New small molecules can effectively reduce neuroinflammation in the brain and glial cells

In a preclinical study published in the journal Glia, Dr.

Glial cells are non-neuronal cells of the central nervous system (CNS) that help support and protect neurons

King and Nabors are both professors in the Department of Neurology at the University of Alabama at Birmingham.

Neuroinflammation occurs when the activated microglia and astrocytes in the brain or spine secrete cytokines and chemokines such as il-1β, IL-6, TNF-α, iNOS, CXCL1 and CCL2

The colleagues of King, Nabors, and UAB have previously demonstrated that HuR, an RNA regulatory protein that binds to AREs, plays a major active role in regulating the production of inflammatory cytokines, making it the main control point of neuroinflammation

HuR is usually concentrated in the nucleus of glial cells

In previous work, UAB researchers showed that in acute central nervous system diseases, spinal injuries, and strokes, HuR tends to be located outside the nucleus of astrocytes

It is important that HuR monomer cannot pass through the nuclear membrane, which is the regulatory membrane barrier between the nucleus and the cytoplasm

In the current study, Dr.

In addition, SRI-42127 inhibits the activation of mouse brain microglia and attenuates the recruitment of immune cells, neutrophils and monocytes from outside the blood-brain barrier into the central nervous system

"Our findings," King and Nabors said, "emphasize the key role of HuR in promoting glial activation and the potential of SRI-42127 and other HuR inhibitors to treat neurological diseases caused by this activation

In an unpublished study in collaboration with Dr.

Any potential clinical treatment in the future requires skill

"Therapeutic targeting of glial cells in central nervous system diseases is a balancing act, because these cells also play a role in neuroprotection and neuroplasticity, depending on the recovery stage of central nervous system damage or the stage of neurodegenerative diseases ," King and Nabors said

In the current study, co-authors with King, Nabors and Filippova, "SRI-42127, a new small molecule inhibitor of the RNA regulator HuR, effectively attenuates glial activation in a model of lipopolysaccharide-induced neuroinflammation," They are Rajeshwari Chellappan, Abhishek Guha, Ying Si, Thaddaeus Kwan, Xiuhua Yang, Anish S.

Support comes from the National Institutes of Health NS092651 and NS111275-01, and the U.

In their long-term collaboration, King and Nabors used glioblastoma (a primary brain cancer) as a disease model to study HuR, because many factors that drive neuroinflammation also promote the growth of glioblastoma
.
Nabors focuses on the tumor suppressor properties of SRI-42127 and its potential application in the treatment of glioblastoma and other cancers
.

Journal Reference :

1. Rajeshwari Chellappan, Abhishek Guha, Ying Si, Thaddaeus Kwan, Louis B.
   Nabors, Natalia Filippova, Xiuhua Yang, Anish S.
   Myneni, Shriya Meesala, Ashley S.
   Harms, Peter H.
   King.
   SRI ‐42127, a novel small molecule inhibitor of the RNA regulator HuR, potently attenuates glial activation in a model of lipopolysaccharide-induced neuroinflammation .
   Glia , 2021; DOI: 10.
   1002/glia.
   24094