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Keywords:

  • denervation;
  • DNA microarray;
  • protein tyrosine phosphatase-z;
  • rat striatum;
  • syndecan-3

Abstract

To understand what kind of trophic factors are up-regulated in dopamine (DA)-depleted striatum, we first analysed the up-regulation of mRNAs using a DNA microarray in DA-depleted striatum where DAergic inputs were denervated by 6-OHDA. We then investigated whether or not such trophic factors had an effect on cultured dopaminergic neurons. The microarray analysis revealed that pleiotrophin (PTN), glial-derived neurotopic factor (GDNF) and others were up-regulated in DA-depleted striatum. As PTN has been reported to have a wide range of trophic effects on neurons, we focused on the functional role of PTN in the present study. The increase in PTN mRNA was confirmed by Northern blotting at 1–3 weeks after the lesion, reaching a peak at 1 week. In embryonic day 15 mesencephalic neuron culture, PTN increased the number of tyrosine hydroxylase (TH) -positive neurons in a dose-dependent manner (125.2 ± 2.0% of the control at 50 ng/mL), while a family protein, midkine (10 ng/mL) did not show any trophic effect (99.3 ± 0.7%). In addition, the PTN effect on DAergic neurons was additive to the GDNF effect. As PTN did not increase the number of microtubule-associated protein-2 (MAP 2)-positive neurons or promote the proliferation of dopaminergic progenitors in a bromodeoxyuridine (BrdU) labelling study, the effect appeared to enhance the specific survival of dopaminergic neurons. Expression of PTN receptors (syndecan-3, PTP-ζ) was detected on the cultured mesencephalic neurons, and also up-regulated in DA-depleted striatum. The data indicate that PTN is up-regulated in DA-depleted striatum and exhibits a trophic effect specifically on the survival of cultured dopaminergic neurons.