Fractalkine (FKN, CX3CL1) is a transmembrane chemokine expressed by neurons in the central nervous system (CNS). CX3CL1 signals through its unique receptor, CX3CR1, that is expressed in microglia. Within the CNS, fractalkine acts as a regulator of microglia activation in response to brain injury or inflammation. During the last decade, there has been a growing interest in the roles that the CX3CL1/CX3CR1 signaling pathway plays in the neuropathology of a diverse array of brain disorders. However, the reported results have proven controversial, indicating that a disruption of the CX3CL1 axis induces a disease-specific microglial response that may have either beneficial or detrimental effects. Therefore, it has become clear that the understanding of neuron-to-glia signals mediated by CX3CL1/CX3CR1 at different stages of diseases could provide new insight into potential therapeutic targets. Hence, the aim of this review is to provide a summary of the literature on the emerging role of CX3CL1 in animal models of some brain disorders.
Neonatal hypoxia-ischemia (HI) is one of the major causes of death and/or lifelong neurobehavioral and cognitive dysfunction. Undoubtedly, brain damage following HI insult is a complex process with multiple contributing mechanisms and pathways resulting in both early and delayed injury. It is increasingly recognized that one of the leading pathogenic factors of neonatal brain damage is inflammation, induced by activation of the central and peripheral immune system. Immune responses are induced within minutes and can expand for weeks and even months after the insult. Both activated intrinsic (glia) and infiltrating cells (mast cells, monocytes/macrophages) produce soluble inflammatory molecules such as cytokines, chemokines, reactive oxygen, and nitrogen species, which are thought to be pivotal mediators of persistent neuronal injury. This manuscript provides a brief summary of the current knowledge concerning the specific contribution of different cell types and soluble factors to injury of the developing brain caused by neonatal HI. Finally, we discuss the potential forthcoming treatments aimed at targeting inflammation and then attenuation of damaging effects caused by neonatal HI.
BackgroundHistone deacetylase inhibitor (HDACi), sodium butyrate (SB), has been shown to be neuroprotective in adult brain injury models. Potential explanation for the inhibitor action involves among others reduced inflammation. We therefore anticipated that SB will provide a suitable option for brain injury in immature animals. The aim of our study was to test the hypothesis that one of the mechanisms of protection afforded by SB after neonatal hypoxia-ischemia is associated with anti-inflammatory action. We examined the effect of SB on the production of inflammatory factors including analysis of the microglial and astrocytic cell response. We also examined the effect of SB on molecular mediators that are crucial for inducing cerebral damage after ischemia (transcription factors, HSP70, as well as pro- and anti-apoptotic proteins).MethodsSeven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 60 min of hypoxia (7.6% O2). SB (300 mg/kg) was administered in a 5-day regime with the first injection given immediately after hypoxic exposure. The damage of the ipsilateral hemisphere was evaluated by hematoxylin-eosin staining (HE) 6 days after the insult. Samples were collected at 24 and 48 h and 6 days. Effects of SB on hypoxia-ischemia (HI)-induced inflammation (cytokines and chemokine) were assessed by Luminex assay and immunohistochemistry. Expression of molecular mediators (NFκB, p53, HSP70, COX-2, pro- and anti-apoptotic factors Bax, Bcl-2, caspase-3) were assayed by Western blot analysis.ResultsSB treatment-reduced brain damage, as assessed by HE staining, suppressed the production of inflammatory markers—IL-1β, chemokine CXCL10, and blocked ischemia-elicited upregulation of COX-2 in the damaged ipsilateral hemisphere. Furthermore, administration of SB promoted the conversion of microglia phenotype from inflammatory M1 to anti-inflammatory M2. None of the investigated molecular mediators that are known to be affected by HDACis in adults were modified after SB administration.ConclusionsAdministration of SB is neuroprotective in neonatal hypoxia-ischemia injury. This neuroprotective activity prevented the delayed rise in chemokine CXCL10, IL-1β, and COX-2 in the ipsilateral hemisphere. SB appears to exert a beneficial effect via suppression of HI-induced cerebral inflammation.
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