Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway

Abstract

Objective: FK866 is an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), which exhibits neuroprotective effects in ischemic brain injury. However, in traumatic brain injury (TBI), the role and mechanism of FK866 remain unclear. The present research was aimed to investigate whether FK866 could attenuate TBI and clarified the underlying mechanisms. Methods: A controlled cortical impact model was established, and FK866 at a dose of 5 mg/kg was administered intraperitoneally at 1 h and 6 h, then twice per day post-TBI until sacrifice. Brain water content, Evans blue dye extravasation, modified neurological severity scores (mNSS), Morris water maze test, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blot were performed. Results: The results demonstrated that FK866 significantly mitigated the brain edema, blood-brain barrier (BBB) disruption, and ameliorated the neurological function post-TBI. Moreover, FK866 decreased the number of Iba-1-positive cells, GFAP-positive astrocytes, and AQP4-positive cells. FK866 reduced the protein levels of proinflammatory cytokines and inhibited NF-jB from translocation to the nucleus. FK866 upregulated the expression of Bcl-2, diminished the expression of Bax and caspase 3, and the number of apoptotic cells. Moreover, p38 MAPK and ERK activation were significantly inhibited by FK866. Interpretation: FK866 attenuated TBI-induced neuroinflammation and apoptosis, at least in part, through p38/ERK MAPKs signaling pathway. 742

Silencing of circ‐NT5C2 retards the progression of IL‐1β–induced osteoarthritis in an in vitro cell model by targeting the miR‐142‐5p/NAMPT axis

“…47 The NAMPT inhibitor FK866 can also diminish cell apoptosis by upregulating Bcl-2 and reducing Bax expression in traumatic brain injury. 48 Consistent with these findings, our data suggested that NAMPT siRNA (si-NAMPT) could repress cell apoptosis in IL-1β-treated CHON-001 cells by reducing the ratio of Bax to Bcl-2 (Supporting Information: Figures S2D,E). More importantly, we proved, for the first time, that circ-NT5C2 involved the post-transcriptional regulation of NAMPT by functioning as a ceRNA for miR-142-5p.…”

“…Moreover, the NAMPT inhibitor FK866 can increase anti‐apoptotic Bcl‐2 expression and reduce proapoptotic Bax level, thereby reducing permanent damage in spinal cord injury 47 . The NAMPT inhibitor FK866 can also diminish cell apoptosis by upregulating Bcl‐2 and reducing Bax expression in traumatic brain injury 48 . Consistent with these findings, our data suggested that NAMPT siRNA (si‐NAMPT) could repress cell apoptosis in IL‐1β–treated CHON‐001 cells by reducing the ratio of Bax to Bcl‐2 (Supporting Information: Figures ,).…”

Cerebrospinal Fluid MicroRNA Changes in Cognitively Normal Veterans With a History of Deployment-Associated Mild Traumatic Brain Injury

“…For the miRNAs differentially expressed in DepTBI vs. ComC ( Table 2A ) there were 11 overlapping canonical pathways ( Figure 5A ), 4 of which are relevant to TBI: ephrin receptor, axonal guidance, BMP, and RhoA signaling ( Frugier et al, 2012 ; Patel et al, 2017 ; Bi et al, 2019 ; Divolis et al, 2019 ; Zhao et al, 2019 ; Greer et al, 2020 ; Mulherkar and Tolias, 2020 ; Duman et al, 2021 ). Likewise, for the miRNAs differentially expressed in DepTBI vs. DepC ( Table 2C ) there were 20 overlapping canonical pathways ( Figure 5C ), 8 of which are relevant to TBI: ERK/MAPK, TGF-β, senescence, reelin signaling in neurons, Wnt/β-catenin, eIF4 and p70S6K, PAK, and cyclins and cell cycle regulation ( Di Giovanni et al, 2005 ; Chen et al, 2007 ; Zhao et al, 2011 ; Salehi et al, 2018 ; Divolis et al, 2019 ; Sen, 2019 ; Dal Pozzo et al, 2020 ; Hascup and Hascup, 2020 ; Sharma et al, 2020 ; Tan et al, 2020 ; Schwab et al, 2021 ). Interestingly, many of these pathways are inter-related.…”

Hydrogen gas post‑conditioning alleviates cognitive dysfunction and anxiety‑like behavior in a rat model of subarachnoid hemorrhage

“…Activation of the p38 MAPK signal pathway can trigger apoptosis via a variety of downstream pathways, such as p53 phosphorylation ( 52 ), activation of caspase cascades and inhibition of anti-apoptotic proteins, such as Bcl-2( 53 ). The phosphorylation of p38 MAPK was reported to accelerate caspase-3 cleavage and increase the Bax/Bcl-2 ratio in a model of traumatic brain injury ( 54 ). The present study demonstrated that H 2 could reverse the increase in p-p38 MAPK expression by vmPFC neurons.…”