Nimit Kasliwal

 Introduction: Traumatic brain injuries (TBI’s) are a leading cause of morbidity and disability around the world. TBI’s occur when the head and an object impact each other or from accelerative or decelerative forces that produce forceful movement of the brain within the skull, which is referred to as the “primary injury”¹. During the body’s immune response, inflammation is increased due to M1 microglial activation and increased expression of proinflammatory cytokines. However, in moderate to severe TBIs, this inflammation persists for protracted periods and leads to neurodegenerative effects that impair motor and cognitive functions (“secondary injury”)^2,8. Studies demonstrated modulation of microglial activation towards an M2 phenotype and reduction of inflammatory cytokines by inhibiting stimulator of interferon genes (STING) or using a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which alleviated cognitive and motor impairments secondary to neurodegeneration^3,4. Methods: The STING study, using wild type (WT) and STING^-/- mice, performed a 1.5 mm controlled cortical impact (CCI) surgery, and analyzed the brain samples using PCR, Western blot, and immunohistochemistry³. The mGluR5 study administered VuPAM (a mGluR5 positive allosteric modulator) to adult mice that underwent 2 mm CCI and to microglial cultures and analyzed the brains/microglia using PCR, Western blot, and immunohistochemical analyses⁴. Results: The STING knockout mice showed decreased IFN-b expression, decreased microglial activity, and decreased lesion volume compared to the WT mice³. Previous studies have already shown that IFN-b inhibition decreases inflammatory cytokine expression (including TNF-a, NOX2, IL-6, IL-1b, CCL5, CXCL10) after TBI and leads to a reduction in cognitive and motor decline⁵. In the mGluR5 study, when compared to the WT group, the administration of VuPAM decreased expression of proinflammatory cytokines (TNF-a, NOX2, CD68, IL-6) and increased expression of anti-inflammatory markers, including IL-10 and YM-1. Such anti-inflammatory effects were also associated with decreased lesion volume and reduced cognitive and motor impairments⁴. Conclusion: To reduce inflammation that leads to neurodegeneration, it is important to target the proinflammatory processes that cause it. By inhibiting STING or using a positive allosteric modulator of mGluR5, like VuPAM, there was a reduction in inflammation, thus leading to better outcomes after moderate to severe TBI. Therefore, STING inhibitors and VuPAM warrant further exploration as potential therapeutic strategies to treat cognitive and motor impairments due to neurodegenerative effects following a TBI.

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