Vascular smooth muscle cell (vSMC) dysfunction is a critical contributor to cardiovascular diseases, including atherosclerosis, restenosis, and vein graft failure. Recent advances have unveiled a fascinating breadth of non-coding RNAs (ncRNAs) that play a pivotal role in regulating vSMC function. This review aims to provide an in-depth analysis of the mechanisms underlying vSMC dysfunction and the therapeutic potential of various ncRNAs in mitigating this dysfunction, either preventing or reversing it. We explore the intricate interplay of microRNAs, long-non-coding RNAs and circular RNAs, shedding light on their roles in regulating key signalling pathways associated with vSMC dysfunction. Moreover, we discuss the prospects and challenges associated with developing ncRNA based therapies for this prevalent cardiovascular pathology.
Background and Purpose Quetiapine is a second-generation atypical antipsychotic drug that has been commonly prescribed for the treatment of schizophrenia, major depressive disorder (depression), and other psychological disorders. Targeted inhibition of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels, which generate Ih, may provide effective resistance against schizophrenia and depression. We investigated if HCN channels could contribute to the therapeutic effect of quetiapine, and its major active metabolite norquetiapine. Experimental Approach Two-electrode voltage clamp recordings were used to assess the effects of quetiapine and norquetiapine on currents from wild-type and mutant HCN1 and HCN2 expressed in Xenopus laevis oocytes. Key Results Norquetiapine, but not quetiapine nor 7-hydroxy quetiapine, has an inhibitory effect on HCN1 channels. Norquetiapine selectively inhibited HCN1 currents by shifting the voltage-dependence of activation to more hyperpolarized potentials in a concentration-dependent manner with an IC50 of 13.9 ± 0.8 μM for HCN1 and slowing channel opening, without changing the kinetics of closing. Inhibition by norquetiapine primarily occurs from in the closed state. Norquetiapine inhibition is not sensitive to the external potassium concentration, and therefore, likely does not block the pore. Norquetiapine inhibition also does not dependent on the cyclic-nucleotide binding domain. Norquetiapine had no effect on HCN2 channels. Conclusions and Implications HCN channels are key targets of norquetiapine, the primary active metabolite of quetiapine. These data help to explain the therapeutic mechanisms by which quetiapine aids in the treatment of anxiety, major depressive disorder, bipolar disorder, and schizophrenia, and may represent a novel structure for future drug design of HCN inhibitors.
Rationale: Fentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in dose expression and thus may differentially contribute to the racemate’s bidirectional effects. Furthermore, it is unknown which of METH’s monoamine (MA) receptor mechanisms mediate these respiratory effects. Thus, systematic evaluation of monoamine receptor selective agents may identify treatment targets for OIRD. Methods: The two optical isomers of METH, d-METH and l-METH, were tested in adult male mice to determine their effects on basal and fentanyl-depressed minute volume (MVb; i.e., respiratory frequency x tidal volum) using whole-body plethysmography. Next, six selective agonists at MA receptors involved in METH’s activity [phenylephrine (PNE; α1), clonidine (CLON; α2), SKF-82958 (SKF; D1), quinpirole (QPR; D2), 8-OH-DPAT (8-OH; 5HT1A), and DOI (5HT2)] were singly tested on basal MVb, and then in combination with fentanyl. Results: d-METH elevated MVb and l-METH decreased MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were recreated by d-METH while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg. MVb was dose-dependently increased by PNE and SKF and decreased by CLON and QPR. Neither 8-OH nor DOI altered basal MVb. Under fentanyl-depressed conditions, SKF transiently elevated MVb, while PNE more persistently increased it, while DOI transiently increased MVb, and 8-OH decreased MVb. Conclusions: d-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed with the racemate and selective activation of MA receptors altered basal respiration and OIRD.
Background and Purpose: Traumatic brain injury (TBI) imposes life-long physical, psychological, and financial burdens on affected individuals. The current study investigated the effects of chronic nicotine exposure via E-cigarette (E-cig) on TBI-associated behavioral and biochemical changes. Experimental Approach: Adult C57/BL6J male mice were subjected to controlled cortical impact (CCI) followed by daily exposure to E-cigarette (E-Cig) vapor for six weeks. The effects of chronic nicotine exposure on sensorimotor functions, locomotion, and sociability were evaluated by nesting, open field, and social approach, respectively. Immunoblots were performed to assess changes of mature brain-derived neurotrophic factor (mBDNF) and associated downstream signaling proteins (p-Akt and p-Erk). Histological analyses of the cortex were performed to evaluate the effects of chronic nicotine exposure on Microglia-mediated neuroinflammation. Key Results: Post-injury chronic nicotine exposure significantly improved nesting performance in CCI mice. Histology analysis revealed that chronic nicotine exposure increased the survival of cortical neurons in the perilesion cortex. Immunoblots of cortical tissue revealed that chronic nicotine exposure significantly upregulated mBDNF expression, P-Erk, and p-Akt in the perilesion cortical tissue of CCI mice. Additional IF microscopy revealed elevated mBDNF and p-Akt expression was predominantly localized in cortical neurons of CCI mice. Furthermore, immunolabeling of Iba1 showed that chronic nicotine exposure attenuates microglia-mediated chronic neuroinflammation in the perilesional cortex of CCI mice. Conclusions and Implications: Post-injury chronic nicotine exposure via vaping facilitates sensorimotor function recovery by upregulating neuroprotective mBDNF/TrkB/Akt/Erk signaling. Results from this study support the neuroprotective properties of nicotine, further investigation is needed due to its highly addictive nature.
Background and purpose: Bardoxolone methyl (2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor (Nrf)2, which induces anti-oxidative-associated genes. CDDO-Me is known to exert protective effects against chronic inflammatory diseases in the kidney and lungs. However, its pharmacological effects on non-alcoholic steatohepatitis (NASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO-Me in a diet-induced NASH mouse model, and elucidated its pharmacological mechanisms using RNA-seq analysis. Experimental approach: CDDO-Me was orally administered to mice fed a choline-deficient, L-amino acid-defined, high-fat diet, and histological, biochemical, and transcriptome analyses were performed on the livers of mice that developed NASH. Key results: CDDO-Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly improved the symptoms of NASH. Whole-transcriptome analysis revealed that CDDO-Me inhibited the inflammatory pathway that leads to phagocyte recruitment, in addition to activating the Nrf2-dependent pathway. Among inflammatory pathways, CC chemokine ligand (CCL)3 and CCL4 in the downstream of NF-B, which are associated with the recruitment of macrophages expressing CC chemokine receptor (CCR)1 and CCR5, were released into blood in NASH mice. In contrast, CDDO-Me directly inhibited the expression of CCL3-CCR1 and CCL4-CCR5 in macrophages. Conclusions and Implications: Overall, this study revealed the potent hepatoprotective effect of CDDO-Me in a NASH mouse model, and demonstrated that its pharmacological effects were closely associated with the reduction of macrophage infiltration through CCL3-CCR1 and CCL4-CCR5 inhibition, in addition to Nrf2-mediated hepatoprotective effects.
Background and Purpose: Oligomeric Aβ1-42 (oAβ42) exhibits agonist-like action at human α7- and α7β2-nicotinic receptors (collectively, α7*-nAChR). Aβ1-42 and an N-terminal Aβ peptide fragment (N-Aβ fragment: Aβ1-15/16) have been shown to modulate presynaptic Ca2+ and enhance hippocampus-based synaptic plasticity via α7* nAChR. Both the N-Aβ fragment and its essential core sequence, the N-Aβcore hexapeptide (Aβ10-15), protect against Aβ-associated synapto- and neurotoxicity, also involving nAChR. Here, we investigated how oAβ42, the N-Aβ fragment and N-Aβcore regulate the functional activity of α7*-nAChRs. Experimental approach: Single-channel patch clamp recordings measured the impact of ACh, oAβ42, the N-Aβ fragment, and the N-Aβcore on the function of concatenated, human α7- and α7β2-containing nAChR expressed in nAChR-null SH-EP1 cells. Molecular dynamics simulations identified potential sites of interaction between the N-Aβ fragment and the orthosteric α7*-nAChR binding interfaces. Key Results: Relative to the effects of ACh alone, oAβ42 preferentially enhanced α7β2-nAChR open probability and open-dwell times. Co-application with the N-Aβcore neutralized these effects. Further, we demonstrate that the N-Aβ fragment alone, or in combination with ACh or oAβ42, resulted in selective enhancement of α7-nAChR single-channel open probability and open-dwell times (compared to ACh or oAβ42). Conclusions and Implications: Our findings show the functional diversity of Aβ peptides in regulating α7*-nAChR function, with implications for a wide range of nAChR-mediated functions in AD. Single-channel recordings of the differential effects of oAβ42, N-Aβ fragment and/or N-Aβcore on α7*-nAChR isoform function revealed the complexities of their interactions with α7*-nAChR, with new insights into the neuroprotective actions of these N-Aβ-derived peptides.
Abstract Background and Purpose Pneumoconiosis, especially silicosis has emerged as a prominent occupational disease with remarkable global implications with no definitive cure available. While pirfenidone and nintedanib have been approved in treating idiopathic pulmonary fibrosis, their potential efficacy as anti-fibrotic agents in advanced silicosis warrants further investigation. Thus, we aimed to assess the individual and combined effects of pirfenidone and nintedanib in treating advanced silicosis mice and further elucidate the underlying mechanisms involved in their therapeutic actions. Experimental Approach We administrated monotherapy or combination therapy of pirfenidone and nintedanib with low and high doses in silicosis mouse models established after 6 weeks and then evaluated lung function, inflammatory responses, and fibrotic status. Moreover, we employed transcriptomic and metabolomic analyses to unravel the mechanisms underlying different therapeutic strategies. Key Results Both pirfenidone and nintedanib were demonstrated to be effective for advanced silicosis, with superior outcomes when used in combination. Transcriptomic and metabolomic analyses revealed that pirfenidone and nintedanib primarily exerted their therapeutic effects through modulation of immune responses, signaling cascades, circadian rhythm, and metabolic processes of substances including lipid, amino acids, nucleotides, and carbohydrates. Conclusion and Implications In conclusion, pirfenidone and nintedanib, either administered individually or in combination, exhibit remarkable potential in advanced silicosis mouse models. Further, combined therapy outperformed monotherapy even at a half dose. These therapeutic benefits are attributed to their influence on diverse signaling pathways and metabolic processes. Keywords: silicosis, pulmonary fibrosis, pirfenidone, nintedanib, multi-omics.
Title: Orphan peptide and G protein-coupled receptor signalling in alcohol use disorderRoberta Goncalves Anversa1,2*, Xavier J Maddern1,2*, Andrew J Lawrence1,2and Leigh C Walker1,2*Contributed equally1Florey Institute of Neuroscience and Mental Health, VIC 3052 Australia2Florey Department of Neuroscience and Mental Health, University of Melbourne, VIC 3052 Australia
Abstract Background and Purpose Aging is usually accompanied by mitochondrial dysfunction, reduced energy levels, and cell death in the brain and other tissues. Mitochondria play a crucial role in maintaining cellular energy through oxidative phosphorylation (OXPHOS). However, OXPHOS is impaired as mitochondrial oxygen supply decreases with age. We explored whether pharmacologically increased oxygen diffusion by crocetin can restore OXPHOS and help delay aging of brain and other vital organs. Experimental Approach Stress-free chronic treatment of aged C57BL/6J mice with crocetin followed by an analysis of behavior, hippocampi whole transcriptome, and key energy metabolites by LCMS was performed. Key Results The aged mice treated with crocetin for four months displayed significantly improved memory behavior, neuromuscular coordination, and ATP and NAD+ levels in the brain and other vital organs, leading to an increased median life span. The transcriptomic analysis of hippocampi from crocetin-treated mice revealed that enhanced brain energy level was caused by the upregulation of genes linked to OXPHOS, and their expression was close to the expression in young mice. The chronic treatment of aged astrocytes also showed improved mitochondrial membrane potential and energy state of the cells. Conclusion and Implications Our data suggest that restoring the OXPHOS and the normal energy state of the cell can delay aging and enhance longevity. Therefore, molecules like crocetin should further be explored to treat age-related diseases.
Background and Purpose: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics, and further determine whether early ERFE measurements can predict hemoglobin (HGB) responses to rHuEPO. Experimental Approach: By expressing recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone (DFP). Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term HGB responses. Key Results: The rRatERFE protein was successfully expressed and purified. The production of ERFE was deconvoluted and showed two independent peaks (2 h and 8 h). Transient iron decrease was observed at 4h after rHuEPO injection and DFP induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and HGB peak values than that for observed values. Conclusions and Implications: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict HGB responses several weeks after ESA treatment.
Background and Purpose: The classical theory of receptor action has been used for decades as a powerful tool to estimate molecular determinants of ligand-induced receptor activation (i.e. affinity and efficacy) from experimentally observable biological responses. However, it is also a well-recognized fact that the receptor-binding and activation mechanisms, and the parameters thereof, described in the classical theory contradict with the modern view of receptor activation based on allosteric principles. Experimental Approach: We used mathematical analysis, along with some numerical simulations, to answer the key question as to what extent the classical theory is compatible -if at all- with the modern understanding of receptor activation. Key Results: Here, we showed conclusively that 1) receptor activation equations based on allosteric principles contain the logic of the classical theory in disguise, and therefore, 2) estimates of “intrinsic efficacy” () obtained by means of classical techniques (i.e. null methods or fitting the operational model to concentration-response data) are equivalent to the allosteric coupling factors that represent the molecular efficacy of ligands. Conclusion and Implications: Thus, we conclude that despite the right criticisms it has received so far, the classical theory may continue to be useful in estimating ligand efficacy from experimental data, if used properly. Here, we also provide rigorous criteria for the proper use of the theory. These findings not only have implications on ligand classification, but also resolve some long lasting discussions in the field of bias agonism in GPCR, which requires reasonable estimates of relative ligand efficacies at different signalling pathways.
Background and Purpose: Abnormal activation of the NLRP3 inflammasome in macrophages is closely associated with Ulcerative colitis (UC), and targeting the NLRP3 inflammasome has been proposed as a potential therapeutic approach, but the underlying mechanism by which it regulates intestinal inflammation remains unclear. Anemoside B4 (AB4) has anti-inflammatory activity, but whether it alleviates UC by inhibiting the activation of NLRP3 inflammasome remains unclear. More importantly, the molecular targets of AB4 remain unknown. Experimental Approach: We explored the role of AB4 in the development of dextran sodium sulfate (DSS)-induced colitis in wild-type (WT) mice and its effect on NLRP3 inflammasome. We isolated intestinal macrophages and epithelial cells, and validated them in DSS-induced NLRP3-deficient (NLRP3-/-) mice. The target and molecular mechanism of AB4 were identified in LPS-induced macrophages in vitro and DSS-induced macrophage-specific CD1d depletion (CD1d-/-) mice in vivo. Key Results: This study showed that AB4 had a strong anti-inflammatory effect DSS-induced colitis in WT mice, whereas the protective effects were lost in NLRP3-/- mice. AB4 inhibited the activation of NLRP3 inflammasome in colonic macrophages without affecting intestinal epithelial cells. Mechanistically, AB4 might target CD1d thus reducing the AKT-STAT1-PRDX1-NF-κB signaling pathway, eventually inhibiting the activation of NLRP3 inflammasome. Macrophage-specific CD1d depletion had been shown to reverse the protective effect of AB4. Conclusions and Implications: Our data showed that AB4 attenuated DSS-induced colitis by inhibiting CD1d-dependent NLRP3 inflammasome activation in macrophages. Therefore, as a natural product with high safety index, AB4 might be considered a promising candidate drug for the treatment of colitis.
AKB48 is a synthetic cannabinoid illegally sold for its psychoactive cannabis-like effects that has been associated to several acute intoxications and which effects are poorly known. Using a behavioural, neurochemical and immunohistochemical approach we investigated the pharmaco-toxicological effects, plasma pharmacokinetic and neuroplasticity at cannabinoid CB1 receptor (CB1R) in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. The effects of AKB48 varied significantly depending on sex and length of treatment. The 1st injection impaired sensorimotor responses and reduced body temperature, analgesia, and breath rate at a greater extent in females than in males, the 2nd injection induced stronger effects in males while the 3rd injection of AKB48 induced weaker responses in both sexes, suggesting the emergence of tolerance. The CB1R antagonist NESS-0327 prevented the effects induced by repeated AKB48, confirming a CB1R-mediated action of the drug. Blood AKB48 levels were higher in females than in males and repeated administration caused a progressive rise of AKB48 content in blood samples of both sexes, suggesting an inhibitory effect on cytochrome activity. Finally, immunohistochemical analysis revealed higher expression of CB1Rs in the cerebellum and cortex of females, and a rapid CB1R downregulation in cerebellar and cortical areas following repeated AKB48 injections, with neuroadaptation occurring generally more rapidly in females than in males. We showed for the first time that AKB48 effects significantly vary with prolonged use and that sex affects the pharmacodynamic/pharmacokinetic responses to its repeated administration, suggesting a sex-tailored approach in managing AKB48-induced intoxication.
Background and Purpose Voltage sensitivity is a common feature of many membrane proteins, including some G-protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood. Experimental approach In this study, we investigated the voltage sensitivity of the post-synaptic metabotropic glutamate receptor mGlu5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non-excitable HEK293T cells or neurons. Key Results We found that mGlu5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu5 receptor activation, Gq-PLC/PKC stimulation, Ca2+ release, and mGlu5 receptor-gated currents through TRPC6 channels or NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu5. Conclusions & Implications Our findings suggest that mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions.
GPR84 was first identified as an open reading frame encoding an orphan Class A G protein coupled receptor in 2001. Gpr84 mRNA is expressed in a limited number of cell types with the highest levels of expression being in innate immune cells, M1 polarised macrophages and neutrophils. The first reported ligands for this receptor were medium chain fatty acids with chain lengths between 9 and 12 carbons. Subsequently a series of synthetic agonists that signal via the GPR84 receptor were identified. Radioligand binding assays and molecular modelling with site-directed mutagenesis suggest the presence of three ligand binding sites on the receptor, but the physiological agonist(s) of the receptor remain unidentified. Here, we review the effects of GPR84 agonists on innate immune cells following a series of chemical discoveries since 2001. The development of highly biased agonists has helped to probe receptor function in vitro, and the challenge remaining is to follow the effects of biased signalling to the physiological functions of innate immune cell types.
Background and Purpose: Transient hypofunction of NMDARs represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant path synapses, have barely been explored in this pathological condition. Experimental Approach: We identified a series of synaptic alterations of the lateral and medial perforant paths, in animals neonatally treated with the NMDAR antagonist MK-801. The dysregulation here reported suggests decreased cognitive performance, for which the dentate gyrus is critical. Key Results: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of LTP and cannabinoid 1 receptor (CB1R)-mediated LTD. Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol, the endogenous ligand of the CB1R, we restored the LTD in animals treated with MK-801. Additionally, we show for the first time that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDARs. Conclusion and Implications: Descriptive and mechanistic evidence showing the dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus is presented. These findings may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.
Background and Purpose: Although the amphiphilic nature of the widely used antithrombotic drug Ticagrelor is well known, it was never considered as a membranotropic agent, which is able to interact with lipid bilayer in a receptor-independent way. In this work we investigate the influence of Ticagrelor on plasma membrane lipid order in platelets and whether this could modulate affinity of P2Y12 receptor to Ticagrelor. Experimental Approach: Here, we combined fluorescent in situ, in vitro and in silico approaches to probe the interactions between the plasma membrane of platelets and Ticagrelor. The influence of Ticagrelor on the lipid order of the platelets’ plasma membrane and large unilamellar vesicles was studied using advanced fluorescent probe NR12S. Further, the properties of the model lipid bilayers in presence of Ticagrelor were characterized by molecular dynamics simulations. Finally, the influence of an increased lipid order on the dose response of platelets to Ticagrelor was studied. Key Results: Ticagrelor incorporates spontaneously into lipid bilayers and affects the lipid order of the membranes of model vesicles and isolated platelets in non-trivial composition and concentration-dependent manner. We showed that higher plasma membrane lipid order in platelets leads to the lower IC50 for Ticagrelor. It is shown that membrane incorporation of Ticagrelor increases the affinity of the drug to its own therapeutic target, the P2Y12 receptor, by means of increasing the order of the platelet’s plasma membrane. Conclusion and Implications: A novel dual mechanism of Ticagrelor action is suggested that combines direct binding to P2Y12 receptor with simultaneous modulation of receptor’s lipid microenvironment.
Background and Purpose: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of Interferon Genes (STING) protein and its downstream type-I Interferon (IFN) signaling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating detrimental neuroinflammatory response after TBI, exacerbating outcome. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. Experimental Approach: This study investigated the neuroprotective effects of the small-molecule STING inhibitor C-176 in the controlled-cortical impact (CCI) mouse model of TBI in 10–12-week-old male mice. 30-minutes post-CCI surgery, a single 750nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2h- and 24h-post TBI. Key Results: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines TNF-α, IL-1β and CXCL10 compared to their vehicle-treated counterparts 2h post-TBI. Conclusion and Implications: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma induced inflammation and neuroprotective potential.