson’s disease, and Alzheimer’s disease. This suggests that limiting neuroinflammation may represent a promising new approach for treating neurological disorders and neuropathic pain caused by neuroinflammation.

In preclinical studies published in the journal Glia, Peter King, MD, and Burt Nabors, MD show that their small molecule drug SRI-42127 can strongly reduce the trigger of neuroinflammation. These experiments in glial cell cultures and mice open the door for testing SRI-42127 in models of acute and chronic nerve damage.

Glial cells are non-nerve cells of the central nervous system (CNS) that help support and protect neurons. One type, microglia, are brain macrophages that respond to injury and infection. “Microglia and astroglia are important cells of the central nervous system, and when activated, they cause neuroinflammation by secreting toxic inflammatory mediators such as cytokines and chemokines,” said King and Neighbors. increase.

King and Nabors, professors of the Department of Neurology, Birmingham, University of Alabama, have been working together for 25 years to study the mechanisms that cause neuroinflammation and the role of neuroinflammation in nerve injury, degenerative diseases, and cancer. They say that this current study relies on an important RNA-binding protein called HuR, which protects microglia and astroglia cells from degradation of the messenger RNA encoding inflammatory mediators and promotes translation into proteins. It is said that it is based on the previous discovery.

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

Colleagues from King, Nabors, and UAB have previously shown that HuR, an RNA regulator protein that binds to ARE, plays a major positive role in the regulation of inflammatory cytokine production and is a major control point for neuroinflammation. I did.

HuRs are usually concentrated in the nucleus of glial cells. However, when glial cells are activated, HuR translocates from the nucleus to the cytoplasm and stimulates the production of neuroinflammatory cytokines and chemokines.

In a previous study, UAB researchers showed that HuR migrates from the nucleus of stellate cells in spinal cord injury and stroke in acute CNS disease. They also showed that it migrated from the nucleus of the chronic central nervous system disease ALS, or amyotrophic lateral sclerosis microglia.

Importantly, the monomeric HuR cannot cross the nuclear envelope, which acts as a regulatory membrane barrier between the nucleus and cytoplasm. Only HuR dimers composed of the bonds of two single HuR molecules can move from the nucleus to the cytoplasm. This knowledge has enabled a collaborative study by Southern Research in Birmingham, Alabama, and UAB using high-throughput screening to identify the small molecule drug SRI-42127 that inhibits HuR dimerization.

Current studies include King, Nabors, Natalia Filippova, Ph.D. , And a UAB colleague tested the biological association of SRI-42127 using lipopolysaccharide (LPS), activating glial cells and initiating an inflammatory cascade. UAB researchers have found that treatment with SRI-42127 suppresses the transfer of HuR from the nucleus to the cytoplasm of LPS-activated glial cells in both tissue culture and mice. SRI-42127 also significantly suppressed the production of inflammatory mediators such as the cytokines IL1β, IL-6, TNF-α, iNOS, chemokines CXCL1 and CCL2.

In addition, SRI-42127 suppressed microglial activation in the mouse brain and reduced the recruitment of immune cells neutrophils and monocytes from outside the blood-brain barrier to the CNS. Such invasion of neutrophils and monocytes can exacerbate inflammation of the brain and spinal cord. In summary, SRI-42127 crossed the blood-brain barrier and rapidly suppressed the neuroinflammatory response.

“Our findings indicate the important role of HuR in promoting glial cell activation and the potential of SRI-42127 and other HuR inhibitors to treat neurological disorders caused by this activation. Is emphasized. “

King and Neighbors are Robert Sorge, Ph.D., Associate Professor of Psychology, UAB University of Arts and Sciences. In an unpublished study in collaboration with, we found a potential beneficial effect of SRI-42127 on reducing neuropathic pain. It is caused by microglial-induced neuroinflammation. “This will be a non-opioid approach to treating pain,” they said.

Future potential clinical treatments will require sophistication.

“Therapeutic targeting of glia in CNS disease is a balancing act as these cells also exert neuroprotective and neurogenic effects depending on the stage of recovery from CNS damage or the stage of neurodegenerative disease.” King and Nabors said. “In the early stages after spinal cord injury, traumatic brain injury or stroke, inflammation-induced activation of glia exacerbates secondary tissue damage and is chronic, as opposed to the more chronic stages where glia become protective. It induces the pathway of neuropathic pain. Like ALS and Alzheimer’s disease, glia also play a role in changing during the course of the disease during the process of inflammatory degeneration. “

“SRI-42127, a novel small molecule inhibitor of the RNA regulator HuR, strongly attenuates glial activation in models of lipopolysaccharide-induced neuroinflammation,” co-authored by King, Nabors, and Filippova in the current study, Rajeshwari. My name is Chellappan and Abhishek Guha. , Ying Si, Thaddaeus Kwan, Xiuhua Yang, Ash S. Myneni, Shriya Meesala, Ashley S. Harms, UAB Neurology.

There was support from the National Institutes of Health grants NS092651 and NS111275-01, and the US Department of Veterans Affairs grant BX001148.

In a long collaboration, King and Nabors used the primary brain tumor, glioblastoma, as a disease model to study HuR, as many of the factors that cause neuroinflammation also promote glioblastoma growth. I’ve been doing it. Nabors has 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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