Hematopoietic cytokines as therapeutic players in early stages Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a devastating age related neurodegenerative disease that is believed to have a lengthy prodromal state. It is critical to find methods to harness compensatory recovery processes in order to slow or prevent the eventual progression of clinical symptoms. The current perspective paper argues that immune system signaling molecules represent such a promising therapeutic approach. Two cytokines of interest are granulocyte macrophage-colony stimulating factor (GM-CSF) and erythropoietin (EPO). These hematopoietic cytokines have been protective in models of stroke, neuronal injury, and more recently PD. It is our belief that these trophic cytokines can be used not only for cell protection but also regeneration. However, success is likely dependent on early intervention. This paper will outline our perspective on the development of novel trophic recovery treatments for PD. In particular, we present new data from our lab suggesting that EPO and GM-CSF can foster neural re-innervation in a “mild” or partial lesion PD model that could be envisioned as reflecting the early stages of the disease.

Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

“…In this study we used a relatively low dose of 6-OHDA to induce a partial nigrostriatal lesion, which we believe may partially model a prodromal-like PD state. We have recently found that this animal model causes modest striatal lesions, coupled with morphological abnormalities of surviving neurons [ 5 ]. In the present study, we found that PC lipid species were markedly altered in animals treated with 6-OHDA.…”

“…For instance, previous studies have reported that PC lipids modulate anti-inflammatory signaling [ 17 ]. Moreover, it is known that 6-OHDA can induce microglial reactivity [ 5 , 18 , 19 ] and elevations of pro-inflammatory cytokines [ 20 , 21 , 22 ]. Thus, the decrease in PC lipids currently observed may influence cell survival in the context of 6-OHAD treatment by influencing inflammatory processes.…”

“…Further to this point, the intra-striatal 6-OHDA model of PD is also known to induce progressive neuronal degeneration over numerous weeks [ 51 , 52 ] and causes increased neuroinflammatory responses [ 20 , 22 , 53 ]. Additionally, we used a low dose of 6-OHDA which we have recently reported to cause a modest but significant loss of dopamine (DA) striatal terminals, but does not significantly affect the number of neurons within SNc [ 5 ]. Taken together, these findings suggest that the intra-striatal 6-OHDA model of PD can be an important tool for the investigation of the early stages of PD as it mimics the human condition in many key aspects.…”

“…We have recently utilized a low dose of the specific neurotoxin 6-hydroxydopamine (6-OHDA) to induce a prodromal-like PD state. Specifically, an infusion of 6-OHDA into the dorsal striatum resulted in a modest partial lesion which encompassed 10% and 15% of the striatal volume at two and four weeks after toxin administration, respectively [ 5 ]. We also found that our model resulted in no difference in the number of neurons within the substantia nigra (SNc); however, as would be expected in the early stages of PD, many of the neurons had morphology typically seen in unhealthy cells, specifically increased vacuolization, decreased dendritic projections, and an overall decreased cell volume [ 5 ].…”

“…Specifically, an infusion of 6-OHDA into the dorsal striatum resulted in a modest partial lesion which encompassed 10% and 15% of the striatal volume at two and four weeks after toxin administration, respectively [ 5 ]. We also found that our model resulted in no difference in the number of neurons within the substantia nigra (SNc); however, as would be expected in the early stages of PD, many of the neurons had morphology typically seen in unhealthy cells, specifically increased vacuolization, decreased dendritic projections, and an overall decreased cell volume [ 5 ]. Additionally, numerous other reports have indicated that pro-death oxidative and mitochondrial stress pathways are likely involved in the early stages of PD, and that pro-inflammatory factors also arise to contribute to primary or secondary pathological processes active in the disease [ 6 , 7 , 8 ].…”