Urocortin reverses nigral da cell loss in 6-hydroxydopamine and lipopolysaccharide treated rats

Amjad Abuirmeileh1, Christopher S. Biggs2, Rebecca Lever1 and Peter S Whitton1 (1Department of Pharmacology, School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK. 2University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK).

Parkinson’s Disease (PD) is a neurodegenerative disorder with no cure and treatments of limited efficacy. The aetiology of PD is complex involving apoptosis and neuroinflammation (Hirsh et al., 2006). We have recently observed that the CRF-like peptide urocortin (UCN), which is antiapoptotic (Biggs et al. 2006) and anti-inflammatory (Gonzalez-Rey et al. 2005), reverses key features of nigrostriatal (NS) neurodegeneration in the 6-hydroxydopamine (6-OHDA) hemiparkinsonian rat (Biggs et al., 2006). However, this study did not determine whether UCN prevented actual DA cell loss. In the present study we have investigated the effect of UCN on DA neuronal loss in the nigra of 6-OHDA or lipopolysachharide (LPS) treated rats.

Male Wistar rats (250-280g; n = 4-6 per group) were anaesthetised with isofluorane and 2µg of LPS or 3μg of 6-OHDA were injected into the left nigra (treated side) and 7 days later 2 pmol UCN in 2µl phosphate buffered saline (buffer; ascorbic acid, 10uM was injected into the same region. After 14 days rats were given 0.5 mg kg-1 apomorphine to evaluate contralateral circling behaviour prior to decapitation. Brains were rapidly removed, frozen, and slices cut. Tyrosine hydroxylase (TH) positive NS cells were visualized using the method of Brumovsky et al. (2006). Data were subjected to one-way ANOVA.

Table 1. TH positive cells in rat substantia nigra.

In rats given LPS or 6-OHDA alone, apomorphine-induced circling behaviour (turns/120 s) was greatly attenuated by UCN (11.2 ± 1.98 vs 3.77 ± 1.6 for LPS and LPS + UCN and 25.4 ± 4.4 vs 5.7 ± 2.7 for 6-OHDA and 6-OHDA + UCN respectively, p<0.05). As shown in Table 1, both 6-OHDA and LPS caused substantial loss of TH positive cells in the treated side with no effect on the contralateral untreated side. In each case this cell loss was significantly attenuated by post-toxin UCN administration.

*P<0.05 versus untreated or UCN treated side (Dunnett’s post hoc test)

These data provide clear evidence for a protective role for UCN in two PD models. By combining both anti-apoptotic and anti-inflammatory properties it may be that UCN acts to yield an ‘anti-Parkinsonian’ effect, which may in the future constitute a significant development in the therapy of PD.

Biggs, C.S. et al. (2006) http//www.pA2online.org Vol.13: Issue 4 abst 162P.
Brumovsky, P. et al.(2006)Exp. Neurol. 200,153–165.
Gonzalez-Rey, E. et al. (2006) Gut, 55, 824-832.
Hirsh, S. et al. (2005) Parkinsonism and related disorders. 11, S9-S15.