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

Abstract

The neurotrophic factor pleiotrophin (PTN) is upregulated in different brain areas after the administration of different drugs of abuse, including psychostimulants. PTN has been shown to prevent cocaine-induced cytotoxicity in NG108-15 and PC12 cells. We previously demonstrated that specific phosphoproteins related to neurodegeneration processes are differentially regulated in the mouse striatum by a single cocaine (15 mg/kg) administration depending on the endogenous expression of PTN. Since neurodegenerative processes are usually observed in patients exposed to toxicants for longer duration, we have now performed a striatal proteomic study using samples enriched in phosphorylated proteins from PTN knockout (PTN-/-) mice, from mice with transgenic PTN overexpression (PTN-Tg) in the brain, and from wild type (WT) mice after a chronic treatment with cocaine (15 mg/kg/day for 7 days). We have successfully identified 23 proteins significantly affected by chronic cocaine exposure, genotype, or both. Most of these proteins, including peroxiredoxin-6 (PRDX6), triosephosphate isomerase (TPI1), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), and annexins A5 (ANXA5) and A7 (ANXA7), may be of significant importance because they were previously identified in proteomic studies in animals treated with psychostimulants and/or because they are related to neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. The data support a protective role of PTN against chronic cocaine-induced neural alterations.

Metabolomics and biochemical alterations caused by pleiotrophin in the 6-hydroxydopamine mouse model of Parkinson’s disease

“…Genetic inactivation of Ptn exacerbates amphetamine-induced dopaminergic injury in the nigrostriatal pathway 6 , including the unexpected loss of 20% of dopaminergic neurons in the SN that is not observed in amphetamine-treated Wild type (Wt) mice. Interestingly, amphetamine- and cocaine-induced alterations in the striatal phosphoproteome of Ptn −/− mice were similar to those found in PD 7 – 9 , suggesting that PTN may protect against neuronal injury in different brain disorders. PTN is one of the factors upregulated after treatment with levodopa in the denervated striatum of parkinsonian rats 10 , 11 , suggesting a role for this cytokine in the neurotrophic mechanisms and plasticity triggered by treatment with levodopa.…”

“…Ptn -Tg mice on a C57BL/6J background were generated by pronuclear injection as previously described 23 , 24 . PTN specific overexpression in different brain areas, including a ~ 20% upregulation in the striatum, was established previously 9 .…”

Pleiotrophin regulates microglia-mediated neuroinflammation

“…To investigate the effects of a more modest PTN overexpression (~20%, PTN-Tg mouse striatum) [28] on LPS-induced neuroinflammation, we tested the astrocytic and microglial response in striatal sections of WT and PTN-Tg mice treated with saline (Sal-Sal) or LPS (Sal-LPS). We did not find genotypic- or treatment-related significant differences in the number of GFAP+ cells between groups (Fig.…”

“…The acceptor vector contained the regulatory regions responsible for tissue-specific expression of Thy-1 gene, which drives neuron-specific expression of transgenes [25, 26]. PTN-specific overexpression in different brain areas, including an ~3–4-fold upregulation in the prefrontal cortex (PFC) and a 20% increase of PTN protein levels in striatum, was established by quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridization, and by western blot [23, 27, 28]. …”

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

“…The acceptor vector used was pTSC-a2 and contained the regulatory regions responsible for tissue specific expression of Thy-1 gene, which drives neuron-specific expression of transgenes (Aigner et al, 1995;Caroni, 1997). PTN specific overexpression in different brain areas, including a 20% increase of PTN protein levels in striatum, was established by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), in situ hybridization, and by Western blot (Ferrer-Alcón et al, 2012;Vicente-Rodriguez et al, 2015;2014b).…”