Selective A 2A receptors blockade reduces degeneration of substantia nigra dopamine neurons in a rotenone-induced rat model of Parkinson’s disease: A histological study

Background. Mildronate (3-[2,2,2-trimethylhydrazinium] propionate dihydrate) traditionally is a well-known cardioprotective drug. However, our recent studies convincingly demonstrated its neuroprotective properties. The aim of the present study was to evaluate the influence of mildronate on the expression of proteins that are involved in the differentiation and survival of the nigrostriatal dopaminergic neurons in the rat model of Parkinson’s disease (PD). The following biomarkers were used: heat shock protein 70 (Hsp70, a molecular chaperone), glial cell line-derived nerve growth factor (GDNF, a growth factor promoting neuronal differentiation, regeneration, and survival), and neural cell adhesion molecule (NCAM). Material and Methods. PD was modeled by 6-hydroxydopamine (6-OHDA) unilateral intrastriatal injection in rats. Mildronate was administered at doses of 10, 20, and 50 mg/kg for 2 weeks intraperitoneally before 6-OHDA injection. Rat brains were dissected on day 28 after discontinuation of mildronate injections. The expression of biomarkers was assessed immunohistochemically and by Western blot assay. Results. 6-OHDA decreased the expression of Hsp70 and GDNF in the lesioned striatum and substantia nigra, whereas in mildronate-pretreated (20 and 50 mg/kg) rats, the expression of Hsp70 and GDNF was close to the control group values. NCAM expression also was decreased by 6-OHDA in the striatum and it was totally protected by mildronate at a dose of 50 mg/kg. In contrast, in the substantia nigra, 6-OHDA increased the expression of NCAM, while mildronate pretreatment (20 and 50 mg/kg) reversed the 6-OHDA-induced overexpression of NCAM close to the control values. Conclusion. The obtained data showed that mildronate was capable to regulate the expression of proteins that play a role in the homeostasis of neuro-glial processes.

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Decreased tyrosine hydroxylase messenger RNA in the surviving dopamine neurons of the substantia nigra in parkinson's disease: An in situ hybridization study

Neuroscience ◽

10.1016/0306-4522(90)90389-l ◽

1990 ◽

Vol 38 (1) ◽

pp. 245-253 ◽

Cited By ~ 114

Author(s):

F. Javoy-Agid ◽

E.C. Hirsch ◽

S. Dumas ◽

C. Duyckaerts ◽

J. Mallet ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

In Situ Hybridization ◽

Tyrosine Hydroxylase ◽

Substantia Nigra ◽

Messenger Rna ◽

Dopamine Neurons ◽

Hybridization Study

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A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

10.1101/2020.12.16.423140 ◽

2020 ◽

Author(s):

Sejal Patel ◽

Derek Howard ◽

Leon French

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Human Brain ◽

Disease Risk ◽

Brain Regions ◽

Dopamine Neurons ◽

Postmortem Human Brain ◽

Increased Risk

BACKGROUND: Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. OBJECTIVE: To assess pH associations at the RIT2-SYT4 locus. METHODS: Linear models to examine two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. RESULTS: Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain. Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. CONCLUSIONS: These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

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