Trehalose–Carnosine Prevents the Effects of Spinal Cord Injury Through Regulating Acute Inflammation and Zinc(II) Ion Homeostasis

Abstract

Spinal cord injury (SCI) leads to long-term and permanent motor dysfunctions, and nervous system abnormalities. Injury to the spinal cord triggers a signaling cascade that results in activation of the inflammatory cascade, apoptosis, and Zn(II) ion homeostasis. Trehalose (Tre), a nonreducing disaccharide, and l-carnosine (Car), (β-alanyl-l-histidine), one of the endogenous histidine dipeptides have been recognized to suppress early inflammatory effects, oxidative stress and to possess neuroprotective effects. We report on the effects of the conjugation of Tre with Car (Tre–car) in reducing inflammation in in vitro and in vivo models. The in vitro study was performed using rat pheochromocytoma cells (PC12 cell line). After 24 h, Tre–car, Car, Tre, and Tre + Car mixture treatments, cells were collected and used to investigate Zn2+ homeostasis. The in vivo model of SCI was induced by extradural compression of the spinal cord at the T6–T8 levels. After treatments with Tre, Car and Tre–Car conjugate 1 and 6 h after SCI, spinal cord tissue was collected for analysis. In vitro results demonstrated the ionophore effect and chelating features of l-carnosine and its conjugate. In vivo, the Tre–car conjugate treatment counteracted the activation of the early inflammatory cascade, oxidative stress and apoptosis after SCI. The Tre–car conjugate stimulated neurotrophic factors release, and influenced Zn2+ homeostasis. We demonstrated that Tre–car, Tre and Car treatments improved tissue recovery after SCI. Tre–car decreased proinflammatory, oxidative stress mediators release, upregulated neurotrophic factors and restored Zn2+ homeostasis, suggesting that Tre–car may represent a promising therapeutic agent for counteracting the consequences of SCI.

Inhibition of LRRK2 Attenuates Depression-Related Symptoms in Mice with Moderate Traumatic Brain Injury

“…To check alterations in Zn homeostasis after mTBI, we evaluated the expression of the two most relevant zinc transporters, ZnT1 and ZnT3, which belong to the SLC30A family of Zn 2+ efflux transporters [ 24 ], by ELISA assay. ZnT1 ( Figure 2 F) and ZnT3 ( Figure 2 G) levels were noticeably lower in mTBI mice compared to the control group ( p < 0.001), while the expression levels of zinc transporters both were found to be enhanced after PF-475 treatments at a dose of 2.5 mg/kg ( p 0.002), and in particular, at the higher dose of 5 mg/kg ( p < 0.001).…”