Salidroside Improves Behavioral and Histological Outcomes and Reduces Apoptosis via PI3K/Akt Signaling after Experimental Traumatic Brain Injury

Abstract

BackgroundTraumatic brain injury (TBI) induces a complex sequence of apopototic cascades that contribute to secondary tissue damage. The aim of this study was to investigate the effects of salidroside, a phenolic glycoside with potent anti-apoptotic properties, on behavioral and histological outcomes, brain edema, and apoptosis following experimental TBI and the possible involvement of the phosphoinositide 3-kinase/protein kinase B (PI3K)/Akt signaling pathway.Methodology/Principal FindingsMice subjected to controlled cortical impact injury received intraperitoneal salidroside (20, or 50 mg/kg) or vehicle injection 10 min after injury. Behavioral studies, histology analysis and brain water content assessment were performed. Levels of PI3K/Akt signaling-related molecules, apoptosis-related proteins, cytochrome C (CytoC), and Smac/DIABLO were also analyzed. LY294002, a PI3K inhibitor, was administered to examine the mechanism of protection. The protective effect of salidroside was also investigated in primary cultured neurons subjected to stretch injury. Treatment with 20 mg/kg salidroside_significantly improved functional recovery and reduced brain tissue damage up to post-injury day 28. Salidroside_also significantly reduced neuronal death, apoptosis, and brain edema at day 1. These changes were associated with significant decreases in cleaved caspase-3, CytoC, and Smac/DIABLO at days 1 and 3. Salidroside increased phosphorylation of Akt on Ser473 and the mitochondrial Bcl-2/Bax ratio at day 1, and enhanced phosphorylation of Akt on Thr308 at day 3. This beneficial effect was abolished by pre-injection of LY294002. Moreover, delayed administration of salidroside at 3 or 6 h post-injury reduced neuronal damage at day 1. Salidroside treatment also decreased neuronal vulnerability to stretch-induced injury in vitro.Conclusions/SignificancePost-injury salidroside improved long-term behavioral and histological outcomes and reduced brain edema and apoptosis following TBI, at least partially via the PI3K/Akt signaling pathway.

Phenylethanoid Glycosides: Research Advances in Their Phytochemistry, Pharmacological Activity and Pharmacokinetics

“…117 contained additional glucose linking to C-6 of core saccharide compared with 121, and both of them exhibited good bioactivities [58,59,64,65]. In Caco-2 cell monolayer model, compounds 117, 120 and 121 were primarily transported via poorly absorbed passive diffusion down a concentration gradient without efflux [110], which was consistent with the result that the caffeic acid conjugates permeated poorly through the Caco-2 monolayers [111].…”

“…Compound 121 attenuated Aβ [25][26][27][28][29][30][31][32][33][34][35] -induced neurotoxicity by induction of HO-1 via extracellular regulated kinase (ERK) and PI3K/Akt signaling [63]. Similarly, the neuroprotective effects of salidroside (123) following traumatic brain injury were mediated, at least in part, through activation of the PI3K/Akt signaling pathway [64]. In another study, the neuroprotective effect of 121 on Aβ 25-35 -induced neurotoxicity in SH-SY5Y cells was investigated.…”

miR-711 upregulation induces neuronal cell death after traumatic brain injury

“…35 In contrast, Akt inhibition can exacerbate TBI neuropathology. 36 Our study shows that Akt is downregulated at both mRNA and protein levels in the injured cortex after TBI. The reduction in Akt phosphorylation is proportional to the reduction in total Akt, suggesting that changes in expression may have a preeminent role; this contrasts with the reported findings in another model, where phosphorylation appeared to be the primary factor.…”

Post-Injury Treatment with 7,8-Dihydroxyflavone, a TrkB Receptor Agonist, Protects against Experimental Traumatic Brain Injury via PI3K/Akt Signaling

“…Double immunofluorescence was performed by simultaneous incubation of primary antibodies (anti-phospho-TrkB, or anti-phospho-CREB) with anti-neuronal nuclei antigen (NeuN, neuronal marker), anti-glial fibrillary acidic protein (GFAP, astrocyte marker), or anti-F4/80 (microglia marker) [20]. Antibody information is listed in Table 1.…”