Extensive exploration of a novel rat model of Parkinson's disease using partial 6‐hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches

Abstract

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6‐hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH‐positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies.

The Story of the Dopamine Transporter PET Tracer LBT-999: From Conception to Clinical Use

“…For this purpose, we performed in a first step in rats, an extensive test-retest study that demonstrated the ability of [ 18 F]LBT-999 to quantify the DAT with high reproducibility (variability of 8–14%) and reliability (intra-class correlation coefficient, ICC, of 0.9) in the striatum, whereas these parameters were less accurate in the substantia nigra, in relation with the small size of this brain structure (33). In a rat model of early PD induced by a moderate unilateral striatal lesion using 6-hydroxydopamine (6-OHDA), we showed that [ 18 F]LBT-999 was able to accurately quantify in vivo the dopaminergic endings loss (Figure 2), in full agreement with the results obtained by in vitro autoradiography with [ 125 I]PE2I on brain sections (34).…”

The Role of Lipids in Parkinson’s Disease

“…Moreover, the neuroprotective properties of acetylcarnitine have been found in rats treated with 6-OHDA [175,176,177] and rotenone [178,179], and non-human primates treated with MPTP [180]. Additionally, increased levels of carnitine and acylcarnitine 16:0 and 18:0 have been detected in the striatum of 6-OHDA-treated rats and the mesencephalon of MPTP-treated mice, respectively [181,182], suggesting a compensatory mechanism against PD-associated toxicity. Thus, while it remains unclear whether the levels of acylcarnitine change in PD patients, mounting evidence points towards decreased plasma levels and a protective role of acylcarnitine in animal and cellular PD models.…”

Development of a novel radioligand for imaging 18-kD translocator protein (TSPO) in a rat model of Parkinson’s disease

“…Vetel et al also found the specific retention of [ 3 H]DPA-714 in the ipsilateral striatum was significantly higher than that in the contralateral striatum on day 14 p.l. [21]. Besides, previous clinical PET imaging using [ 11 C]PK11195 revealed a high uptake in the brain of PD patients due to the activated microglia [11, 12].…”