Astrocyte-targeted expression of interleukin-6 protects the central nervous system during neuroglial degeneration induced by 6-aminonicotinamide
ABSTRACT 6-aminonicotinamide (6-AN) is a niacin antagonist, which leads to degeneration of gray matter astrocytes mainly in the brainstem. We have examined the role of interleukin-6 (IL-6) in this degenerative process by using transgenic mice with astrocyte-targeted IL-6 expression (GFAP-IL6 mice). This study demonstrates that transgenic IL-6 expression significantly increases the 6-AN-induced inflammatory response of reactive astrocytes, microglia/macrophages, and lymphocytes in the brainstem. Also, IL-6 induced significant increases in proinflammatory cytokines IL-1, IL-12, and tumor necrosis factor-alpha as well as growth factors basic fibroblast growth factor (bFGF), transforming growth factor-beta, neurotrophin-3, angiopoietin, vascular endothelial growth factor, and the receptor for bFGF. In accordance, angiogenesis was increased in GFAP-IL6 mice relative to controls after 6-AN. Moreover, oxidative stress and apoptotic cell death were significantly reduced by transgenic IL-6 expression. IL-6 is also a major inducer in the CNS of metallothionein I and II (MT-I+II), which were significantly increased in the GFAP-IL6 mice. MT-I+II are antioxidants and neuroregenerative factors in the CNS, so increased MT-I+II levels in GFAP-IL6 mice could contribute to the reduction of oxidative stress and cell death in these mice.
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- "Further clinical evaluation was stopped because the neurotoxicity limited dose escalation. The cause of this side effect is not known, though it is theorized to be due to the death of glial cells by 6-AN (Kim and Wenger, 1973; Penkowa et al., 2003). Importantly, in contrast to what was observed with 6-AN, in our xenograft experiments thionicotinamide did not cause neurotoxicity in mice, suggesting that other inhibitors of NADK and or G6PD may not induce this deleterious side effect. "
ABSTRACT: NAD+ kinase (NADK) is the only known cytosolic enzyme that converts NAD+ to NADP+, which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein and fatty acid synthesis found in proliferating cells, as well as for neutralizing high levels of reactive oxygen species (ROS). The aim of this study was to determine whether inhibition of NADK activity is a valid anti-cancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either shRNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced ROS produced by several chemotherapeutic drugs and produced synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination and should be explored further. The American Society for Pharmacology and Experimental Therapeutics.Molecular pharmacology 07/2015; 88(4). DOI:10.1124/mol.114.096727 · 4.13 Impact Factor
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- "IL-6 has been shown to increase in experimental models of both mild (Shohami et al., 1994; Holmin et al., 1997) and moderate/severe (Woodroofe et al., 1991; Taupin et al., 1993) TBI in rodents and has been detected at high levels for weeks following severe human brain injuries (Kossmann et al., 1995). In mice lacking IL-6, experimental cortical freeze injuries or cytotoxic brain injuries result in increased oxidative stress, decreased cell survival, and lengthened recovery times compared to WT mice, suggesting that in the absence of IL-6, the brain's intrinsic repair mechanisms are deficient (Penkowa et al., 2000, 2003). These data compliment a series of both human brain injury cases and in vitro studies, whereby IL-6 secretion leads to elevated production of NGF in astrocytes and suppresses the production of both TNF-α and IL-1β (Kushima et al., 1992; Kossmann et al., 1996; Ley et al., 2011). "
ABSTRACT: Mild traumatic brain injuries (mTBI) have been associated with long-term cognitive deficits relating to trauma-induced neurodegeneration. These long-term deficits include impaired memory and attention, changes in executive function, emotional instability, and sensorimotor deficits. Furthermore, individuals with concussions show a high co-morbidity with a host of psychiatric illnesses (e.g., depression, anxiety, addiction) and dementia. The neurological damage seen in mTBI patients is the result of the impact forces and mechanical injury, followed by a delayed neuroimmune response that can last hours, days, and even months after the injury. As part of the neuroimmune response, a cascade of pro- and anti-inflammatory cytokines are released and can be detected at the site of injury as well as subcortical, and often contralateral, regions. It has been suggested that the delayed neuroinflammatory response to concussions is more damaging then the initial impact itself. However, evidence exists for favorable consequences of cytokine production following traumatic brain injuries as well. In some cases, treatments that reduce the inflammatory response will also hinder the brain's intrinsic repair mechanisms. At present, there is no evidence-based pharmacological treatment for concussions in humans. The ability to treat concussions with drug therapy requires an in-depth understanding of the pathophysiological and neuroinflammatory changes that accompany concussive injuries. The use of neurotrophic factors [e.g., nerve growth factor (NGF)] and anti-inflammatory agents as an adjunct for the management of post-concussion symptomology will be explored in this review.Frontiers in Cellular Neuroscience 12/2012; 6:58. DOI:10.3389/fncel.2012.00058 · 4.29 Impact Factor
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- "Activation of STAT3 through only gp130 by Interleukin-6 (IL-6) signaling is known to trigger reactive astrogliosis (Sofroniew, 2009). The role of IL-6 is ambivalent, depending on the animal model and the disease that occurs in the experimental paradigms (Campbell et al., 1993; Penkowa et al., 2003; Quintana et al., 2009). "
ABSTRACT: Research of the past 25 years has shown that astrocytes do more than participating and building up the blood brain barrier and detoxify the active synapse by reuptake of neurotransmitters and ions. Indeed, astrocytes express neurotransmitter receptors and, as a consequence, respond to stimuli. Deeper knowledge of the differentiation processes during development of the central nervous system (CNS) might help explaining and even help treating neurological diseases like Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS) and psychiatric disorders in which astrocytes have been shown to play a role. Astrocytes and oligodendrocytes develop from a multipotent stem cell that prior to this has produced primarily neuronal precursor cells. This switch towards the more astroglial differentiation is regulated by a change in receptor composition on the cell surface and responsiveness of the respective trophic factors Fibroblast growth factor (FGF) and Epidermal growth factor (EGF). The glial precursor cell is driven into the astroglial direction by signaling molecules like Ciliary neurotrophic factor (CNTF), Bone Morphogenetic Proteins (BMPs), and EGF. However, the early astrocytes influence their environment not only by releasing and responding to diverse soluble factors but also express a wide range of extracellular matrix (ECM) molecules, in particular proteoglycans of the lectican family and tenascins. Lately these ECM molecules have been shown to participate in glial development. In this regard, especially the matrix protein Tenascin C (Tnc) proved to be an important regulator of astrocyte precursor cell proliferation and migration during spinal cord development. On the other hand, ECM molecules expressed by reactive astrocytes are also known to act mostly in an inhibitory fashion under pathophysiological conditions. In this regard, we further summarize recent data concerning the role of chondroitin sulfate proteoglycans and Tnc under pathological conditions.Frontiers in Pharmacology 06/2012; 3:120. DOI:10.3389/fphar.2012.00120 · 3.80 Impact Factor