SUMMARY The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor, pleiotrophin (PTN), in regulating HSC function in the niche. PTN−/− mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking the protein tyrosine phosphatase receptor-zeta (PTPRZ), which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC-autonomous but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche which regulates HSC self-renewal and retention in vivo.

Midkine (MK) and pleiotrophin (PTN) are two neurotrophic factors that are highly up-regulated in different brain regions after the administration of various drugs of abuse and in degenerative areas of the brain. A deficiency in both MK and PTN has been suggested to be an important genetic factor, which confers vulnerability to the development of the neurodegenerative disorders associated with drugs of abuse in humans. In this review, evidence demonstrating that MK and PTN limit the rewarding effects of drugs of abuse and, potentially, prevent drug relapse is compiled. There is also convincing evidence that MK and PTN have neuroprotective effects against the neurotoxicity and development of neurodegenerative disorders induced by drugs of abuse. Exogenous administration of MK and/or PTN into the CNS by means of non-invasive methods is proposed as a novel therapeutic strategy for addictive and neurodegenerative diseases. Identification of new molecular targets downstream of the MK and PTN signalling pathways or pharmacological modulation of those already known may also provide a more traditional, but probably effective, therapeutic strategy for treating addictive and neurodegenerative disorders. LINKED ARTICLESThis 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 Abbreviations ALDH1A1, aldehyde dehydrogenase family 1 member A1; ALK, anaplastic lymphoma kinase; ANXA7, annexin; BBB, blood brain barrier; CKMT1, creatine kinase U-type; COPS5, COP9 signalosome subunit 5; CPP, conditioned place preference; KA, kainic acid; MK, midkine; NGF, nerve growth factor; PD, Parkinson's disease; PTK, protein tyrosine kinase; PTN, pleiotrophin; PTP, protein tyrosine phosphatase; PTPRZ, protein tyrosine phosphatase type Z IntroductionThe neurotoxic effects of drugs of abuse underlie not only drug-seeking behaviours but also the neurodegeneration processes associated with chronic drug consumption . For example, chronic alcohol consumption is associated with an increase in the incidence of a variety of diseases, including CNS degeneration (Collins and Neafsey, 2012). These addictive and neurotoxic effects of psychostimulants and other drugs of abuse have been associated with enhanced damage of dopaminergic neurons in the nigrostriatal pathway (Ferrucci et al., 2008;Valverde and Rodríguez-Árias, 2013). Drugs of abuse promote the intracellular accumulation of dopamine (Kalivas and O'Brien, 2008), which could elicit neuronal death by blocking mitochondrial complex 1, as occurs, for example, with Parkinsonian agents (Fahn and Sulzer, 2004). In addition, cocaine has been shown to cause significant increases in α-synuclein levels in dopaminergic neurons (Mash et al., 2003). Interestingly, α-synuclein is known to be the main component of Lewy bodies in patients with Parkinson's disease (PD) (Spillantini et al., 1997). Furthermore, it was recently found that BJP British Journal of Pharmacology DOI:10.1111/bph.12312 www.brjpharmacol.org Briti...

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Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 µM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.

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