From: Urocortin, a CRF-like peptide, restores key indicators of damage in the substantia nigra in a neuroinflammatory model of Parkinson's disease...

We are unclear as to the precise mechanism by which UCN I exerts its protective effect. Our unpublished data indicates that UCN I treatment leads to a preservation or restoration of TH+cells in the SNc.

Whether this is the result of cytoprotection, such as might occur due to an anti-inflammatory action, or a stimulation of neurogenesis remains to be determined. One possibility could be that UCN I might reduce the massive astrogliosis which arises in the SNc as a result of LPS toxicity [17]. Additionally, the potential contribution of the SNc relative to the ventral tegmental area in restoring nigrostriatal function is also unclear, although we intend to investigate this.

In summary, our data constitutes the first report of a restoration of key indicators of nigrostriatal damage in a neuroinflammatory model of PD after the lesion has become established by a molecule known to have antiinflammatory properties [7].

Although activation of the HPA axis by a CRF agonist might have potentially deleterious side effects, evidence suggests that these may be averted.

Thus, CRF and UCN both reduced weight gain in rodents but CRF was much more effective than UCN in this respect and only CRF produced effects consistent with increased sympathetic activity[18]. In order to achieve substantial therapeutic relevance a means by which central CRF1 sites can be activated is clearly essential as may be refinement to ensure an appropriate pharmacological response.

While UCN is a relatively large molecule with poor blood brain barrier penetration, recently small, lippophillic, CRF1 selective antagonists have become available and CRF receptor pharmacology is a rapidly expanding field.

As such we consider it highly likely that CRF1 agonists will become available offering new possibilities in the study of UCN mediated neuroprotection as well as being of potential therapeutic value in PD.

http://www.jneuroinflammation.com/content/4/1/19

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Discussion
Abstract Introduction Materials and methods Results Discussion Acknowledgements References

In the present study we have used a variety of measures, behavioural, neurochemical and histological, that indicate a clear protective role for UCN against 6-OHDA- or LPS-mediated nigrostriatal lesions. These findings support a potential protective role for UCN in these two paradigms of PD and clearly demonstrate that, when UCN is given concomitantly with either 6-OHDA or LPS, a comprehensive reversal of all selected markers of nigrostriatal cellular loss results. Importantly, the effects of UCN were not restricted to when it was coadministered with 6-OHDA or LPS but were also manifest when given 7 days after toxin injection when neurotoxic damage is already becoming well established (present data; He et al., 2000). This suggests that UCN is able to rescue dopaminergic neurones once damage is established. Taken as a whole, our data reveal that UCN can act as a potent neuroprotective agent in two distinct rodent models of PD and at a dose that was found to be effective in a variety of other studies (Brar et al., 2000, 2002; Facci et al., 2003; Choi et al., 2006). Moreover, we have assessed multiple parameters of NS pathway activity and nigral neuronal integrity. This approach has important strengths over 'single-parameter' studies, given that human PD pathology is complex and multicomponent (Tatton et al., 1998; Blum et al., 2001; Gandhi & Wood, 2005). Of particular significance is our finding that UCN is able to arrest and possibly reverse NS lesions once the neurodegenerative process has commenced. This principle (if reproduced in the human brain) would have obvious clinical significance as patients generally present with symptoms only once nigral neuronal loss reaches 70–80% of the total nigral complement and striatal DA levels have fallen significantly (Abercrombie et al., 1990). Apart from an apparent facility for preservation of cells, it is possible that UCN may act to stimulate dopaminergic neurones via several distinct mechanisms. Recent studies have shown that UCN potentiates the release of [3H]DA from electrically stimulated rat striatal slices (Bagosi et al., 2006) and increases the TH mRNA levels expressed by PC12 cells (Nanmoku et al., 2005), a cell type phenotypically related to midbrain dopaminergic neurones. We investigated the possible effects of UCN on TH in intact unlesioned rats by injecting the peptide alone into the SNc. Rats studied 1, 7 and 14 days later showed no significant effect on tissue DA, TH activity or protein levels (data not shown). In the present study, UCN appears to 'reverse' the loss of TH-positive cell bodies, as sections taken from rats killed 7 days post-6-OHDA or post-LPS clearly show fewer TH-positive cells than those treated with UCN at the 7-day time point (Figs 3d and 4dcf.3f and 4f).

The underlying cellular mechanism responsible for this highly significant finding is, as yet, unclear although it is possible that UCN increases expression of TH protein in PC12 cells (Nanmoku et al., 2005). No such effect was observed in the present study in vivo. It is possible that UCN effects a regrowth and remodeling of surviving dendrites as observed by Swinny et al. (2004) using cerebellar Purkinje cells in vitro. Interestingly, Scarabelli et al. (2002) also reported an apparent restorative action of UCN, albeit observed in cardiac myocytes. In addition, it is probable that UCN achieves a neuroprotective effect partly via prevention of apoptotic cell death (Scarabelli et al., 2002; Intekhad-Alam et al., 2004). Our own studies have shown that the peptide significantly reduces the number of end-stage apoptotic nuclei observed in nigral sections following intracerebral 6-OHDA injection (Biggs et al., 2006), a significant finding as apoptosis is an important mechanism in 6-OHDA neurotoxicity (Cutillas et al., 1999) and human PD (Tatton et al., 1998; Mochizuki et al., 1996). Our use of the single-dose LPS PD model (Herrera et al., 2000) increases the significance of our data, given that recent evidence supports a neuroinflammatory component in the aetiology of human PD (Gao et al., 2003b; Block et al., 2007; Whitton, 2007) and that UCN itself possesses anti-inflammatory properties (Gonzalez-Rey et al., 2006). It is possible that UCN is instigating de-novo neurogenesis, presumably from recruited stem cells, as has been postulated in other studies (Borta & Hoglinger, 2007). The determination of this is, however, beyond the scope of the present study. Although it is yet to be proven, we would be inclined to the idea that the peptide is able to rescue DA neurones that would otherwise have been damaged beyond repair as well as possibly stabilizing the nigral environment due to its anti-inflammatory properties. The precise neuroanatomical site at which UCN acts is, as yet, unclear although a local action at the level of nigral cell bodies and dendrites seems likely, given the presence of CRF1 immunoreactivity here (Sauvage & Steckler, 2001) and widespread distribution of UCN in the brain (Yamamoto, 1998; Vasconcelos et al., 2003). Studies utilizing cerebellar granule cells and hippocampal neurones (Pederson et al., 2002) also suggest that the engagement of CRF1 is necessary for neuroprotection. It has recently been shown that UCN II, which has a high selectivity for the CRF2 receptor subtype, is able to block voltage-gated calcium channels in PC12 cells (Tao et al., 2006). These authors have proposed that this could be the basis for neuroprotection. Whether this applies to UCN and could be shown in vivo remains to be seen.

Overall, our results add significantly to a growing knowledge base, whereby UCN mediates cytoprotection in cardiac tissues (Brar et al., 2000, 2002; Scarabelli et al., 2002) and cultured neurones (Pederson et al., 2002; Facci et al., 2003; Choi et al., 2006), with the crucial refinement that we have demonstrated efficacy in two distinct in-vivo models of a currently incurable neuropathology. The apparent ability of UCN to arrest NS damage and possibly stimulate the remaining cells suggests a novel mechanism that, if translated therapeutically, would offer a significant advance in PD treatment. This principle has recently been proposed as an essential prerequisite for the basis of a meaningful advance in PD therapy (Meissner et al., 2004). The rapidly expanding interest in UCN itself and central CRF receptor pharmacology heralds the development of novel small molecule agonists with selectivity for CRF1 and CRF2 subtypes, some of which will probably be suitable for evaluation in pre-clinical and clinical settings. We believe that our studies are an important first step towards validating UCN and central CRF receptors as potential future targets in the treatment of human PD.