Pleiotrophin (PTN) is a cytokine found highly upregulated in the brain in different disorders characterized by overt neuroinflammation such as neurodegenerative diseases, drug addiction, traumatic injury, and ischemia. In the present work, we have explored whether PTN modulates neuroinflammation and if Toll-like receptor 4 (TLR4), crucial in the initiation of an immune response, is involved. In immunohistochemistry assays, we studied lipopolysaccharide (LPS, 7.5 mg/kg i.p.)-induced changes in glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adaptor molecule 1 (Iba1, microglia marker) expression in the prefrontal cortex (PFC) and striatum of mice with transgenic PTN overexpression in the brain (PTN-Tg) and in wild-type (WT) mice. Cytokine protein levels were assessed in the PFC by X-MAP technology. The influence of TLR4 signaling in LPS effects in both genotypes was assessed by pretreatment with the TLR4 antagonist (TAK-242, 3.0 mg/kg i.p.). Murine BV2 microglial cells were treated with PTN (0.5 μg/ml) and LPS (1.0 μg/ml) and assessed for the release of nitric oxide (NO). We found that LPS-induced microglial activation is significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. The levels of TNF-α, IL-6, and MCP-1 in response to LPS were significantly increased in the PFC of PTN-Tg mice compared to that of WT mice. Pretreatment with TAK-242 efficiently blocked increases in cytokine contents in a similar manner in both genotypes. Concomitant incubation of BV2 cells with LPS and PTN significantly potentiated the production of NO compared to cells only treated with LPS. Our findings identify for the first time that PTN is a novel and potent regulator of neuroinflammation. Pleiotrophin potentiates LPS-stimulated microglia activation. Our results suggest that regulation of the PTN signaling pathways may constitute new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN cerebral levels and neuroinflammation.

The functional role of midkine during development, following injury and in disease has been studied in a variety of tissues. In this review, we summarize what is known about midkine in the vertebrate retina, focusing largely on recent studies utilizing the zebrafish (Danio rerio) as an animal model. Zebrafish are a valuable animal model for studying the retina, due to its very rapid development and amazing ability for functional neuronal regeneration following neuronal cell death. The zebrafish genome harbours two midkine paralogues, midkine‐a (mdka) and midkine‐b (mdkb), which, during development, are expressed in nested patterns among different cell types. mdka is expressed in the retinal progenitors and mdkb is expressed in newly post‐mitotic cells. Interestingly, studies of loss‐ and gain‐of‐function in zebrafish larvae indicate that midkine‐a regulates cell cycle kinetics. Moreover, both mdka and mdkb are expressed in different cell types in the normal adult zebrafish retina, but after light‐induced death of photoreceptors, both are up‐regulated and expressed in proliferating Müller glia and photoreceptor progenitors, suggesting an important and (perhaps) coincident role for these cytokines during stem cell‐based neuronal regeneration. Based on its known role in other tissues and the expression and function of the midkine paralogues in the zebrafish retina, we propose that midkine has an important functional role both during development and regeneration in the retina. Further studies are needed to understand this role and the mechanisms that underlie it.Linked Articles: This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐4

Parkinson's disease (PD) is generally a sporadic disease, and only a small proportion of cases have a clear genetic component. During the last few years, a possible specific cause triggering death of dopaminergic neurons in the substantia nigra, drug of abuseinduced neurotoxicity, is being considered as a potential mechanism to develop PD, especially in the case of abuse of amphetamine and its derivatives. Recent evidences have shown pleiotrophin, a growth factor with important functions in remodeling and repair of injured neural tissue, as an important factor involved in the pathogenesis of both diseases by preventing neurodegeneration in Parkinson's disease, neurotoxicity induced by drug abuse and by its ability to modulate drugs addictive effects. This review discusses targeting growth factors such as glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) to treat Parkinson’s disease and/or drug addiction and compiles recent evidences to propose the pleiotrophin/receptor protein tyrosine phosphatase β/ signaling pathway as a new therapeutic target to treat Parkinson's disease and to prevent drug of abuse-induced neurotoxicity and addictive effects.