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Abstract：The peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist rosiglitazone inhibits NF-κB expression and endogenous neural stem cell differentiation into neurons and reduces the inflammatory cascade after spinal cord injury (SCI). The aim of this study was to explore the mechanisms underlying rosiglitazone-mediated neuroprotective effects and regulation of the balance between the inflammatory cascade and generation of endogenous spinal cord neurons by using a spinal cord-derived neural stem cell culture system as well as SD rat SCI model. Activation of PPAR-γ could promote neural stem cell proliferation and inhibit PKA expression and neuronal formation in vitro. In the SD rat SCI model, the rosiglitazone + forskolin group showed better locomotor recovery compared to the rosiglitazone and forskolin groups. MAP2 expression was higher in the rosiglitazone + forskolin group than in the rosiglitazone group, NF-κB expression was lower in the rosiglitazone + forskolin group than in the forskolin group, and NeuN expression was higher in the rosiglitazone + forskolin group than in the forskolin group. PPAR-γ activation likely inhibits NF-κB, thereby reducing the inflammatory cascade, and PKA activation likely promotes neuronal cell regeneration.
1. Introduction
Acute spinal cord injuries (SCI) are severe and often permanent and can prove expensive for patients and the community. SCI is the highest cause of death in young people (15–29 years of age) [1]. There are currently no treatments which have a proven positive effect on neurological outcome [2, 3], following acute SCI. Spinal cord injury results in primary initial damage and subsequent secondary damage [4]. The secondary damage due to early inflammatory responses after spinal cord injury is the main cause for neurological defects and exacerbates the initial degree of injury [5] and the secondary damage usually caused by ischemia, cellular and tissue edema, and oxidative damage [6]. In our previous research, we found that activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) could promote locomotor recovery after spinal cord injury [7]. PPAR-γ is a PPAR nuclear receptor subtype. There are two types of PPAR-γ ligands: natural ligands such as fatty acids and eicosanoid derivatives [8] and synthetic ligands such as thiazolidinediones ketones (thiazolidinedione, TZD), of which rosiglitazone (rosiglitazone) and pioglitazone (pioglitazone) are used in clinical medicine as a treatment for type 2 diabetes [9]. Rosiglitazone is part of the thiazolidinediones nuclear hormone receptor superfamily and is known for its anti-inflammatory actions via the activation of PPAR-γ. Rosiglitazone attenuates the expression of proinflammatory genes and cytokine production by regulating ligand activation of transcription factors [10, 11]. And rosiglitazone has neuroprotective effects in neurodegenerative diseases and spinal cord injury [12, 13]. We previously reported that application of the PPAR-γ agonist rosiglitazone could significantly inhibit activation of the key inflammatory cascade target nuclear transcription factor kappa B (nuclear factor kappa B; NF-κB) after spinal cord injury [7]. NF-κB is extracted from B lymphocytes and is named because of its binding to the immunoglobulin chain gene enhancer sequence-specific κB [14]. The NF-κB family of transcription factors has an essential role in inflammation and innate immunity. The active form of NF-κB is a dimer, typically a P50 / P65 heterodimer, and is the main component of the NF-κB family involved in gene transcription [15]. Members of the NF-κB family participate in many physiological processes, including regulation of the immune response, stimulation of immune cell maturation, and the production and survival of essential transcription factors for B cells [15]. In our preliminary research, we found that PPAR-γ could inhibit NF-κB activation and promote proliferation and inhibit neural differentiation of endogenous neural stem cells [7]. The NF-κB and PPAR-γ signaling pathways are closely related; PPAR-γ activation along with inhibition of the NF-κB-cytokine cascade could protect against dextran sulfate sodium-induced colitis in mice [16]. PPAR-γ could also attenuate inflammation via NF-κB inhibition in lipopolysaccharide-induced peritonitis [17]. In addition to functions in glucose and lipid metabolism and cell proliferation and differentiation, PPAR-γ can also alleviate the acute and chronic inflammatory response after nerve injury and ameliorate neuronal apoptosis and ischemic brain injury by suppressing NF-κB-driven p22phox transcription [18]. 
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