Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: recent progress and perspectives

Abstract

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...

Chronic Cocaine Use Causes Changes in the Striatal Proteome Depending on the Endogenous Expression of Pleiotrophin

“…54 Activation of PKC by PTN 55 has been suggested to play a role in the neurotrophic actions of PTN against druginduced neurotoxicity. 13 Our data suggest that the counteractive mechanism against chronic cocaine treatment, possibly involving activation of ANXA7 and its tissue remodeling function, 56 is compromised in the presence of normal levels of PTN (WT mice) or in the absence of endogenous PTN (PTN−/− mice) but is readably induced by cocaine in PTNTg mice compared to that in saline-treated mice. Interestingly, amphetamine downregulates ANXA7 levels in the striatum of the most vulnerable genotype to the neurotoxic effects of amphetamine, the PTN−/− mouse.…”

Pleiotrophin overexpression regulates amphetamine-induced reward and striatal dopaminergic denervation without changing the expression of dopamine D1 and D2 receptors: Implications for neuroinflammation

“…Also, it has to be noted that amphetamine-induced increase of GFAP-positive astrocytes, a hallmark of the neuroinflammation induced by this type of psychostimulants, was slightly increased in the striatum of PTN-/-mice (Gramage et al, 2010a). Overall, the data clearly suggest a modulatory role of PTN on amphetamine effects (Herradon and Perez-Garcia, 2014). However, the knockout mouse models, although invaluable as screening tools in research, have intrinsic limitations including ubiquitous absence of the targeted gene and possible developmentally-related mechanisms of compensation.…”

“…As a result, PTN causes increases in the phosphorylation levels of substrates of RPTPβ/ζ known to be important for neuronal function (e.g. Fyn kinase and β-catenin) which, in turn, trigger other signaling pathways involved in different functions including mitogenic, differentiation, survival and inflammation (Herradon and Perez-Garcia, 2014). Thus, it seems reasonable to hypothesize that some substrates of RPTPβ/ζ, or downstream factors in their signaling pathways, could be involved in compensatory developmental mechanisms in PTN-/-mice.…”

Functional Receptors and Intracellular Signal Pathways of Midkine (MK) and Pleiotrophin (PTN)

“…At present, anti-cancer drugs targeting MK and PTN and their receptors or intracellular pathways are being developed [101][102][103][104] ; Targeting MK and PTN signaling pathways for curing drug addiction and neurodegenerative disorders also be discussed by Herradon group. 105) Furthermore, more and more research support that MK and PTN not only have potential therapy for ischemic injury of heart and brain, [23][24][25][26][27][28] Alzheimer's disease, 29) hematopoiesis of bone marrow, 21,22) bone and muscle injury, 31) and even human immunodeficiency virus (HIV) infection 69) but also play an important role in tissue regeneration for adult body. 14) So, in the future, clarification of the specific receptor and intracellular pathways of MK and PTN on different kinds of diseases should be basic for MK and PTN related new drug development.…”