1. Investigación

Pleiotrophin (PTN) is a recently discovered cytokine which has been found highly upregulated in the substantia nigra and striatum of rodents in experimental models of Parkinson´s disease. Interestingly, immunohistochemical studies have shown increased levels of PTN expression in the substantia nigra of patients with Parkinson´s disease. Since, in other contexts, PTN has been shown to be critical in repair processes in the injured nervous system, the antecedents suggest that PTN could exhibit protective effects in Parkinson´s disease. This hypothesis was confirmed when PTN was shown to support survival of dopaminergic neurons and to promote the differentiation of neural stem cells to dopaminergic neurons. These findings suggest a new therapeutic approach in the treatment of Parkinson´s disease based on the molecular mechanism of action of PTN. Pleiotrophin receptor, receptor protein tyrosine phosphatase (RPTP) β/ζ, is found active in monomeric form in neurons and glia within the central nervous system. Pleiotrophin induces dimerization of RPTPβ/ζ inactivating its phosphatase activity, thus increasing the phosphorylation levels of its substrates such as β-catenin, Fyn and βadducin. These substrates have been shown to be critical for the proliferation of dopaminergic progenitors and the survival and differentiation of dopaminergic neurons. This review summarizes the strong scientific basis to consider blocking RPTPβ/ζ as a potentially novel therapeutic strategy in the treatment of Parkinson´s disease and discusses various starting points to design antagonists of this receptor.

Pleiotrophin (PTN) is a growth factor that exhibits neurotrophic actions and is upregulated at sites of nerve injury. Upregulation of PTN levels in injured dorsal root ganglion (DRG) correlates with decreased mechanical allodynia and faster recovery from Chronic Constriction Injury (CCI) of the rat sciatic nerve. Despite the evidence pointing to a role of PTN in the development of chronic pain, the role of this neurotrophic factor in pain transmission has not been assessed in acute pain models. We have now studied the behaviour of PTN genetically deficient (PTN-/-) and wild type (WT+/+) mice in the hot-plate and tail-immersion tests. We found that basal central pain responses do not differ between PTN-/- and WT+/+ mice in the hot-plate test. Very interestingly, basal latencies to a tail flick were significantly increased in PTN-/- mice as assessed in the tail-immersion test. It was also aimed to evaluate morphine-induced analgesia in PTN-/- and WT+/+ mice. We did not find differences among genotypes using a high dose of morphine (10 mg/kg) in the hot-plate test, reaching this dose the analgesia peak 25 minutes after injection (i.p.) and returning to almost basal values 125 minutes after injection. In contrast, we found that an intermediate dose of morphine (5 mg/kg) significantly delayed pain responses in PTN-/- mice compared to WT+/+ mice in both the hot-plate and tail-immersion tests. The data strongly suggest that PTN is of critical importance for pain processing at the spinal level and, furthermore, that endogenous PTN modulate morphine-induced analgesic effects in mice.